Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.CSC.B>C1COCC1>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
4-(4-Hydroxy-phenyl)-butyric acid (22.1 g, 123 mmol) is dissolved in THF (750 ml) and borane-dimethyl sulfide (23.3 ml, 245 mmol) is slowly added. The yellow suspension formed is heated at reflux for 3 hours until most of the solid slowly dissolves. The flask is removed from the heating mantle, and MeOH is slowly added until bubbling ceases and the residual solid has dissolved. The flask is cooled to room temperature and water (1 L) is added. The pH is corrected to 3 with AcOH, then the mixture is extracted with EtOAc (2×500 ml). The organics are washed with brine, dried (MgSO4) and concentrated. The crude product is slurried with silica (500 g) in 25% EtOAc/iso-hexanes (1 L). This is filtered, then flushed with 50% EtOAc/iso-hexanes (2 L) to elute the product. The organics are concentrated to give 4-(4-Hydroxy-butyl)-phenol as a brown oil which crystallizes on standing; 1H NMR (CDCl3): 1.55-1.72 (4H, m), 2.58 (2H, t, J=7.0 Hz), 3.1 (2H, br signal), 3.70 (2H, t, J=6.4 Hz), 6.77 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:30]([NH:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:43])=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCNC
Product: CCCCCCCCCCCCN(C)C(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 56 %

Procedure:
The same procedure as employed in the preparation of Example 5, step d, but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and dodecyl-methyl-amine gave the title compound as a colorless oil (56%). HPLC (Condition A), Rt: 7.41 min (HPLC purity: 82%).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].S(OCCC)(O[CH2:32][CH2:33][CH3:34])(=O)=O.CO>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:32][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCCOS(=O)(=O)OCCC
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
130 mg (0.35 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (8 ml), and 0.39 ml (0.39 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) is added. Then 68 μl (0.41 mmol) of di-n-propyl sulfate are added to the dark red solution. The decolorized solution is stirred for 10 min, then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 63 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=O)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.Br.[Br:49][CH2:50][CH2:51][CH2:52][NH2:53]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([NH:53][CH2:52][CH2:51][CH2:50][Br:49])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(OCC(=O)O)c1
Reactant: NCCCBr
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(OCC(=O)NCCCBr)c1
Reaction time: 0.67 h

Procedure:
A solution of (3-acetyl-phenoxy)-acetic acid (0.194 g, 1.0 mmol) and diisopropylethylamine (0.38 g, 3 mmol) in dry DMF (3 ml) is treated with [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (0.38 g, 1.0 mmol). After stirring for 5 minutes 3-bromo-propylamine hydrobromide (0.26 g, 1.2 mmol) is added and stirring continued for a further 40 minutes. The solvent is evaporated and the crude mixture partitioned between ethylacetate and saturated aqueous NaHCO3. The ethyl acetate phase is dried over MgSO4 and evaporated to afford 2-(3-acetyl-phenoxy)-N-(3-bromopropyl)-acetamide. This crude material is taken up in acetonitrile (3 ml) and treated with triethylamine (0.38 g, 3 mmol) and 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.11 g, 1.2 mmol). The reaction mixture is stirred at ambient temperature for 20 hours, the solvent evaporated and the crude product purified by flash silica chromatography (elution 10:90 methanol/dichloromethane) to afford 2-(3-acetyl-phenoxy)-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-acetamide. [MH]+ 401.14.
Reaction SMILES: [O:1]1[CH:7](C2C=CC=CC=2CCCCCCCCC2C=CC=CC=2)[CH:2]1[C:3]([O:5][CH3:6])=[O:4].[SH:28][C:29]1[N:33]([CH2:34][C:35]([O:37]CC)=[O:36])[N:32]=[N:31][N:30]=1.C(N(CC)CC)C>CO>[OH:1][CH:2]([CH2:7][S:28][C:29]1[N:33]([CH2:34][C:35]([OH:37])=[O:36])[N:32]=[N:31][N:30]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C1OC1c1ccccc1CCCCCCCCc1ccccc1
Reactant: CCOC(=O)Cn1nnnc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(O)CSc1nnnn1CC(=O)O
Temperature: 25 °C

Procedure:
The methyl 2,3-epoxy-3-[2-(8-phenyloctyl)phenyl]propanoate (0.4 g) of Example 14(a) was dissolved in 5 ml of methanol containing 2% triethylamine under an argon atmosphere. The reaction mixture was cooled using an ice/methanol bath. A solution of 0.205 g of 5-mercapto-1-carbethoxymethyltetrazole and 0.61 ml of triethylamine in 5 ml of methanol containing 2% triethylamine was added. The bath was removed and the reaction was permitted to warm to room temperature. The reaction was concentrated and flash chromatographed on silica with 20% ethyl acetate/hexane as eluant to give the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1ccsc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccsc1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.4 mg of the 3-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 157.8 mg (65%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[S:5][C:6]=1[CH:7]=[C:8]([CH3:10])[CH3:9].C([O:21][C:22]1[C:31]([CH3:32])=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][C:23]=1[CH2:33][CH3:34])C1C=CC=CC=1>>[CH2:33]([C:23]1[CH:24]=[C:25]([C:26]2[O:13][C:11]([C:4]3[S:5][C:6]([CH2:7][CH:8]([CH3:9])[CH3:10])=[C:2]([CH3:1])[CH:3]=3)=[N:29][N:28]=2)[CH:30]=[C:31]([CH3:32])[C:22]=1[OH:21])[CH3:34]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CC(C)=Cc1sc(C(=O)O)cc1C
Product: CCc1cc(-c2nnc(-c3cc(C)c(CC(C)C)s3)o2)cc(C)c1O

Procedure:
2-Ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol is prepared from 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide in analogy to Example 29; LC-MS: tR=1.13 min, [M+1]+=357.49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (34.7 g, 115.5 mmol) in acetonitrile (300 ml) were added 4-trifluoromethylbenzyl bromide (27.6 g, 115.5 mmol) and potassium carbonate (31.9 g, 231 mmol), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was diluted with water (1 L) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Hexane was added to the residue and the precipitated crystals were washed with hexane to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (31 g, 76%).
Reaction SMILES: [O-]CC.[Na+].O1CCCC1.[C:10]([C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1)(=[O:12])[CH3:11].[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>O>[Cl:19][C:18]1[C:13]([C:10](=[O:12])[CH2:11][C:26](=[O:27])[C:25]([F:32])([F:31])[F:24])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:17]=1
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 98 %

Procedure:
608 mg of a sodium ethoxide 21% ethanol solution was added at 0° C. to a tetrahydrofuran (dehydrated) 9 mL solution of 1 g of 2-acetyl-3-chloro-5-(trifluoromethyl)pyridine and 635 mg of ethyl 2,2,2-trifluoroacetate, followed by stirring at room temperature for 13 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.4 g of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4,4-trifluorobutan-1,3-dione (after-mentioned intermediate No. IX-25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
3,4-Dichlorotoluene was nitrated with concentrated sulfuric acid and fuming nitric acid (d=1.52).
Reaction SMILES: [C:1]1([N:7]2[C:11](O)=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19].Cl>>[C:1]1([N:7]2[C:11]([Cl:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nnn(-c2ccccc2)c1O
Agent: Cl
Product: CCOC(=O)c1nnn(-c2ccccc2)c1Cl
Temperature: 70 °C

Procedure:
11.65 g of 20A was mixed with 13.8 g of phosphorus pentachloride, and the mixture was slowly heated to ca. 70° C., when vigorous reaction occurred. When reaction had subsided, heating was continued until evolution of hydrogen chloride ceased (about 1 hour), after which phosphoryl chloride was removed in vacuo, and the residue chromatographically purified to yield 1-phenyl-4-ethoxycarbonyl-5-chloro-1,2,3-triazole (20B), as a solid, m.p.: 80°-81° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH3:21][C:19](=[CH2:20])[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)=[O:22]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
71.5 g (0.3 mol) of 4-(6-hydroxy-hexyloxy)-benzoic acid and 101.5 g (1.18 mol) of methacrylic acid were dissolved in 950 ml of chloroform. After the addition of 7.2 g (0.07 mol) of hydroquinone and 7.2 g (0.04 mol) of p-toluenesulphonic acid the batch was boiled under reflux on a water separator for 48 hours. The clear brown solution was subsequently evaporated, the residue was taken up in 1.5 l of diethyl ether, filtered and shaken five time with 300 ml of H2O each time. The organic phase was dried over Na2SO4, evaporated and the residue was recrystallized twice from methanol. After drying at 40° C. in a water-jet vacuum 47.33 g of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid remained behind as a white powder; m.p. 83° C.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH2:7]([S:9][C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[CH3:8]>O.CC(C)=O>[CH2:7]([S:9]([C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:1])[CH3:8]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
Oxone (4139 mg, 6.73 mmol) as a solution in water (volume: 40.0 mL) was added to a stirred suspension of 4-(ethylthio)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (910 mg, 3.06 mmol) in acetone (volume: 40 mL) at rt. The reaction mixture was stirred at rt for 3 hr. After the reaction mixture was diluted with water (5 ml), the acetone was removed by rotovap and the resulting suspension was filtered and the filter cake was washed with water. Drying afforded the title compound (890 mg, 2.84 mmol, 93% yield) as a yellow solid. The material was used as is in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, J=7.5 Hz, 3 H) 3.31-3.39 (m, 2 H) 7.31 (t, J=7.4 Hz, 1 H) 7.40-7.48 (m, 2 H) 7.74 (s, 1 H) 7.80 (d, J=7.3 Hz, 2 H) 7.98 (d, J=1.7 Hz, 1 H) 8.19-8.30 (m, 1 H) 8.49 (s, 1 H) 8.67 (d, J=1.8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>>[NH:18]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1)[NH2:19]
Reactant: COc1ccc(F)c(-c2cnc(Cl)cn2)c1
Reactant: NN
Solvent: O
Product: COc1ccc(F)c(-c2cnc(NN)cn2)c1

Procedure:
An ethanolic solution of 2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazine and hydrazine monohydrate (10 equiv.) was refluxed under a N2 atmosphere for 6 h. The ethanol was removed under reduced pressure and the residue was partitioned between 5% HCl and CH2Cl2. The CH2Cl2 layer was extracted several times with 5% HCl and the combined aqueous portions were washed (1×) with CH2Cl2. The aqueous solution was made basic with 10N NaOH and then extracted (4×) with CH2Cl2. The combined CH2Cl2 portions were washed (1×) with brine, dried (Na2SO4), treated with decolorizing charcoal and filtered through celite. Evaporation of the solvent under reduced pressure yielded 2-hydrazino-5-(2-fluoro-5-methoxyphenyl)-pyrazine as a beige oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>ClCCl>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 72 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and dichloromethane (60 ml) was heated to reflux while stirring for 72 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and then evaporated. The evaporation residue was purified by column chromatography to obtain a target substance (0.5 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([Cl:28])[CH2:26][CH3:27].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:27][CH2:26][CH2:25][Cl:28])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep36, 3 g, 8.77 mmol) and K2CO3 (1.2 g, 8.77 mmol) were suspended in dry DMF (45 mL) and stirred at room temperature for 1 h. Then, bromo-chloro-propane (2.7 mL, 17.5 mmol) was added dropwise and the mixture stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give the title compound as a pale yellow oil (3.6 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[CH:6]2
Reactant: COC(=O)CBr
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-methoxy-1H-indole (500 mg, 3.40 mmol) in dry DMF (8 ml), cooled at 0° C., sodium hydride (60% w/w dispersion in mineral oil, 136 mg, 3.40 mmol) was slowly added portionwise and the reaction was stirred at 0° C. for 45 minutes; then methyl 2-bromoacetate (315 μl, 3.40 mmol) was added dropwise, and the reaction was stirred at room temperature for 15 hours. Water was slowly added, and the product was extracted with Et2O and then with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to dryness. The title compound was obtained and used for the next step without further purification (745 mg, 3.40 mmol, quantitative yield). MS/ESI+ 220.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.N([O-])=O.[Na+].S(=O)(=O)(O)O.[BrH:21]>C(OCC)(=O)C>[Br:21][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11]
Reactant: Br
Reactant: COc1cc(F)c(C)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C)cc1Br
Temperature: 110 °C
Yield: 47 %

Procedure:
A suspension of 4-fluoro-2-methoxy-5-methyl-phenylamine (25.75 g, 0.17 mol) in 180 mL of HBr (48%, 0.9 M) in an ice bath was treated dropwise with an aq solution of sodium nitrite (12.6 g, 0.18 mol, 3.6 M). A brown gas was evolved and the temperature of the reaction was monitored so that the internal temperature did not raise above 10° C. In the meantime, a suspension of CuBr (13.1 g, 0.09 mol) in 6.5 mL of HBr (48%, 13.9 M) was heated to 110° C. Next, the solution at 0° C. was slowly poured (over a period of 20 minutes) into the stirring CuBr suspension. The combined reaction mixture was heated for 2.5 h at 110° C. After cooling to room temperature, the solution was diluted with ethyl acetate and treated with aq sulfuric acid (50% v/v). The organic layer was separated and was washed successively with water, sulfuric acid, water, 1.25 M NaOH, water, and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified via silica gel flash chromatography (5% ethyl acetate in heptane) to afford 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (17.1 g, 47%) as a clear liquid: Rf 0.70 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.34 (d, J=8.4 Hz, 1 H), 6.61 (d, J=10.8 Hz, 1 H), 3.85 (s, 3 H), 2.18 (d, J=1.8 Hz, 3 H); Anal. calcd for C8H8BrFO: C, 43.86; H, 3.68; Br, 36.48. Found C, 44.01; H, 3.68; Br, 36.57.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[NH:21][N:20]=1>>[O:11]=[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[C:19]([C:18]([F:17])([F:29])[F:28])=[N:20]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=C(CCc1ccc(Br)cc1)N1CCCC1
Product: O=C(CCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1

Procedure:
The title compound was prepared from 1-[3-(4-bromophenyl)propanoyl]pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 19.