Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][O:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:37][C:38]1[C:43](O)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]>O1CCCC1>[F:37][C:38]1[C:43]([O:33][C:32](=[O:34])[CH2:31][NH:30][C:28](=[O:29])[C:27]2[CH:35]=[CH:36][C:24]([O:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]
Reactant: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(OCc2ccccc2)cc1)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 17 h
Yield: 95 %

Procedure:
N-(4-(Phenylmethoxy)benzoyl)glycine pentafluorophenyl ester. N-(4-(Phenyl-methoxy)benzoyl)glycine methyl ester (14.75 g, 49.2 mmol) was boiled under reflux with methanolic sodium hydroxide (1M) (80 mL) for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in water and was acidified by addition of aqueous hydrochloric acid. The suspension was extracted with ethyl acetate. The extract was washed with saturated brine and was dried with anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine (6.59 g, 47%). Dicyclohexylcarbodiimide (720 mg, 3.5 mmol) was added to N-(4-(phenylmethoxy)benzoyl)glycine (100 g, 3.5 mmol) in dry tetrahydrofuran (100 mL) and the mixture was taken to 0° C. Pentafluorophenol (640 g, 3.5 mmol) was added dropwise and the mixture was stirred for 17 h at 0° C. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and was washed with saturated aqueous sodium hydrogen carbonate (2×75 mL), with aqueous sulphuric acid (10%) and with water. The solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give N-(4-(phenylmethoxy)benzoyl)glycine pentafluorophenyl ester (Intermediate B) (1.5 g, 95%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16]>CS(C)=O>[NH2:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16])[CH:3]=1
Reactant: CC(=O)NCCN
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Temperature: 130 °C
Yield: 66 %

Procedure:
6-Chloro-2-phenylpyrimidin-4-amine (2.87 g) was dissolved in DMSO (50 ml) and N-acetylethylenediamine (14.28 g) added. The stirred solution was heated at 130° C. for 8 hrs then partitioned between ethyl acetate (500 ml) and saturated brine solution (400 ml). The organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by flash chromatography on silica gel eluting with first ethyl acetate then a mixture of ethyl acetate and methanol (9:1 then 8:2 v/v) yielded the title compound (2.50 g).
Reaction SMILES: [N:1]1[C:10]2C(=C[CH:7]=[CH:8][CH:9]=2)C=CC=1.[Br-:11].[CH3:12][O:13][N:14]=[C:15]([C:23]1[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=1)[CH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Br-:11].[CH3:12][O:13][N:14]=[C:15]([C:23]1[CH:24]=[CH:25][C:26]([N:1]2[CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:27][CH:28]=1)[CH2:16][N+:17]1[C:18]2[C:19](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CON=C(C[n+]1ccccc1)c1ccc(C)cc1
Reactant: c1ccc2ncccc2c1
Agent: [Br-]
Solvent: CC(C)=O
Product: CON=C(C[n+]1cccc2ccccc21)c1ccc(N2CCCC2)cc1
Yield: 61 %

Procedure:
A solution of quinoline (149 μl, 1.26 mmol) and (8) (486 mg, 1.64 mmol) was refluxed in acetone (4 mL) for 5 days. A dark red solid was separated by filtration in 61% yield: mp 178-180° C.; 1H NMR 400 MHz (DMSO-d6) δ 1.90 (s, 4H), 3.15 (s, 4H), 3.99 (s, 3H), 6.39 (m, 4H), 7.36 (d, 2H, J=7.3 Hz), 8.05 (t, 1H, J=7.0 Hz), 8.18 (m, 1H), 8.30 (m, 2H), 8.46 (d, 1H, J=8.1 Hz), 9.29 (d, 1H, J=8.1 Hz), 9.65 (d, 1H, J=5.1 Hz); FABHRMS: found M+, 346.1920 (calcd for C22H24ON3: M+, 346.1914).
Reaction SMILES: C(OC([N:11]([CH2:28][CH2:29][O:30][C@H:31]1[O:50][C@H:49]([CH2:51][O:52][C@H:53]2[O:61][C@H:60]([CH2:62][OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@@H:54]2[OH:55])[C@@H:47]([OH:48])[C@H:34]([O:35][C@H:36]2[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]2[OH:38])[C@@H:32]1[OH:33])[C@H:12]([C:18]([O:20]CC1C=CC=CC=1)=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].O>[C@H:36]1([O:35][C@H:34]2[C@H:47]([OH:48])[C@@H:49]([CH2:51][O:52][C@H:53]3[O:61][C@H:60]([CH2:62][OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@@H:54]3[OH:55])[O:50][C@H:31]([O:30][CH2:29][CH2:28][NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])[C@H:32]2[OH:33])[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]1[OH:38]
Reactant: NC(=O)CC[C@@H](C(=O)OCc1ccccc1)N(CCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Product: NC(=O)CC[C@H](NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O)C(=O)O
Reaction time: 16 h

Procedure:
A mixture of benzyl N2-[(benzyloxy)carbonyl]-N-{2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}-L-glutaminate (1.41 g, 1.57 mmol) and Pearlman's catalyst (110 mg, 0.157 mmol) in H2O (30 mL) was agitated under 50 Psi H2 on a Parr shaker at room temperature. After 16 hours, catalyst was filtered off and the filtrate was freeze-dried to give the title compound. 1H NMR (D2O) δ 5.07 (s, 1H), 4.87 (s, 1H), 4.81 (s, 1H), 4.08-3.55 (m, 22H), 3.41-3.36 (m, 1H), 2.32 (t, J=7.5, 2H), 2.10-2.06 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 62.8 %

Procedure:
3-Isopropoxyphenol (80 mg, 0.53 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (35 mg, 0.09 mmol) was reacted using K2CO3 (60 mg, 0.43 mmol) as described above to give the title compound (28 mg, 61%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:21][CH:22]=1>>[CH:23]1([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(C2CCCCC2)n1
Product: c1cn(CCCc2ccc(OCc3coc(C4CCCCC4)n3)cc2)cn1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-cyclohexyloxazole to give 2-cyclohexyl-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 38%. Recrystallization from ether-hexane gave colorless prisms, mp 46-47° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COc1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-methoxy-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.79-0.90 (m, 6H), 1.46 (ddd, J=13.33, 6.85, 6.72 Hz, 1H), 1.64 (ddd, J=13.63, 7.09, 6.91 Hz, 1H), 1.87-1.98 (m, 1H), 3.67-3.77 (m, 4H), 6.87-6.95 (m, 2H), 7.43-7.54 (m, 4H), 7.59-7.69 (m, 3H), 7.73 (d, J=8.07 Hz, 2H); Calcd for C26H25F3O3 (M+Na) 465.18, Found 465.
Reaction SMILES: FC(F)(F)C1C=C(C(C)(C)C(N(C2C=NC([I:31])=CC=2C2C=CC=CC=2Cl)C)=O)C=C(C(F)(F)F)C=1.[F:36][C:37]([F:71])([F:70])[C:38]1[CH:39]=[C:40]([C:48]([CH3:69])([CH3:68])[C:49]([N:51]([C:53]2[CH:54]=[N:55][C:56](Cl)=[CH:57][C:58]=2[C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=2[CH3:66])[CH3:52])=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>>[F:36][C:37]([F:71])([F:70])[C:38]1[CH:39]=[C:40]([C:48]([CH3:69])([CH3:68])[C:49]([N:51]([C:53]2[CH:54]=[N:55][C:56]([I:31])=[CH:57][C:58]=2[C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=2[CH3:66])[CH3:52])=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Product: Cc1cc(F)ccc1-c1cc(I)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yl]-N-methyl-isobutyramide (Example 25) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide instead of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was added dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with H2O, 1N aq. HCl and brine, dried (MgSO4), filtered and concentrated under reduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LCMS: Anal. Calcd. for C15H22N2O3 278.16 found 279.23 (M+H)+; HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzoic acid (1.0 g, 5.8 mmol) in methanol (30 mL) was added sulfuric acid (3 mL, 56.3 mmol) and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. The residue was partitioned between a saturated solution of K2CO3 and ethyl acetate (3×30 mL), dried, filtered and concentrated in vacuo to yield methyl 3-chloro-4-hydroxy-benzoate (0.9 g, 83%) as a white solid. ESI-MS m/z calc 186.5. found 187.5 (M+1)+; Retention time: 1.17 minutes (3 min run). 1H NMR (400.0 MHz, CDCl3) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2; H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][C:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=1[CH2:20][C:21](O)=[O:22])=[CH:7]2.[CH3:24][O:25][C:26]([N:28]=C=NC(C)(C)C)=[O:27]>C1COCC1>[CH3:24][O:25][C:26](=[O:27])[NH:28][C:21](=[O:22])[CH2:20][C:14]1[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:13]=1[CH2:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[CH:7]=1
Reactant: O=C(O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Reactant: COC(=O)N=C=NC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)NC(=O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Yield: 74.8 %

Procedure:
A mixture of [2-(5-bromo-naphthalen-2-ylmethyl)-3-oxo-cyclohex-1-enyl]-acetic acid (1.1 g, 2.95 mmol), N-methoxycarbonyl-N'-tert-butylcarbodiimide (0.51 g, 3.25 mmol), and THF (20 mL) was refluxed for 4 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting solvent hexane/EtOAc 2/1 ) to give a white solid (0.95 g, 76% yield, m.p. 128°-129° C.).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=[N+]([O-])c1ccc(C2SCCCS2)c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])ccc1C1SCCCS1
Reaction time: 1 h

Procedure:
To a solution of 3.47 g (12.8 mmol) of the Compound 3c in methylene chloride (100 mL) was added pyridinium chlorochromate (4.15 g, 19.2 mmol). The mixture was stirred for one hour, an additional pyridinium chlorochromate (2.0 g) was added, and the mixture was stirred 15 hours. Diethyl ether (200 mL) was added to the reaction mixture, and the solvent was decanted and evaporated. The residue was purified by chromatography (silica gel, chloroform) to afford the Compound 3d as light yellow crystals; m.p. 99°-101° C.; IR 1730 cm-1 (C=O); 1H NMR δ1.7-2.3 (m,2H, --CH2CH2CH2 --), 2.8-3.3 (m, 4H,--CH2CH2CH2 --), 6.13(s, 1H, --SCHS--), 7.8-8.7 (m,--3H, ArH), 10.45 (s, 1H,CHO).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13].[CH3:15]O>>[CH3:15][O:13][C:12]([C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]1[NH2:5])=[O:14]
Reactant: CO
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (5.48 g, 46.1 mmol) was added dropwise to a solution of cis-2-aminocyclohexanecarboxylic acid (2.0 g, 14.0 mmol) in methanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stir for 18 h. The clear solution was then evaporated to dryness, and the residual volatiles were removed on high vacuum. The crude product, cis-2-aminocyclohexanecarboxylic acid methyl ester, was isolated in quantitative yield and used in the next reaction without purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (s br, 2 H), 3.78 (s, 3 H), 3.59 (s br, 1 H), 3.18 (s br, 1 H), 2.27 (m, 1 H), 2.08 (m, 1 H), 1.88 (m, 2 H), 1.45 (m, 4 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:29])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]C(=O)C)=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:29])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)OC(C)=O)cc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Yield: 76.6 %

Procedure:
To a suspension of 0.95 g of 2-acetamido-4-hydroxy-6-[2-(4-acetoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 50 mL of water was added 1N aqueous sodium hydroxide until a homogenous solution was obtained. Acidification with acetic acid resulted in the formation of a yellow precipitate which was collected by filtration. The filter cake was washed sequentially with water, methanol, acetone and ether. The residual solid was recrystallized from DMF to give 0.65 g (77%) of the title compound, which can be alternatively named as 2-acetamido-6-(4-carboxystyryl)-5-deaza-4(3H)-pteridinone, as a microcrystalline yellow solid, mp >300° C.; NMR (TFA-d1) delta 2.5 (s, 3H), 6.85, 7.32 (AB q, 2H, J=12 Hz), 7.45, 8.18 (AB q, 4H, J=9 Hz), 8.65 (s, 1H), 9.02 (s, 1H); IR (Nujol) 3300-2200 (br), 1685, 1655, 1630, 1600, 1565 cm-1 . MS: Calc'd. for C18H14N4O4 : 350. Found: m/e 350 (base), 308.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]#[N:20].Cl[CH2:22][C:23]([NH2:25])=[O:24].CC[O-].[Na+]>C(O)C>[NH2:20][C:19]1[C:3]2[C:4]([CH3:18])=[N:5][C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=3)=[N:7][C:2]=2[S:1][C:22]=1[C:23]([NH2:25])=[O:24]
Reactant: NC(=O)CCl
Reactant: Cc1nc(-c2ccc(OC(C)C)cc2)nc(S)c1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc(C(N)=O)c(N)c12
Yield: 31.3 %

Procedure:
4.0 g (14 mmol) 6-mercapto-4-methyl-2-(4-iso-propoxy-phenyl)-pyrimidine-5-carbonitrile and 1.6 g (17 mmol) 2-chloroacetamide are suspended in 100 ml ethanol and 1.9 g (28 mmol) sodium ethylate is admixed. The reaction mixture is refluxed for 3 h. It is filtrated, washed with ethanol and water and dried. 1.5 g (31%) 5-amino-4-methyl-2-(4-iso-propoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
Reaction of 3-bromo-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (95% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12 (1H, m, aromatics), 7.48 (1H, m, aromatic), 7.82 (1H, m, aromatic), 7.97 (1H, s, CH).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](O)=[O:35])[CH:27]=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[C:29]=3[C:30]([F:33])([F:31])[F:32])=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Product: Cn1ncc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c1C(F)(F)F

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=509.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(C(=O)O)c1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100° C. for 30 minutes. The heat was removed, the reaction was cooled to room temperature and let stand overnight. The reaction mixture was then slowly poured into ice-water (250 mL) to precipitate a white solid. The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.O.O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-nitropyridine (4.48 g) was added in portions to a mixture of sodium phenoxide trihydrate (4.80 g) in DMF (140 ml) with stirring at ambient temperature under nitrogen. The mixture was then heated at 60° C. for 2 hours and then at 90° C. for 3 hours. The mixture was allowed to cool over 18 hours. The mixture was poured into ice water and extracted with dichloromethane to give a residue which was stirred in petroleum ether, b.p. 60°-80° C. at ambient temperature for 30 minutes and then filtered to give 5-nitro-2-phenoxypyridine, m.p. 84°-86° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 7 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 6.40 g, 18.21 mmol), KF (5.34 g, 91.0 mmol), piperazin-2-one (5.64 g, 54.6 mmol) were suspended in NMP (60 mL). The RM was stirred at 180° C. for 7 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in DCM to afford the title compound as a beige solid (tR 3.02 min (conditions 1), (tR 7.58/10.54 min (conditions 3, MH+=409.1, 1H-NMR in DMSO-d6: 8.94 (d, 1H); 8.45 (d, 1H); 8.05 (s, 1H); 7.83 (d, 1H); 7.63 (m, 1H); 7.62 (s, 1H); 7.59 (m, 1H); 7.05 (d, 1H); 4.99 (m, 1H); 3.97 (d, 1H); 3.69 (d, 1H); 3.51 (m, 2H); 3.19 (m, 1H); 3.12 (m, 1H); 1.88 (d, 3H)).