Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl.[O:19]=[C:20]1[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]1.CO>CN(C)C1C=CN=CC=1>[O:19]=[C:20]1[CH2:23][CH:22]([C:24]([O:26][CH3:1])=[O:25])[CH2:21]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (7.17 g, 0.0347 mol) in methylene chloride (8 mL, 0.1 mol) was added dropwise to a stirred mixture of 3-oxocyclobutanecarboxylic acid (3.6 g, 0.032 mol), methanol (2.6 mL, 0.063 mol) and 4-dimethylaminopyridine (3.08 g, 0.0252 mol) in methylene chloride (20 mL, 0.2 mol). The mixture was stirred at rt for 24 h, then filtered through Celite. The filtrate was washed with 0.5 M HCl and sat. sodium bicarbonate, dried and concentrated to dry. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired ester (3.26 g, 80.64%). 1H NMR (CDCl3, 400 MHz): 3.78 (s, 3H), 3.43˜3.20 (5H, m) ppm.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH2:15])[NH:13][N:14]=2)=[CH:6][CH:5]=1.[CH3:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][C:26](O)=[O:27]>>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([NH:15][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][CH2:22][C@@H:18]3[CH3:17])[NH:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: Nc1cc(-c2ccc(OC(F)F)cc2)n[nH]1
Reactant: C[C@H]1CCCN1CCCC(=O)O
Product: C[C@H]1CCCN1CCCC(=O)Nc1cc(-c2ccc(OC(F)F)cc2)n[nH]1

Procedure:
Prepared following the general synthetic method for the one-pot synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides, starting from 5-(4-Difluoromethoxy-phenyl)-2H-pyrazol-3-ylamine (112.5 mg, 0.5 mmol, 1.0 eq) and 4-((S)-2-Methyl-pyrrolidin-1-yl)-butyric acid (155.0 mg, 0.8 mmol, 1.5 eq).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:21]O>O>[CH3:21][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([O:14][CH3:15])[CH:7]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(C)(C)C)c(OC)c1

Procedure:
To a solution of 4-tert-butyl-3-methoxy-benzoic acid (3.00 g, 14.4 mmol; commercially available from Apin, 41226B) in MeOH (30 mL) is added H2SO4 conc. (3 mL) and the mixture is refluxed for 5 hrs. After cooling, the mixture is diluted with water, extracted twice with diethyl ether, the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound as yellowish oil. MS: 223.0 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.12 min. 1H-NMR (CDCl3): δ 1.41 (s, 9H), 3.91 (s, 3H), 3.92 (s, 3H), 7.36 (dd, 1H), 7.54 (d, 1H), 7.60 (dd, 1H) ppm.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=C[C:28]=1[O:34][CH3:35])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.COC1C(B(O)O)=CC=C[N:40]=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[C:28]([O:34][CH3:35])=[N:40][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1ncccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (83%). MS (ESI): m/z=266.11 [M+H]+.
Reaction SMILES: [N:1]1([C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[C:17]([NH2:26])[C:16]=3[N:15]=[C:14]2[CH2:27][CH2:28][CH3:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pt](=O)=O.FC(F)(F)C(O)=O>[N:1]1([C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]=[C:17]([NH2:26])[C:16]=3[N:15]=[C:14]2[CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1CCCCCC(=O)N1CCOCC1)CCCC3
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A mixture of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 4.9 mmol), platinum (IV) oxide (1.5 g, 6.6 mmol), and trifluoroacetic acid (50 mL) was placed in a Parr vessel and shaken under hydrogen pressure (50 psi, 3.5×105 Pa) for 24 hours. The trifluoroacetic acid was removed under reduced pressure, and the residue was sonicated with 10% aqueous sodium hydroxide. The resulting solid was mixed with material from another run and recrystallized from water. The crystals were isolated by filtration and dried overnight at 80° C. to provide 0.978 g of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline powder, mp 162-163° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.Cl.[CH3:15][O:16][C:17](=[O:22])[C:18]([NH2:21])([CH3:20])[CH3:19].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:15][O:16][C:17](=[O:22])[C:18]([NH:21][C:11]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]=1[OH:1])=[O:13])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc2ccsc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1O
Yield: 39.7 %

Procedure:
To a solution of 1.40 g 7-hydroxy-benzo[b]thiophene-6-carboxylic acid in 20 ml N,N-dimethylformamide were added 0.21 g 1-hydroxy-benzotriaziole and 1.42 g 2-amino-2-methyl-propionic acid methyl ester hydrochloride. At 0° C. 6.4 ml (4.99 g) ethyl-diiso-propyl-amine and 2.22 g (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added. After 2 days at room temperature the reaction mixture was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 0.84 g 2-[(7-hydroxy-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4(3,4-methylenedioxybenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]2[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=2)[N:10]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: O=C(O)c1cccc2oc(-c3cccs3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cccs4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
A mixture of 2-thiophen-2-ylbenzoxazole-4-carboxylic acid (64 mg, 0.26 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (70 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.52 mmol) and 1-hydroxybenzotriazole (99 mg, 0.74 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.17 mL, 1.3 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-2-ylbenzoxazole-4-carboxamide (55 mg, 56%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 7.95 (dd, J=4.0, 1.0 Hz, 1H), 7.67-7.63 (m, 2H), 7.45 (t, J=4.0 Hz, 1H), 7.27-7.23 (m, 1H), 4.62-4.56 (m, 1H), 3.15-3.09 (m, 2H), 2.67-2.59 (m, 2H) 2.54 (s, 3H), 2.18-1.88 (m, 3H), 1.65-1.57 (m, 5H); MS (ESI+) m/z 382 (M+H); HPLC>99% (AUC), tR=24.24 min.
Reaction SMILES: [CH:1]1([C:7]2[N:8]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[N+:20]([O-])=O)[CH:9]=[C:10]([CH3:12])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[CH:1]1([C:7]2[N:8]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[NH2:20])[CH:9]=[C:10]([CH3:12])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])c(C2CCCCC2)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1cn(-c2cc(F)ccc2N)c(C2CCCCC2)n1
Temperature: 42.5 °C

Procedure:
3.03 g 2-(2-Cyclohexyl-4-methyl-imidazol-1-yl)-4-fluoro-nitrobenzene (10 mmol) were dissolved in 50 ml ethanol, 0.5 g Raney-Nickel was added and the mixture was heated 5 hours in a closed vessel at 40-45° C. and 10 bar hydrogen. After cooling the catalyst was removed and the filtrate was distilled to dryness.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH2:28][CH2:29]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)OCCCCC1C(=O)Nc2cc(F)ccc21
Product: O=C1Nc2cc(F)ccc2C1CCCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared according to process B by applying processing method 1 starting from 6-fluoro-3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(pyridin-2-yl)-piperazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH2:15])[CH:14]=2)[CH:5]=1.CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:29]([C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][C:22]([NH:15][C:13]2[CH:14]=[C:9]([N:6]3[CH:7]=[CH:8][C:4]([CH2:3][O:2][CH3:1])=[CH:5]3)[CH:10]=[CH:11][C:12]=2[N+:16]([O-:18])=[O:17])=[O:21])[CH:33]=[CH:32][CH:31]=1)#[N:30]
Reactant: COCc1ccn(-c2ccc([N+](=O)[O-])c(N)c2)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COCc1ccn(-c2ccc([N+](=O)[O-])c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1

Procedure:
The title compound was prepared from 5-(3-methoxymethyl-pyrrol-1-yl)-2-nitro-phenylamine (Example F7) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a yellow solid (102 mg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH:33][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC1CCCN1c1cccc(N)n1
Reactant: COC(=O)c1ccc(-c2cc(Br)c3nccn3n2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
A mixture of methyl 4-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (208 mg, 0.63 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (168 mg, 0.95 mmol), Pd2(dba)3 (37 mg, 0.063 mmol), BINAP (157 mg, 0.252 mmol), Cs2CO3 (616 mg, 1.89 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1) to give methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo [1,2-b]pyridazin-6-yl)benzoate (120 mg, 45%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.81 (s, 1H), 8.09-7.98 (m, 5H), 7.59 (d, 1H, J=1.5 Hz), 7.42 (t, 1H, J=8.4 Hz), 6.27 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.29-4.21 (m, 1H), 3.96 (s, 3H), 3.62-3.58 (m, 1H), 3.43-3.40 (m, 1H), 2.16-2.12 (m, 3H), 1.78-75 (m, 1H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 429, tR=1.989 min, HPLC: 94.6% at 214 nm, 96.8% at 254 nm, tR=5.255 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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.C(#N)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2ccc3ccccc3c2)ncn1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C)c(-c2cc(-c3ccc4ccccc4c3)ncn2)c1
Yield: 97 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 3.3 g of 4-chloro-(6-naphthalen-2-yl)pyrimidine, 2.1 g of 2,5-dimethylphenylboronic acid, 1.5 g of sodium carbonate, 0.11 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 1.0 g of 2,5-dimethylphenylboronic acid, 0.73 g of sodium carbonate, 0.050 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1, so that a pyrimidine derivative Hdmp2npm was obtained (pale yellow oil, yield of 97%). A synthesis scheme (s-2) of Step 2 is shown below.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C:3](=[O:35])[CH:4]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[N:22]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Br[CH2:38][CH2:39][OH:40].N12CCCN=C1CCCCC2.O>CN(C)C=O>[NH2:1][C:2]([C:3]1([CH:4]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[N:21]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:22]2)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[O:40][CH2:39][CH2:38][O:35]1)=[O:36]
Reactant: OCCBr
Reactant: NC(=O)C(=O)C(Cc1ccc(F)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccc(Cl)cc2Cl)n1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: NC(=O)C1(C(Cc2ccc(F)cc2)NC(=O)c2cccnc2-n2ccc(-c3ccc(Cl)cc3Cl)n2)OCCO1
Temperature: 25 °C

Procedure:
N-[3-amino-1-(4-fluorobenzyl)-2,3-dioxopropyl]-2-[3-(2,4-dichlorophenyl)-1H-pyrazol-1-yl]nicotinamide (0.09 g, 0.171 mmol) was dissolved in dimethylformamide (DMF, 1.7 ml) forming a slight yellow solution. Then, 2-bromoethanol (0.059 ml, 0.838 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.090 ml, 0.598 mmol) were added with stirring at room temperature. Stirring was continued over night. Water was added to reaction mixture resulting in precipitation of the desired product. The suspension was stirred for 30 min. at 0-5° C. The suspension was filtered under reduced pressure, the precipitate washed three times with ice cold water, and subsequently dried at 40° C. under reduced pressure. The remaining residue (85 mg) was treated with a dichloromethane/methanol mixture (97:3 v/v) and the resulting suspension was stirred at room temperature for 30 min. The precipitate was filtered under reduced pressure. washed with few amounts of dichloromethane and subsequently dried at 40° C. under reduced pressure resulting in 19 mg off-white powder. An additional amount of pure desired product could be obtained by column chromatography of the evaporated filtrate.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([O:14][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
190 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 5[a]), 0.2 ml. of freshly distilled dihydropyran, and 1.4 mg. of p-toluenesulfonic acid in 5 ml. of absolute methylene chloride were stirred for 30 minutes at ice bath temperature under argon. After dilution with methylene chloride, the mixture was shaken successively with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated under vacuum. The residue was recrystallized from diisopropyl ether/methylene chloride, thus obtaining 204 mg. of the title compound as colorless crystals, m.p. 113°. IR: 1770, 1630, 1600, 975 cm-1.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]>O1CCOCC1.O>[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:2])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Yield: 70.6 %

Procedure:
To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added a mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3 g.) and dioxane (2.5 ml.) at 110° C. with stirring. The mixture was stirred for 30 minutes at the same temperature, and selenium dioxide (0.055 g.) was further added thereto and then the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction liquid is separated by decantation, and the residue was washed with a small amount of dioxane. The reaction liquid and washing were combined together, and then the solvents were distilled off. The residue was dissolved in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([NH2:17])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClS([N:22]=[C:23]=[O:24])(=O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]1([C:7]2[S:8][C:9]([NH:17][C:23]([NH2:22])=[O:24])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1N
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccccc2)sc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 2-phenyl-5-aminothiazole-4-carboxylate (116 mg, 1.0 eq) in dichloromethane (3 ml) at −78° C. was added chlorosulfonyl isocyanate (0.06 ml, 1.3 eq) dropwise (Redman et al J. (2000) Org. Lett. 2:2061-2063). The reaction was slowly warmed to room temperature and stirred for 40 minutes. The reaction was concentrated. To the residue was added 6N HCl (2.5 ml) and mixture was heated to 100° C. for 20 minutes. Reaction mixture was allowed to cool down to room temperature, and was neutralized with saturated aq. NaHCO3. Solid was collected by filtration to yield ethyl 2-phenyl-5-ureidothiazole-4-carboxylate 63 as a beige solid which was used in the next reaction without further purification.
Reaction SMILES: C(C1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[CH:5]=1)(=O)C.C[Si](O[Si](C)(C)C)(C)C.[C:37]([O:40][CH2:41]C)(=[O:39])[CH3:38].CO>>[OH:27][C:14]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:38]([C:37]([O:40][CH3:41])=[O:39])[CH:13]=[CH:12]2)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2c1
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: CO
Product: COC(=O)c1ccc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2c1

Procedure:
Methyl 6-[1-hydroxy-1-phenyl-1-(3-pyridyl)methyl]-2-naphthoate is prepared from 2-acetyl-6-(1-hydroxy-1-phenyl-1-(3-pyridyl) methyl)naphthalene in analogy to 3a without intermediate protection of the hydroxyl group as the trimethylsilyl ether. RF (ethyl acetate/methanol): 0.53.