Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C>[N:8]1([C:6]2[N:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=[C:2]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[N:7]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: c1nc[nH]n1
Reactant: CN(C)c1nc(Cl)nc(-n2ccnc2)n1
Solvent: CN(C)C=O
Product: CN(C)c1nc(-n2ccnc2)nc(-n2cncn2)n1
Reaction time: 4 h
Yield: 17.5 %

Procedure:
The obtained 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine (113 mg, 0.503 mmol) was dissolved in DMF (1 ml), added with 1,2,4-triazole (149 mg, 2.15 mmol) and stirred at 110° C.-120° C. for 4 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (9:1) as eluant, to obtain 22.7 mg (yield: 17.6%) of the titled compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3C)[C:3]=12.[I:25]C1C=C(C=CC=1)C=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([I:25])[CH:18]=3)[C:3]=12
Reactant: O=Cc1cccc(I)c1
Reactant: Cc1ccccc1-c1nn(C)c2nnc(-c3ccccc3)c(Cl)c12
Product: Cn1nc(-c2cccc(I)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 3 was synthesised following similar procedures outlined in Example 25 (Compound 20), using 3-iodobenzaldehyde instead of 2-methylbenzaldehyde in Step 1. As a slightly modified procedure, the crude residue of Step 3 was purified by column chromatography (silica gel, gradient 80 to 100% CH2Cl2/isohexane to 2% diethyl ether/CH2Cl2), yielding Compound 3 as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][C:46]1=[O:54]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:42][CH2:43][CH2:44][N:45]4[C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:47][C:46]4=[O:54])[CH2:16][CH2:17]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2N1CCCCl
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a solution of tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.175 g, 0.4 mmol), sodium iodide (0.018 g, 0.12 mmol) and potassium carbonate (0.083 g, 0.6 mmol) in 2-butanone (4 mL), was added 1-(3-chloropropyl)indolin-2-one (0.095 g, 0.4 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) and preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.077 g, 31%); 1H NMR (DMSO-d6): δ 1.56 (s, 9H), 1.67 (d, 2H, J=12.4 Hz), 2.02 (br, 2H), 2.28-2.34 (m, 2H), 2.62-2.67 (m, 2H), 3.17-3.23 (m, 2H), 3.52-3.56 (m, 4H), 3.72 (t, 2H, J=6.4 Hz), 4.61 (s, 2H), 4.82 (s, 2H), 6.11-7.14 (m, 6H), 7.23-7.27 (m, 3H), 7.41 (t, 1H, J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82 (d, 1H, J=8 Hz); MS for C36H41FN4O4 m/z 613.15 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]([O-])=[O:24])=[CH:19][C:18]=3[CH:17]=[C:16]([F:26])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].F[B-](F)(F)F.[C:33]1(=O)[N:37](OC(N(C)C)=[N+](C)C)[C:36](=O)CC1.C(N(CC)CC)C.Cl.CNC>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]([N:37]([CH3:33])[CH3:36])=[O:24])=[CH:19][C:18]=3[CH:17]=[C:16]([F:26])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc2cc(F)cc(N3CCN(Cc4ccccc4)CC3)c2o1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2cc(F)cc(N3CCN(Cc4ccccc4)CC3)c2o1
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Lithium 7-(4-benzylpiperazin-1-yl)-5-fluorobenzofuran-2-carboxylate (0.86 g, 2.38 mmol) was dissolved in dry dimethylformamide (10 mL), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) (0.93 g, 3.10 mmol) was added followed by triethylamine (1.16 mL, 8.34 mmol). The reaction was stirred for 20 min then dimethylamine hydrochloride (0.78 g, 9.54 mmol) was added. The reaction was stirred at rt over night. The solvent was evaporated and water and dichloromethane were added. The layers were separated. The aqueous phase was extracted with dichloromethane (3×). The combined organic phases were washed with water (3×) and brine, dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (SiO2; DCM/MeOH; 97/3) to give 0.62 g (68%) of the product.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.Cl[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([Cl:23])[CH:14]=1)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Cl:23][C:15]1[CH:14]=[C:13]([S:10]([NH:2][C:3]2[S:4][C:5]([Cl:8])=[CH:6][N:7]=2)(=[O:12])=[O:11])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of 2-amino-5-chlorothiazole hydrochloride (2.62 g, 15.3 mmol, 3 eq) in pyridine (10 ml) was added methyl 4-(chlorosulfonyl)-2-chlorobenzoate (2.28 g, 5.1 mmol, 1 eq) portionwise and the reaction mixture stirred at room temperature for 1 hour. The solution was added to 6M HCl (40 ml) and the resultant precipitate collected by filtration. The crude material was triturated with t-butylmethyl ether to yield the title compound (410 mg, 1.1 mmol, 22%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([F:34])=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:35])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][C:15]=1[F:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2c(F)ccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1c(-c2c(F)ccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.71 (dd, J=8.7, 4.4 Hz, 1H), 7.26 (t, J=16.7 Hz, 2H), 7.20 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 3.39 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.93 (dt, J=13.7, 6.8 Hz, 1H), 2.57 (s, 3H), 1.28 (m, 12H), 1.22 (m, 2H), 0.96 (m, 2H), 0.57 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[CH:24]([N:27](CC)[CH:28](C)C)(C)C.Cl.CNC>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:27]([CH3:28])[CH3:24])[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.5 g, 1.40 mmol) in anhydrous DMF (5 mL) at room temperature under Ar atmosphere was added N,N-diiso-propylethylamine (0.0.54 mL, 3.09 mmol) and dimethylamine hydrochloride (0.126 g, 1.54 mmol). The resulting solution was stirred at 85° C. for 16 hours at which time the reaction mixture was concentrated to dryness and the residue chromatographed over silica gel eluting with 50% EtOAc in n-hexane to give methyl [4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.505 g, 99% yield) as a brown oil.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(NC1Cc2ccc3[nH]ncc3c2CN(Cc2ccncc2)C1=O)OCc1ccccc1

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with 4-(aminomethyl)pyridine followed by treatment with acetic acid in refluxing toluene to give (8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 65% yield. MS (ESI) 442 (M+H); Rf=1.10.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:24]=[C:25]([NH2:27])[S:26][CH:2]=3)=[C:6]([CH3:23])[CH:7]=2)=[CH:14][CH:15]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(N)n1
Yield: 61.4 %

Procedure:
A mixture of 2-bromo-1-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)ethanone (16-5, 2.57 g, 6.8 mmol) and thiourea (0.60 g, 7.8 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 4.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (16-6, 1.48 g) as yellow solids in 61% yield: 1H NMR (500 MHz, DMSO-d6) 6.94 (m, 6 H), 6.62 (s, 2 H), 6.33 (s, 1 H), 4.54 (t, J=6.0 Hz, 1 H), 2.05 (s, 6 H), 1.26 (s, 3 H), 1.25 (s, 3 H).
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[NH2:26][C:27]1([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH:15]1[C:16]2[CH:4]([CH2:3][O:2][C:1]([NH:26][C:27]3([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]3)=[O:17])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.2 g, 9.5 mmol) in dioxane (30 ml) was added to a solution of 3-amino-oxetane-3-carboxylic acid (1.17 g, mmol) and potassium carbonate (2.76 g, 20.0 mmol) in water (30 ml). The light yellow opaque solution was stirred at room temperature for 75 minutes. During that time, a white solid precipitated. The mixture was diluted with water and extracted two times with diethyl ether. The white solid did not dissolve and was kept therefore in the aqueous layer, which was acidified to pH 2 by addition of 1N HCl and extracted three times with EtOAc. The combined EtOAc layers were washed with brine, dried with Na2SO4 and evaporated. The crude title compound was obtained as white solid and was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:24]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(N3CCOCC3)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(cc1N1CCOCC1)CNCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of tert-butyl 7-(morpholin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.538 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (134 mg, 81.2%) as a solid.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na].Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>[Cu]I.O>[CH2:1]([O:11][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Brc1ccsc1
Reactant: CCCCCCCCCCO
Agent: [Cu]I
Agent: [Na]
Solvent: O
Product: CCCCCCCCCCOc1ccsc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
3-Decyloxythiophene was synthesized as follows. 1-Decanol (0.51 mol, 80.27 g) was added dropwise to 3.5 g (0.15 mol) of sodium metal. After complete disappearance of sodium, the residual alcohol was removed in vacuum and the remaining solid was dissolved in 20˜30 ml DMF. After the solution was heated to 110° C., 12.2 g (0.075 mol) of 3-bromo-thiophene and 1.0 g (0.00053 mol) of copper (I) iodide were added. After 16 hrs of stirring at 110° C., the mixture was poured into water and extracted with ether three times. The filtrate was concentrated in vacuo and the yellow oily residue was chromatographed on a silica column using hexane as the eluent to yield 15.5 g of yellow liquid (86% yield). Mw=240.4. Element Anal. Calcd for C14H24SO: C, 69.94; H, 10.06; 0, 6.66; S, 13.34. Found: C, 69.90; H, 10.00; 0, 6.64; S, 13.30.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[C:10](Br)=[CH:9][S:8][CH:7]=1>C(N)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:10]([C:3]#[C:2][CH2:1][OH:4])=[CH:9][S:8][CH:7]=1
Reactant: Brc1cscc1Br
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1cscc1C#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Pd(Ph3P)4 (116 mg, 2%), CuI (28 mg, 3%) and propargyl alcohol (0.9 ml, 15 mmol) are added successively to a solution of 3,4-dibromothiophene (1.18 g, 5.0 mmol) in n-propylamine (15 ml), and the reaction mixture is stirred at RT for 1 h and then under reflux for 7 h. More Pd(Ph3P)4 (58 mg, 1%), CuI (14 mg, 1.5%) and propargyl alcohol (0.45 ml, 7.5 mmol) are then added and the mixture is stirred under reflux for another 8 h. After cooling, the reaction mixture is filtered off through kieselguhr and washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (0.84 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.22.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:39][N:38]=2)=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccc(OC(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(OC(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of 4-hydroxy-3-(4-trifluoromethoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (307 mg, 0.60 mmol) produced in Synthesis Example 19 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 120 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (190 mg, yield 63%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:41]>CO>[CH2:14]([O:13][C@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:41])[C:3]=2[CH:10]=[CH:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N
Reactant: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CO
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3 g of 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 3 ml of methanol, and 20 ml of liquid ammonia is placed in a stainless steel reactor and heated at 100° C. for 5 hours. The ammonia is allowed to evaporate and the residue, after evaporation of the methanol, is distributed between ethyl acetate and water. The aqueous layer is reextracted with ethyl acetate and the dried (MgSO4) ethyl acetate solution is evaporated in vacuo to provide 2.6 g of 7-(2,3,5tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a crude yellow syrup. Chromatography of this material over silica gel with ethyl acetate provides 2.6 g of pure product as a colorless syrup.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine (321.3 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 350 mg; 80%. HPLC-MS: m/z: 512.2 (M+H)+; Rt: 2.09 min.
Reaction SMILES: [CH2:1]([P:4]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])(=[O:7])[O:5]C)[CH2:2][CH3:3].Cl>>[CH2:1]([P:4]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])(=[O:5])[OH:7])[CH2:2][CH3:3]
Reactant: CCCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Product: CCCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the method of Example 3 or Example 13, methyl P-n-propyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate and 6N HCl are reacted to give P-n-propyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:13]([OH:16])(=[O:15])[CH3:14]>C(#N)C.[Zn]>[C:13]([OH:16])(=[O:15])[CH3:14].[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
3,3-Dibromo-7-azaoxindole (2.9 g) was dissolved in a mixture of 20 mL of acetic acid and 30 mL of acetonitrile. To the solution was added 6.5 g of zinc dust. The mixture was stirred for 2 hrs at room temperature. The solid was filtered from the mixture and the solvent evaporated. The residue was slurried with ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel. The collected ethyl acetate solution was evaporated and the residue dried under vacuum to give 1.8 g (yield 91%) of 7-azaoxindole acetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: CC(C)(CO)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 45 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of ethanolamine, to the title compound (110 mg, 45%) which was obtained as a white solid. MS: m/e=402.2 [M+H]+.