Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
N-Cbz-L-leucine (Chemical Dyanamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) were combined, dissolved in 25 mL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0.1 N HCl, saturated aqueous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, 66%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 5H), 6.28 (d, 1H), 5.28 (m, 3H), 4.61-4.58 (m, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92 (m, 12H).
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.C>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 250 °C
Yield: 61 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (14 g), copper powder (1.5 g) and copper turnings (1.5 g) are suspended in diphenyl ether (60 cc) and heated at 250° C. for 30 minutes. After cooling, the reaction mixture is diluted with methylene chloride (100 cc), decolourizing charcoal (1 g) is added and the mixture is filtered. The filtrate is extracted three times with a 10% (w/v) aqueous solution of sodium carbonate (total 150 cc), and then washed twice with distilled water (total 100 cc). The combined aqueous phases are acidified to pH 1 by the addition of 12N concentrated hydrochloric acid and extracted four times with methylene chloride (total 200 cc). The combined methylene chloride solutions are washed three times with distilled water (total 90 cc), dried over anhydrous sodium sulphate and evaporated. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.5 g) in the form of an oil is thus obtained.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32](=[O:41])[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH3:30][O:31][C:32](=[O:41])[CH2:33][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:7])[CH2:5][N:4]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1](=[O:3])[CH3:2]
Reactant: COC(=O)CNc1ccccc1
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CN(C(=O)CN(C(C)=O)c1ccccc1)c1ccccc1

Procedure:
To 20 parts by volume of chloroform was added 0.96 part by weight of N-acetylphenylglycine. With ice cooling, 1.03 parts by weight of dicyclohexylcarbodiimide was added, and the mixture was stirred. Furthermore, 0.83 part by weight of phenylglycine methyl ester was added, and about 3 hours later, the temperature was returned to room temperature. The mixture was then stirred overnight. After the reaction, the precipitate was collected by filtration, and washed with chloroform. The filtrate was concentrated to dryness. The resulting solid was washed with ethyl acetate, and extracted with a mixture of chloroform and petroleum ether to give 1.2 parts by weight of the captioned compound having a melting point of 198° to 200° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:33][CH:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[C:44]([O:49][CH3:50])[CH:43]=2)[CH2:38][CH2:37]1)[CH3:35].[I-].[K+].S(=O)(=O)(O)O>C(O)C(F)(F)F.C1COCC1>[F:32][C:27]1[CH:28]=[C:29]([F:31])[CH:30]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:46][C:45]3[CH:47]=[CH:48][C:42]([N:39]4[CH2:40][CH2:41][N:36]([CH:34]([CH3:33])[CH3:35])[CH2:37][CH2:38]4)=[CH:43][C:44]=3[O:49][CH3:50])[N:3]=2)[C:23]=1[C:24]([NH2:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A suspension of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzamide (2.71 g, 5.68 mmol), 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (2.12 g, 8.52 mmol), potassium iodide (catalytic), and sulfuric acid (2.72 ml, 51 mmols) in trifluoroethanol (150 ml) was heated at 90C for 4 hrs. The reaction was diluted with 1:1 THF:ethyl acetate (300 ml) and washed with saturated NaHCO3 (300 ml). The organic layer was removed and concentrated by rotary evaporation. The solids were then added to THF (300 ml) followed by ammonium hydroxide (300 ml) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed to silica gel and purified by LC (DCM to 5% MeOH/DCM) to afford 2,4-difluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.5 g, 38% over two steps). ESIMS (M+H)+=691.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 110 °C
Yield: 29.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.214 g, 0.46 mmol), methanesulfinic acid sodium salt (71 mg, 80%, 0.55 mmol), L-proline (11 mg, 0.09 mmol), Cul (9 mg, 0.05 mmol) and NaOH (4 mg, 0.09 mmol) in DMSO (2.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. The mixture was cooled to ambient temperature and was poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 to give 62.5 mg (29%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.4 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7].C(Br)(Br)(Br)[Br:22]>ClCCl>[Br:22][CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCO)C1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCBr)C1
Reaction time: 3.5 h
Yield: 75.9 %

Procedure:
A solution of (S)-3-[2-(2-hydroxyethoxy)acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (4 g) prepared in Step B and carbon tetrabromide (5.52 g, Wako Pure Chemical Industries) in dichloromethane (52 ml) was added with PS (polystyrene)-triphenylphosphine (7.86 g, Aldrich) at 0° C., and the mixture was stirred at the same temperature for 3.5 hours. The insoluble solids were removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.7 g).
Reaction SMILES: C(OC(=O)CC)(=O)CC.[CH3:10][O:11][C:12]([C@@H:14]1[CH2:27][C@H:26]([OH:28])[C:25](=[O:29])[C@H:24]2[C@@:15]1([CH3:37])[CH2:16][CH2:17][C@H:18]1[C@:23]2([CH3:30])[CH2:22][C@@H:21]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)[O:20][C:19]1=[O:36])=[O:13].[C:38](Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:27][C@H:26]([O:28][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:25](=[O:29])[C@H:24]2[C@@:15]1([CH3:37])[CH2:16][CH2:17][C@@H:18]1[C@:23]2([CH3:30])[CH2:22][C@@H:21]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)[O:20][C:19]1=[O:36])=[O:13]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: CCC(=O)OC(=O)CC
Product: COC(=O)[C@@H]1C[C@H](OC(=O)C(C)C)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 62 %

Procedure:
Using a procedure similar to that described in Example 4 except replacing the propionic anhydride used therein with the requisite anhydride, the title compound 10 (0.04 g, 62%) was prepared as a white solid, mp 209-211° C.; 10 was synthesized as described for 9 from 8a using isobutyryl chloride to afford 0.04 g (62%) of 10 as a white solid, mp 209-211° C.; 1H NMR (CDCl3): δ 1.13 (3H, s, H-19); 1.24 (3H, d, J=6.9 Hz, CH3CH(CH3)CO2); 1.26 (3H, d, J=6.9 Hz CH3CH(CH3)CO2,); 1.46 (3H, s, H-20); 1.52-1.78 (3H, m, H-7α,β and H-11β); 1.80 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.12 (2H, m, H-3α and H-8); 2.20. (1H, s, H-10); 2.25-2.35 (2H, m, H-3β and H-6β); 2.51 (1H, dd, J=5.1, 13.2 Hz, H-11α); 2.68 (1H, sept, J=6.9 Hz, CH3CH(CH3)CO2); 2.77 (1H, dd, J=8.4, 8.4 Hz, H-4); 3.74 (3H, s, CO2CH3); 5.15 (1H, dd, J=9.9, 10.3 Hz, H-2); 5.52 (1H, dd, J=5.3, 11.9 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.5 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.5 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)(=O)=O.[NH:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15]>CN(C=O)C>[CH3:1][O:15][C:14](=[O:16])[C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[NH:8]1
Reactant: CO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
To methanol (30.0 mL), cooled to -10 to -15° C., was slowly added sulfuryl chloride (11.0 mL, 178 mmol), DMF (0.133 mL) and L-pyroglutamic acid (L=(S) configuration, 10.0 g, 77.5 mmol, Sigma Chemical Co.). The stirred mixture was allowed to warm slowly and then stirred at room temperature for 36 hours. The methanol was removed under vacuum, and the residue was dissolved in ethyl acetate (400 mL). Water (~10 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, the slurry was washed with ethyl acetate (4×15 mL), and the organics were then combined and dried over magnesium sulfate. Removal of the solvent gave crude pyroglutamic methyl ester (10.04 g, 91%). NMR and MS analysis indicated >95% purity.
Reaction SMILES: CCN(C(C)C)C(C)C.C([N:12]1[C:17]([S:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([C:25]#[N:26])[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[N:14][CH:13]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.CCO>C1(C)C=CC=CC=1>[NH2:26][C:25]1[C:16]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)=[N:14][C:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:12][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CSC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)=NC(c2ccccc2)N1CC
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Temperature: 0 °C
Reaction time: 48 h

Procedure:
DIPEA (20.0 ml) was added to a stirred solution of ethyl 5-cyano-4(3-nitrophenyl)-2-phenyl-6-(ethoxycarbonylmethylthio)-pyrimidine (example 31(c), 19.7 g) in a mixture of abs. EtOH (100 ml) and toluene p.a. (100 ml). After 48 h at 100° C., the mixture was cooled to 0° C. The resulting precipitate was filtered off, washed with cold EtOH and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:11][CH2:12][CH2:13][C:14]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([CH3:9])=[C:3]([CH3:10])[C:2]=1[CH3:1])=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Cc1ccc(C)c(C)c1C
Product: Cc1cc(C(=O)CCCl)c(C)c(C)c1C

Procedure:
3-Chloro-1-(2,3,4,5-tetramethyl-phenyl)-propan-1-one is prepared from 1,2,3,4-tetramethyl-benzene and 3-chloro propionyl chloride by a procedure analogous to that of Preparation 1.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[C:3](Cl)=[O:4].[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1.CN(C)C1C=CC=CC=1.Cl>C(Cl)Cl.O>[O:1]=[C:2]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[C:3]([O:21][C:14]1[CH:13]=[CH:12][C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=C(Cl)C(=O)N1CCOC1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOC1=O

Procedure:
3.6 g. of α,2-dioxo-3-oxazolidineacetyl chloride, from Example 1(a), dissolved in methylene chloride are added dropwise at 0° to a solution of 2.78 g. of p-nitrophenol and 2.52 g. dimethylaniline in methylene chloride. After thirty minutes, the mixture is shaken with water and dilute hydrochloric acid. The organic phase is dried, concentrated, and the precipitated product is recrystallized from toluene to yield white crystalline α,2-dioxo-3-oxazolidineacetic acid, 4-nitrophenyl ester; m.p. 159°.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[OH:16]/[N:17]=[C:18](\Cl)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:17][O:16][C:3]=1[CH3:4])=[O:5])[CH3:8]
Reactant: CC#CC(=O)OCC
Reactant: O/N=C(\Cl)c1ccccc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 2-butynoate (65.5 mL, 562 mmol) and triethylamine (80.7 mL, 576 mmol) in ethanol (600 mL) was added, at 0-4° C. over 2 h, 500 mL of a solution of (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (83.3 g 480 mmol) in ethanol (900 mL). Ethyl 2-butynoate (44.6 ml, 383 mmol) in ethanol (125 mL) was added at 0° C., then the remaining 400 ml of the (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride solution were added over a 1 h period. The resulting mixture was then stirred for 48 h at room temperature and evaporated. The mixture was then poured onto HCl (1.2 L), and extracted with tert-butyl methyl ether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title product (73.6 g, 62%) which was obtained as a yellow oil, MS: m/e=250.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:33])(=[O:32])[NH2:34])=[O:14])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.5 mmol) of 3-(4-methoxybenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.93 g (17.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 1.5 g (yield: 31.0%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:9][C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: N#Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccnc1C#N
Temperature: 0 °C
Yield: 98.9 %

Procedure:
2-Cyano-3-hydroxypyridine (5.00 g) is dissolved in acetone (50 ml), and thereto are added methyl bromoacetate (7.0 g) and potassium carbonate (6.3 g). The mixture is heated under reflux for 1.5 hours. After allowing to cool, ice-water is poured to the reaction solution and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (7.91 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][C:28]([F:31])([F:30])[F:29]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[O:27][C:28]([F:29])([F:31])[F:30]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(OC(F)(F)F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(OC(F)(F)F)c1
Yield: 67.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 4-fluoro-3-(trifluoromethoxy)-aniline in place of the 2,4-difluoroaniline. 270 mg of N-[4-fluoro-3-(trifluoromethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd]>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1

Procedure:
A solution of 104 g of 2,5-dibromopyrimidine, 100 g of 4-benzoxyphenylboronic acid, 4.75 g of Pd (10% on activated charcoal), 4.5 g of triphenylphosphene and 93 g of sodium carbonate in 1 l of toluene, 0.5 l of ethanol and 0.3 l of water is heated at 80° C. for 24 hours. After filtration, the organic phase is separated off and evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile: 83 g of solids of melting point 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:28])[CH2:26][CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.29 g (5.48 mmol) of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy- 8-amino-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole [compound (+)I], 690 mg (6.8 mmol) of triethylamine and 40 ml of methylene chloride were stirred at room temperature while 610 mg (6.6 mmol) of propionyl chloride was added thereto. The mixture was stirred at room temperature for four hours. The reaction mixture was extracted with 600 ml of ethyl acetate and 300 ml of water. The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate and the residue obtained after distilling off the solvent were crystallized from a solvent mixture comprising 10 g of ethyl acetate and 5 g of hexane, allowed to stand in a refrigerator overnight and then filtered by means of suction. The obtained crystals were washed with 3-ml portions of ethyl acetate/hexane (2 1) twice and dried under reduced pressure to thereby give the titled compound in the form of a colorless product.