Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([N:34](CC)[CH2:35]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:12])[N:34]([CH3:35])[CH3:32])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
The hydrogenated compound 44 (4.3 g, 10.0 mmol) was dissolved in CH2Cl2 (50 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.68 mL, 12.0 mmol) and BOP reagent (4.9 g, 11.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 25.0 mL, 50.0 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×10 mL), water (2×50 mL) and brine (1×50 mL). Drying and concentration of the organic layer gave the desired amide 45 (4.4 g, 96%). 1H NMR (400 MHz, DMSO-d6): 7.56 (overlapped d, J=8.4 Hz, 2H), 7.55 (overlapped d, J=8.4 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 4.58 (m, 1H), 3.60 (s, 3H), 2.94 (s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.79-2.83 (m, 5H), 2.67 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21]>>[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])[C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: C#CCCC(=O)OC
Reactant: COC(=O)CCc1nc(I)ccc1O
Product: COC(=O)CCC#Cc1ccc(O)c(CCC(=O)OC)n1
Yield: 84.3 %

Procedure:
Under the conditions of example 5A, 2 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 0.8 g of 4-pentynoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate. 1.6 g of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-4-pentynoic acid methyl ester of melting point 119°-121° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[CH2:8][CH2:7]2)=[O:3]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc2c1NC(=O)CC2
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc2c1NC(=O)CC2
Temperature: 25 °C
Yield: 75.9 %

Procedure:
To a solution of 6-acetyl-8-methoxy-3,4-dihydrocarbostyril (3.1 g) in chloroform (30 ml) was added dropwise a solution of bromine (2.26 g) in chloroform (20 ml) with stirring at room temperature. After completion of addition, the mixture was stirred for 30 minutes at room temperature, thereafter, the reaction mixture was concentrated and the residue was recrystallized from methanol to give 3.2 g of 6-(α-bromoacetyl)-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Br-:22]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21]
Reactant: COc1ccc(C(=O)CCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 96.1 %

Procedure:
A procedure similar to step 3 of Example 1 was used, 1-(4-methoxy-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 3 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was white crystal in a yield of 96.1%, mp: 120-122 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.46 (1H, dd, J=14.28, 7.28 Hz), 3.74 (1H, dd, J=14.28, 7.28 Hz), 3.88 (3H, s, OCH3), 5.27 (1H, t, J=7.28 Hz, CHBr), 6.94 (2H, d, J=8.96 Hz, ArH), 7.46 (2H, d, J=8.60 Hz, ArH), 7.96 (2H, d, J=8.96 Hz, ArH), 8.16 (2H, d, J=8.60 Hz, ArH); ESI-MS: 366.1 (M+2, 93), 364.2 (M, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[CH:32]=O)=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:32](/[CH:31]=[CH:30]/[C:29]2[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C/C=C/c1ccc(F)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 66 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-fluorocinnamaldehyde [Arch. Pharm. 316 574 (1983)] to obtain the title compound, a major product as an oil in a yield of 66%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][N:16]([CH3:26])[C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:26])[C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][N:22]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Product: CN(C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cn1

Procedure:
N,N-Dimethyl-5-(4-nitroquinolin-2-yl)pyridin-2-amine T480P was prepared using general procedure A from 2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and (6-(dimethylamino)pyridin-3-yl)boronic acid (34 mg, 0.2 mmol). The product was obtained as a yellow solid (40 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 8.99 (d, J=2.4 Hz, 1H), 8.36-8.34 (m, 2H), 8.30 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.65 (m, 1H), 6.66 (d, J=9.0 Hz, 1H), 3.21 (s, 6H); MS (ESI): 295 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:4].S(C1C=CC(C)=CC=1)(O[CH2:15][C@@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[NH:23][CH:22]=3)[N:18]([CH3:32])[CH2:17]1)(=O)=O>CN(C)C=O>[CH2:3]([C:5]1[N:6]([CH2:15][C@@H:16]2[CH2:30][C@H:29]3[C@@H:19]([CH2:20][C:21]4[C:31]5[C:24](=[CH:25][CH:26]=[CH:27][C:28]3=5)[NH:23][CH:22]=4)[N:18]([CH3:32])[CH2:17]2)[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CCc1nc(C)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)cn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
1.6 g of 50% sodium hydride in an oil was added in small portions to a mixture of 9.0 g of 2-ethyl-4-methylimidazole and 70 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 4.1 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue. The precipitated crystals were separated by filtration, washed with water and recrystallized from methanol to obtain 1.0 g of the titled compound as colorless needles having a melting point of 172°-174° C.
Reaction SMILES: [C:1]1([CH2:15][OH:16])[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:23][C:24]([Cl:34])=[CH:25][C@@H:26]1[C@H:28]([C:29](Cl)=[O:30])[C:27]1([CH3:33])[CH3:32]>C1C=CC=CC=1>[Cl:23][C:24]([Cl:34])=[CH:25][C@@H:26]1[C@H:28]([C:29]([O:16][CH2:15][C:1]2[C:14]3[CH2:13][CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:30])[C:27]1([CH3:32])[CH3:33]
Reactant: OCc1cccc2c1CCc1ccccc1-2
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 9,10-dihydrophenanthrene-1-methanol (0.5 gram, 0.0024 mole) and pyridine (1 gram, 0.013 mole) in benzene (25 ml) was added to a stirred solution of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.7 gram, 0.0031 mole) in benzene (25 ml). The mixture was stirred at room temperature for 2.5 days, then partitioned between water (80 ml) and diethyl ether (50 ml). The organic phase was separated and washed consecutively with water, 10% aqueous sodium carbonate and water. The organic phase was then dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give a yellow oil. The oil was purified by chromatography on silica gel to give (9.10-dihydro-1-phenanthryl)methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:3][CH2:2]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:46]2[CH:50]=[CH:49][NH:48][N:47]=2)[CH:40]=1>C1COCC1>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:46]2[CH:50]=[CH:49][N:48]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)(=[O:8])=[O:9])[CH:11]=3)=[O:15])[N:47]=2)[CH:40]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Oc1ccc(Cl)cc1-c1cc[nH]n1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(c1cccc(S(=O)(=O)N2CCOCC2)c1)n1ccc(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-(morpholinosulfonyl)benzoic acid (50 mg, 0.184 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (37.4 mg, 0.276 mmol), EDC (53.0 mg, 0.276 mmol) and Sodiumbicarbonate (17.03 mg, 0.203 mmol) was dissolved in THF (10 mL) and then 4-chloro-2-(1H-pyrazol-3-yl)phenol (35.9 mg, 0.184 mmol) was added at room temperature and reaction mixture was allowed to stirred for overnight at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (3-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-1-yl)(3-(morpholinosulfonyl)phenyl)methanone (43 mg, 0.094 mmol, 51.0% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.39 (d, 1H, J=7.6 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.53 (d, 1H, J=2.4 Hz), 7.38 (dd, 1H, J=2.4 & 8.4 Hz), 7.27 (d, 1H, J=8.4 Hz), 6.52 (s, 1H), 3.75 (m, 4H), 3.05 (m, 4H). ESI-MS: 448.0 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[Br:18][C:19]1[CH:20]=[C:21]([S:26]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:3]=2[Cl:2])(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1Oc1ccc(Cl)cc1Cl)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,4-Dichlorophenoxy)aniline HCl (1.14 g, 3.94 mmol) and 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.26 g, 4.33 mmol) were dissolved in pyridine (4 mL) and allowed to stir at ambient temperature for 1 hour. The reaction mixture was then diluted with 100 mL of ethyl acetate, 80 mL of 0.5 M HCl. The organic layer was washed successively with 100 mL of 0.5 M HCl, twice with 100 mL of water, 100 mL of half-saturated brine and finally 100 mL of brine. Drying of the organic layer over sodium sulfate was followed by filtration and solvent removal under reduced pressure. The resulting residue was purified by silica gel chromatography (linear gradient 60-100% DCM in hexanes) to yield 5-bromo-6-chloro-N-[2-(2,4-dichlorophenoxy)phenyl]pyridine-3-sulfonamide, giving proton NMR and mass spectral data consistent with theory.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5])#[N:2].[OH-].[Na+].O>C(O)C>[C:1]([CH:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethyl 2-cyano-3-(3-indolyl)propionate (350 mg, 1.45 mmol) (S. Masanori, et al., Heterocycles, 1981, 16: 941-9) was dissolved in ethanol (6 mL). 2N Sodium hydroxide solution (4 mL) was added and the reaction mixture was stirred at ambient temperature for 20 hours. Water (10 mL) was added and the ethanol was removed under reduced pressure. The pH of the aqueous solution was adjusted to approximately 1 with 6N hydrochloric acid solution and it was extracted with ethyl acetate. The ethyl acetate solution was concentrated in vacuo to give the title compound which was carried on to the next step without purification.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccc(N)nc3)cc1OCC2
Yield: 62 %

Procedure:
Following the same procedure as for 182, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine provided 219 in 62% yield. LS/MS (ESI+): m/z 388 (M+H). 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=8.4, 1H), 8.33 (d, J=2.4, 1H), 7.93 (d, J=6.5, 2H), 7.77 (dd, J=8.7, 2.5, 1H), 7.41 (dd, J=8.5, 1.9, 1H), 7.26 (d, J=1.8, 1H), 6.53 (d, J=8.6, 1H), 6.16 (s, 2H), 5.92 (dt, J=13.2, 6.6, 1H), 4.60-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1O.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1cc(F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole 1,3(2H)-dione (Becker, Y. J. J. Org. Chem. 1980, 45, 2145–51) was diluted with 40 mL THF then treated in order with 7.0 g triphenyl phosphine, 4.0 g of 2,5-difluorophenol and finally with 5.0 mL of diethylazocarboxylate. The reaction became warm to the point of reflux and was allowed to cool to room temperature and stirred at room temperature overnight. The solvent was removed in vacuo and the resulting brown oil was taken up in ethyl acetate (EtOAc). The solution was washed sequentially with aqueous sodium bicarbonate, aqueous ammonium chloride, and brine. Removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate-hexane, to afford 5.4 g of the title compound of Step A as a clear colorless oil: 1H NMR (CDCl3) δ 1.57 (d, 3H), 4.22 (dd, 1H), 4.57 (t, 1H), 4.82 (m, 1H), 6.55 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.72 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7](I)[N:6]=1)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:25]#[N:26])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 120 °C
Yield: 61.9 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-5-iodo-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (113 mg, 0.26 mmol) and CuCN (46 mg, 0.52 mmol) in DMF (3 mL) was heated at 120° C. for 8 min. After cooling to r.t., CH2Cl2 (50 mL) and 4 M HCl (50 mL) were added. The mixture was stirred vigorously until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (100% CH2Cl2) to give 54 mg of the title compound. MS: (−) m/z 334.30 (M−1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:17]=2)[CH2:11][C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:24]3)[N:17]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(S(C)(=O)=O)C2)no1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CC(c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 88.7 %

Procedure:
A solution of methyl (3R)-6-cyclohexyl-3-{3-[1-(methylsulfonyl)-3-azetidinyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 38) (780 mg, 1.05 mmol) in dioxan (20 ml) and H2O (10 ml) was treated with LiOH.H2O (218 mg, 5.2 mmol) and stirred at room temperature for 2.25 hours. The reaction mixture was acidified with 2M HCl (20 ml) and extracted with EtOAc. The organic extract was washed with H2O and the solvent was removed under reduced pressure. The oil was purified on a silica column eluting with a solvent gradient of DCM:MeOH:AcOH (100:0:0) gradually changing to (90:10:1) to afford a colourless oil which solidified on standing. The solid was triturated with pentane, filtered off and dried under reduced pressure to afford the title compound as a white solid (372 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=1)=[O:6].[CH3:24][S:25][C:26](SC)=[N:27][C:28]#[N:29]>C(O)C>[C:28]([N:27]=[C:26]([S:25][CH3:24])[NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=1)=[O:6])#[N:29]
Reactant: CN(C)Cc1ccc(CSCCNC(=O)c2cccc(N)c2)o1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)Nc1cccc(C(=O)NCCSCc2ccc(CN(C)C)o2)c1
Yield: 25.1 %

Procedure:
A mixture of 20 g of 3-amino-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide and 8.8 g of dimethyl cyanodithioiminocarbonate in 150 ml of absolute ethanol is heated with reflux for 30 hours, then it is concentrated under reduced pressure and the crude oil thus obtained is poured on a silica column and eluted with a mixture chloroform:methanol 4:1. The fairly pure fractions are collected and the solvent is evaporated under reduced pressure. Thus, 6.5 g of 3-(3-cyano-2-methylisothioureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide are obtained as an oil which is mixed with 10 ml of a 33% solution of methylamine in ethanol. The mixture thus obtained is left to stand 48 hours at room temperature, then the excess of methylamine is eliminated under reduced pressure. Thus 5 g of an oil are obtained which is submitted to a flash chromatography on silica by eluting with a mixture chloroform:ethanol 1:1. The pure fractions are collected and evaporated, the residue is crystallized twice from isopropanol. Thus, 2.5 g of 3-(2-cyano-3-methylguanidino)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide are obtained; m.p. 140°-142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18](=[O:41])[CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:16][O:17][C:18](=[O:41])[CH2:19][CH:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[N:4][C:5]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=4)=[N:6][CH:7]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: Fc1cccc(Nc2ncc(Br)cn2)c1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(F)c4)nc3)cc2)CC1
Temperature: 125 °C

Procedure:
The mixture of (5-bromopyrimidin-2-yl)-(3-fluorophenyl)-amine (75 mg, 0.28 mmol), {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (Patent WO2004 047755) (100 mg, 0.28 mmol), PdCl2dppf (12 mg, 0.014 mmol), sodium carbonate (2M solution, 0.35 mL) and DME (2 mL) is heated in a microwave at 125° C. for 15 Min. The reaction mixture is extracted with EtOAc, washed with NH4Cl solution. The organic phase is dried with MgSO4, filtered and it is used directly in the next step: (M+H)+ 420.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1.[CH3:21][NH:22][O:23][CH3:24]>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[N:22]([O:23][CH3:24])[CH3:21])=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)cc1
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Thirteen grams of 4-(2-naphthyloxy)phenyl isocyanate were dissolved in 100 ml of benzene, and a solution of 4 g of N,O-dimethylhydroxylamine in 50 ml of benzene was added dropwise thereto at a temperature below 30° C. The reaction mixture was allowed to stand at room temperature for 30 minutes, and the solvent was then removed under reduced pressure. The residue was recrystallized from ethanol to obtain 14 g of N'-[4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea as white needles. M.P., 102°-103° C.