Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=1[F:62]>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:57][C:56]=1[F:62]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (45 mg, 0.19 mmol), HOBt (20 mg) and EDCI.HCl (80 mg, 0.31 mmol) in DMF (2.5 mL) was added 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (56 mg, 0.18 mmol) at rt, and the reaction mixture was stirred over the weekend at rt. It was directly purified by preparative HPLC to afford the product (35 mg, 30%) as a beige-colored TFA salt solid. 1H NMR (CD3OD) δ 12.21 (s, 1H), 8.60 (dd, 2H, J=9.9, 1.6 Hz), 8.01 (d, 1H, J=12.6 Hz), 7.90 (dd, 1H, J=7.6, 1.6 Hz), 7.74 (s, 1H), 7.45-7.37 (m, 5H), 7.24 (t, 2H, J=8.2 Hz), 6.89 (d, 1H, J=6.6 Hz), 6.65 (t, 1H, J=6.6 Hz), 4.03 (s, 3H), 4.00 (s, 3H); MS(ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:15]N1C(=O)CCC1=O.Cl>CN(C)C=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([Cl:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC(C)=O)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCc1ccc(NC(C)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 103.4 %

Procedure:
A mixture of 67 (7.0 g; 36.6 mmol) and N-chlorosuccinimide (7.8 g; 58.6 mmol) was dissolved in N,N-dimethylformamide (70 mL). The reaction was heated at 70° C. for 6 hours, cooled to room temperature, then poured into aqueous hydrochloric acid (400 mL; 2M), and stirred for 15 minutes. The resulting precipitate was isolated by filtration and dried under vacuum to give the title product as an orange solid (8.54 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([OH:13])=O)[N:4]=1.[CH3:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][C@@H:21]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([N:22]2[CH2:23][CH2:24][CH2:25][C@@H:20]([CH3:19])[C@H:21]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][N:29]=2)=[O:13])[N:4]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: COc1ccnc(-c2ccc(C)cc2C(=O)O)n1
Product: COc1ccnc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-(4-methoxypyrimidin-2-yl)-5-methylbenzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 500 [M+1]+.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:28][CH2:27][CH2:26][S:25]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=3)[S:28][CH2:27][CH2:26][S:25]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCCC2)c1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 12 was prepared from Compound 8 using the same procedure as described above for Compound 9. Yield 3.60 g (79.2%) as an oil. Rf=0.56 (hexane:ethyl acetate 92:8); IR (neat) 2925, 1206, 1067, 832, 693 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.31–3.10 (m, 4H), 2.40–2.32 (m, 1H), 1.96–1.30 (m, 12H). 13C NMR δ 160.38, 148.94, 106.52, 98.48, 81.99, 70.21, 55.60, 51.27, 45.22, 39.34, 32.82, 29.80, 28.04, 27.77; MS: (ESI, Pos.) m/z 361 ([M+23]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10](F)=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7].[C:18](=O)([O-])[O-:19].[K+].[K+].Cl>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([O:19][CH3:18])=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(OC)c(F)c1C(=O)O
Reaction time: 3 h
Yield: 83 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser, a stirrer and a dropping funnel, 20 ml of a methanol solution of 10 g (0.0397 mol) of the 3,4,5,6-tetrafluorophtalic acid-monomethyl ester prepared in Example 14 was charged. Then, 8.21 g (0.060 mol) of potassium carbonate was added thereto. The mixture was stirred for 3 hours under reflux. After completion of the reaction, the reaction mixture was neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 8.7 g of 4-methoxy-3,5,6-trifluorophthalic acid-1-methyl ester. (=5-methoxy-3,4,6-trifluorophthalic acid-2-methyl ester.) The yield was 83.1%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(Cl)=[O:31]>C1COCC1.O>[Cl:1][C:2]1[N:11]2[C:30](=[O:31])[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:20]=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1n(-c2ccccc2)nc2c3c(nc(Cl)n12)CCCC3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline [prepared according to the procedure described by M. Botta et al., 40, Tetrahedron, (1984), 3313] (500 mg, 2.4 mmol), phenylhydrazine (270 mg, 2.5 mmol) and N,N-diisopropylethylamine (1 ml, 5.7 mmol) in THF (50 ml) was heated at reflux temperature overnight. The reaction was cooled to room temperature and phosgene (200 ml, 20% in toluene) was added slowly and stirred for an additional 10 min. The mixture was poured into water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 5-chloro-2-phenyl-7,8,9,10-tetrahydro-1,2,4-triazolo[4,3-c]quinazolin-3-one, m.p. 205°-207° C.
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[CH:14][CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C1(N)C=CC=C(N)C=1>>[N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)O)cc21
Agent: Nc1cccc(N)c1
Product: O=C(O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 11 in U.S. Pat. No. 6,534,524, issued Mar. 18, 2003, herein incorporated by reference in its entirety for all purposes, except using 2-[3-(Pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid instead of N-methyl-N-{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine. 1H NMR (DMSO-d6) δ 13.12 (1H, s), 12.70 (1H, s), 8.94 (1H, s), 8.10 (1H, d, J=8.7 Hz), 7.91 (1H, dd, J=1.7, 7.7 Hz), 7.50 (2H, t, J=2.3 Hz), 7.36 (1H, d, J=7.9 Hz), 7.27 (1H, d, J=1.5 Hz), 7.16 (1H, t, J=7.5 Hz), 6.94 (1H, dd, J=1.7, 8.7 Hz), 6.68 (1H, t, J=7.5 Hz), 6.19(2H, t, J=2.3 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.BrC[C:8]1(C2C=CC(Cl)=CC=2Cl)[O:12][CH:11]([CH2:13][O:14]C2C=CC(Cl)=CC=2)C[O:9]1.[I-].[Na+].CN(C)[CH:34]=[O:35].[OH2:37]>>[C:34]([OH:35])(=[O:37])[C:8]([OH:12])=[O:9].[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:11]([OH:12])(=[O:35])[C:13]([OH:14])=[O:37].[C:34]([OH:35])(=[O:37])[C:8]([OH:12])=[O:9].[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(C)C=O
Reactant: O
Reactant: Clc1ccc(OCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)cc1
Agent: [I-]
Agent: [Na+]
Agent: c1c[nH]cn1
Product: O=C(O)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 6.8 parts of imidazole, 8.5 parts of B -2-(bromomethyl)-4-(p-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, 2 parts of sodium iodide and 100 parts of dimethylformamide is stirred and refluxed for 36 hours. The reaction mixture is allowed to cool to room temperature and poured into water. The product is extracted twice with benzene. The combined organic layers are washed twice with water, dried and the solvent is removed in vacuo. The residue is purified by column-chromatography over silica gel using chloroform as eluent. The pure fractions are collected and the eluent is evaporated. The residue of B-1-[4-(p-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-imidazole is converted into the oxalate salt in 4-methyl-2-pentanone: upon the addition of diisopropylether, the salt is precipitated. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding 3.1 parts of trans-1-[4-p-chlorophenoxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-ylmethyl]-imidazole sesquioxalate; mp. 101°C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O1CCCC1.[OH-].[Na+]>CO>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][C@@H:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:35])=[O:2])=[O:14])[N:16]=1)#[N:34]
Reactant: COC(=O)C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1nc(C(=O)N[C@H](CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
3-(R)-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-3-pyridin-3-yl-propionic acid methyl ester (25 mg, 0.0533 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL.) Sodium hydroxide solution (2 mL, 2M) was added and the reaction was permitted to stir overnight at room temperature. After 18 hours, the pH was adjusted to 4 and reaction lyophilized. The crude product was purified by HPLC to provide the title compound in 80% yield. LC-MS ESI+: 455 (M+1)+; ESI−: 453 (M−1)−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[K].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.O>CN(C)C=O>[O:36]=[C:34]1[C:33]2[C:32](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](=[O:41])[N:35]1[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Nc1nc(-c2ccc(CCCBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (82 mg) in N,N-dimethylformamide (0.82 ml) was added phthalimide potassium salt (30.8 mg), and the mixture was stirred for 2 hrs. at 50° C. The reaction mixture was cooled to 20° C., then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated to give a crude material (92.0 mg). The crude material was purified by preparative thin-layer chromatography over silica gel to give N-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide.
Reaction SMILES: O.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:3]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Product: O=C(O)CCCCc1c[nH]c2ccccc12
Reaction time: 96 h

Procedure:
In a water separator, indole (50 g, 0.43 mol.), δ-valerolactone (tetrahydropyran-2-one, 49.2 g, 0.49 mol.), potassium hydroxide (35.9 g, 0.64 mol.) in p-cymene (1-isopropyl-4-methylbenzene, 250 ml) were heated at boiling for 4 d, with stirring. For working up, water (200 ml) was added to the mixture, the phases were separated, and the aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 d at 4° C. in a refrigerator. The resulting solid was filtered off with suction and washed with water (3×20 ml). Recrystallisation from ether (50 ml) yielded 5-(1H-indol-3-yl)pentanoic acid in the form of a white solid having a melting point of 80–83° C. in a yield of 38.8 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][C:41]([OH:40])([CH3:46])[C:42]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:43]
Reactant: CC(C)(O)C(=O)O
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)C(C)(C)O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrochloride (1 g, 4.34 mmol) in DMF (50 mL) was added HATU (9.89 g, 26.0 mmol), 2-hydroxy-2-methylpropanoic acid (0.677 g, 6.50 mmol), and DIPEA (2.272 mL, 13.01 mmol). After stirring overnight at rt, the solvent was removed, the residue was redissolved in DCM (100 mL), washed with 1M HCl (100 mL), adsorbed to silica gel, and purified by column chromatography (10% to 40% ethyl acetate/hexanes) to afford 2-methyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanol (0.84 g, 69%). ESIMS (M+H)+=281.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[O:17]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-fluoronitrobenzene (0.50 mL) and phenol (443 mg) in 5.0 mL of dimethylformamide was added K2CO3 (1.27 g). The reaction was warmed to 70° C. for 20 h, then cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed with water, sat. aq. NaHCO3 solution, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a yellow solid.
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]([C:23]2[S:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[CH2:28]([C:25]1[S:24][C:23]([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)=[CH:27][CH:26]=1)[CH3:29]
Reactant: CCc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: CCc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 55 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-ethyl-2-thienyl)oxazole to give 2-(5-ethyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 55%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 57-58° C.
Reaction SMILES: [F:1][CH2:2][CH:3]([CH2:22][F:23])[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:8]([OH:10])=O.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:5]([O:4][CH:3]([CH2:2][F:1])[CH2:22][F:23])[CH:6]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2)cc(OC(CF)CF)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(OC(CF)CF)c2)s1

Procedure:
The title compound was prepared from 3-(2-fluoro-1-fluoromethyl-ethoxy)-5-(4-fluoro-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH3:13][NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:13])[N:7]=1
Reactant: CNC1CCCCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(N(C)C2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 25.00 g; 120 mmol) in THF (500 mL) was treated with a solution of n-methylcyclohexylamine (Aldrich, 15.7 ml; 121 mmol) and triethylamine (18.4 ml; 133 mmol) in THF (250 mL). The reaction mixture was stirred for 16 hours at RT. Water (250 mL) was poured into the reaction mixture which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by recrystallisation from MTBE. The title product was obtained as a beige solid (25.7 g, 75%).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:24][CH2:25][C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:24][CH2:25][C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: COC(=O)C#CCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C#CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
0.41 ml of boron trifluoride etherate was added to a suspension of 4.70 g (25 mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 14.3 g (125 mmols--5 equivalents) of methyl 4-hydroxy-2-butinoate (R. A. Earl, Organic Synthese 60, 81) in 40 ml of anhydrous methylene chloride at room temperature. The mixture was stirred at room temperature for 1 hour, whereupon a clear solution formed. The solution was then poured into dilute NaHCO3 solution, the mixture was extracted with methylene chloride and the extracts were washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been filtered on 120 g of silica gel (toluene:ethyl acetate 2:3), 4.74 g (63%) of methyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]-2-butinoate were obtained as colorless crystals, melting point: 142°-143° C, RF : 0.29 (toluene:ethyl acetate 2:3), [α]D20 =18.37° (1.0345 percent in acetone).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.CN(C)C=O.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.O>[CH3:21][Si:22]([C:25]#[C:26][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of 150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine-palladium (II) dichloride was stirred for 2 hours and then 500 ml of ice-cooled water were added. The mixture was extracted 3 times with 500 ml of ethyl acetate and the organic phase was washed with salt water, then dried over sodium sulfate, and evaporated under reduced pressure to obtain 136.542 g of a brown oil which was purified by distillation under reduced pressure to obtain 106.979 g of the expected product with a boiling point of 75°-82° C. under 0.2 mbar and a melting point of 62° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([NH2:20])[N:3]=1.[C:21]([O-:24])([O-])=[O:22].[Na+].[Na+].[CH3:27][C:28]#[N:29]>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.O>[NH2:29][C@@H:28]([CH2:27][C:10]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([S:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[N:5]=[C:4]([NH2:20])[N:3]=2)=[CH:12][CH:11]=1)[C:21]([OH:24])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)cc(SCc2ccc3ccccc3c2)n1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Nc1nc(SCc2ccc3ccccc3c2)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1

Procedure:
4-Chloro-6-(naphthalen-2-ylmethylthio)pyrimidin-2-amine (0.1 g, 0.331 mmol), L-p-boronophenylalanine (83 mg, 0.397 mmol), Pd(PPh3)2Cl2 (14 mg, 0.020 mmol), Na2CO3 (77 mg, 0.729 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 57 mg of the title compound. M+1=431; 1H NMR (CD3OD) δ 7.85 (s, 1H), 7.79 (d, 2H), 7.72 (d, 3H), 7.46 (dd, 1H), 7.35 (m, 4H), 6.95 (s, 1H), 4.58 (s, 2H), 4.17 (m, 1H), 3.26 (m, 1H), 3.11 (m, 1H).