Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:20][CH2:19]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1CCc2cc(F)ccc21
Product: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-5-fluoro-indan-1-ylamine (CAS no: 148960-33-2); MS: m/e=294.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>CC(C)=O>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 50) (2 g, 8.60 mmol) and p-toluenesulfonyl chloride (1.640 g, 8.60 mmol) was taken up in acetone (12 mL) and stirred under nitrogen and cooled to between −5° C. and 5° C. To this solution was added 2.0M NaOH solution (5.50 mL, 10.99 mmol) while maintaining the internal temperature at less than 5° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The white solid was filtered off and washed well with acetone to afford 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.28 g, 99%) as a pale cream solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 5.5 h

Procedure:
To a solution of 20 g (161.1 mmol) of p-fluorobenzaldehyde in 300 ml of DMF, 19.8 g (290.8 mmol) of imidazole and 44.5 g (322.24 mmol) of potassium carbonate are step by step added at r.t. After being stirred for 5.5 h at 100° C., the reaction mixture is cooled to r.t., diluted with ice water and then the mixture is extracted with AcOEt and CH2Cl2. The combined extracts are concentrated under reduced pressure to give 4-imidazol-1-yl-benzaldehyde as a pale yellow powder. 1H-NMR (400 MHz, CDCl3): 7.26 (s, 1H), 7.38 (2, 1H), 7.59 (d, 2H, J=8.56 Hz), 7.98 (s, 1H), 8.02 (d, 2H, J=8.56 Hz), 10.05 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: N[C:2]1[C:13]([C:14]([O:16]N2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1)([O-:28])=[O:27].O1CC(=O)C1.CO>C1COCC1>[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:35]1[CH2:36][CH2:37][N:38]([CH:13]2[CH2:14][O:16][CH2:2]2)[CH2:39][CH:40]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cnccc1C1=CCNCC1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C1COC1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnccc1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
Sodium triacetoxyborohydride (Sodium Ion (1)) (1.189 g, 5.608 mmol) was added in portions to a stirred solution of 3-nitro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (523 mg, 2.549 mmol) and 3-oxetanone (312.2 mg, 277.8 μL, 4.333 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to warm to ambient temperature and was stirred for 16 hours. MeOH (2 mL) was added dropwise and the mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was partitioned between water and EtAOc. The pH of the aqueous layer was adjusted to pH 7-8 by the addition of NH4OH and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo to give 3′-nitro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as a red oil (615 mg, 92% Yield). MS (ES+) 262.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C(Cl)CCl.C1C=[N:30]C2N(O)N=NC=2C=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:30])=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20]
Reactant: On1nnc2cccnc21
Reactant: CNc1ccc(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNc1ccc(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-[4-(methylamino)-3-nitrophenoxy]pyridine carboxylic acid in tetrahydro-furan was added EDC (2 eq) and HOAT (1.5 eq) and ammonium chloride (2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethylacetate and water. A solid crashes out in the aqueous layer which was filtered and was found to be the product on LC/MS. The organic layer was then dried with sodium sulfate and concentrated. Purification on silica gel gave 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(OCC3CO3)ccc2c2oc3ccccc3c12
Temperature: 55 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
In N,N-dimethylformamide was dissolved 10.0 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one, and to the solution were added 28.0 g of epibromohydrin and 5.5 g of potassium carbonate. The mixture was stirred at 55° C. for 3 hours. Into the reaction mixture was poured water, and precipitates were collected by filtration, washed with water, and dried to obtain 11.8 g of 3-(2,3-epoxypropoxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]1C=CC=C[C:17]=1[C:18](Cl)=[Se:19].[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:29](=[O:25])[C:28]3[CH:27]=[CH:26][CH:16]=[CH:17][C:18]=3[Se:19]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: ClC(=[Se])c1ccccc1Cl
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: O=c1c2ccccc2[se]n1-c1ccc(O)cc1

Procedure:
of 4-aminophenol dissolved in 200 cc. of tetrahydrofurane (THF) and 2 cc. of pyridine are added with stirring and ice-cooling (temperature below 10° C.) under a nitrogen atmosphere to a solution of 3.3 g. of o-chloroselenobenzoic acid chloride in 30 cc. of THF. After termination of the addition, the mixture is stirred at room temperatur, the solvent is evaporated under vacuum and the residue is pured into a mixture of ice and dilute hydrochloric acid. The resulting precipitate is filtered off and is recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14].[CH2:18](N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>C(Cl)Cl.O>[CH2:1]([O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:6][C:5]=1[CH2:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH3:18]
Reactant: COC(=O)c1ccc(N)cc1CSC(C)(C)C
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Amino-2-tert-butylsulfanylmethyl-benzoic acid methyl ester (5.1 g, 19.1 mmol) and triethylamine (6.6 mL, 47.8 moml) were combined in CH2Cl2 (200 mL) and cooled to 0° C. Pivaloyl chloride (2.8 mL, 22.9 mmol) was added dropwise by syringe, and the reaction was stirred at room temperature for 1 hour. The mixture was worked up with EtOAc and H2O to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)[CH3:2].[NH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[OH:22])=[S:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N=C=S)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CO
Product: CCc1ccc(NC(=S)Nc2cc([N+](=O)[O-])ccc2O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Ethylphenyl isothiocyanate (3.48 mmol, 1 eq) was added to 2-amino-4-nitrophenol (3.48 mmol, 1 eq) dissolved in 10 mL of methanol, and stirred at room temperature for 24 hours. The organic solvent was removed by evaporation under reduced pressure, and then the precipitate was filtered under reduced pressure with hexane to yield the title compound (a). Yellow-green powder (79%), mp 137-138° C.; 1H NMR (Acetone-d6 400 MHz) δ 9.475 (s, 1H), 9.351 (s, 1H), 8.755 (s, 1H), 7.968 (d, J=9.8 Hz, 1H), 7.464 (d, J=8.0 Hz, 2H), 7.282 (d, J=8.8 Hz, 2H), 7.089 (d, J=9.2 Hz, 1H), 2.658 (q, J=7.6 Hz, 2H), 1.225 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17](Cl)[O:18][CH:19]=1)=[O:14])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.CCCCCC>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:18][CH:19]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1coc(-c2ccccc2)n1
Yield: 83 %

Procedure:
A mixture of phenylboronic acid (729 mg, 5.98 mmol), 2-chloro-oxazole-4-carboxylic acid ethyl ester (prepared according to the procedures described in Org. Lett. 2002, 4 (17), 2905 and J. Med. Chem. 1971, 14, 1075) (1.0 g, 5.70 mmol), Pd[PPh3]4 (329 mg, 0.285 mmol), and sodium carbonate (2M, 2 mL) in ethylene glycol dimethyl ether (10 mL) were heated at 90 degrees overnight. After cooling the reaction, solvent was removed to give the crude residue. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-45% ethyl acetate in hexane for 35 min) gave 2-phenyl-oxazole-4-carboxylic acid ethyl ester (1.03 g, 83%) as colorless oil. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH:24][C:25](OCC2C=CC=CC=2)=O)[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(=O)([O-])[O-].[K+].[K+].I[C:44](I)([CH2:47]C)[CH2:45][CH3:46]>CO.[Pd].C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([N:24]2[CH2:25][CH2:46][CH2:45][CH2:44][CH2:47]2)[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(I)(I)CC
Reactant: [H][H]
Reactant: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
The compound of Step 1 (5.33 g, 11.36 mmol) was dissolved in methanol (200 mL), and palladium on carbon (50% water, 5.0 g) was then added. A hydrogen atmosphere was established using balloons and the reaction stirred at r.t. for about 4 hours. The catalyst was removed by filtration with ethyl acetate (200 mL) through a bed of celite. Compound was isolated, and the residue (1.0 g, 2.13 mmol) was dissolved in acetonitrile (55 mL). Potassium carbonate (1.18 g, 8.52 mmol) was added, and the mixture was heated to reflux and then diiodopentane (0.76 g, 2.34 mmol) in acetonitrile (10 mL) was added dropwise. The reaction was stirred overnight and cooled to r.t., filtered and concentrated under reduced pressure. The compound was purified by using silica gel chromatography (1% ammonium hydroxide in ethyl acetate) to afford the final compound (0.95 g, 83%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br.[C:10](O)(=[O:12])[CH3:11]>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)c1ccc(O)cc1O

Procedure:
A process of claim 1, wherein 1,3-dihydroxy-4-acetylbenzene is prepared by combining resorcinol with acetic acid and hydrobromic acid at a temperature between about the boiling point of the reaction mixture to about 75° C. for between about one hour to about five days.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 83.8 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (0.16 g, 0.52 mmol), 1-[4-(bromomethyl)phenyl]-1H-pyrazole (0.26 g, 1.03 mmol), potassium carbonate (0.72 g, 5.17 mmol) and potassium iodide (0.02 g, 0.10 mmol) in 5 ml dimethylformamide were stirred at 65° C. for 5 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane (90/10 to 1/0) yielded 0.20 g (87%) 4-chloro-N-(2-oxo-azepan-3-yl)-N-(4-pyrazol-1-yl-benzyl)-benzenesulfonamide as light yellow solid, MS: m/e (%)=459.1 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]1[Cl:11].C(=O)([O-])O.[Na+].[CH3:19][C:20]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH3:27])[O:22][N:21]=1.C1(C=CC(O)=CC=1)O>C(OCC)(=O)C>[CH3:27][CH:26]1[C:4]2([Cl:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:7]([Cl:8])([C:6]([Cl:9])=[C:5]2[Cl:10])[CH:25]1[C:23]1[O:22][N:21]=[C:20]([CH3:19])[CH:24]=1
Reactant: COC1(OC)C(Cl)=C(Cl)C(Cl)=C1Cl
Reactant: C/C=C/c1cc(C)no1
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(c1cc(C)no1)C2C
Temperature: 180 °C
Reaction time: 7 h
Yield: 44.6 %

Procedure:
1.07 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 0.34 g of sodium hydrogen carbonate, 0.50g of trans-1-(3-methylisoxazol-5-yl)-1-propene and 0.05 g of hydroquinone were mixed and heated with stirring at 180° C. for 7 hours. The reaction solution was cooled and ethyl acetate was added. Insoluble matter was removed by filtration. Then the solvent was concentrated under reduced pressure. The obtained crude product was purified on silica gel column chromatography (elution with benzene) to give 0.70 g of the title compound as a mixture of isomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][CH2:27][CH2:26][CH:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[OH:35])[CH:12]=1.[I:36][CH2:37][CH3:38].[C:39](#N)[CH3:40]>>[I-:36].[CH2:39]([O:35][C:14]1[CH:15]=[C:16]([NH:19][C:20]2[S:21][C:22]3[CH2:28][CH2:27][CH2:26][CH:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]=3[N:24]=2)[CH:17]=[CH:18][C:13]=1[N:11]1[CH:12]=[C:8]([CH3:7])[N+:9]([CH2:37][CH3:38])=[CH:10]1)[CH3:40]
Reactant: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2O)cn1
Reactant: CCI
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cc(C)[n+](CC)c1
Product: [I-]
Yield: 45 %

Procedure:
Potassium carbonate (41.5 mg, 0.3 mmol) was added to a solution of 2-(4-methyl-imidazol-1-yl)-5-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-phenol (60.4 mg, 0.15 mmol), iodoethane (15 uL, 0.18 mmol) in acetonitrile (1.5 mL). The reaction was refluxed over night and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (9:1:0.1 v/v/v) as eluent to yield the title compound (29 mg, 45%) as a beige solid. MS ISP (m/e): 459.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.39 (s, 1H), 9.31 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.34 (d, 1H), 7.29 (t, 2H), 7.14-7.21 (m, 3H), 6.82 (d, 1H), 4.18 (q, 2H), 3.99 (m, 1H), 3.59 (dq, 1H), 3.50 (dq, 1H), 2.64-2.82 (m, 2H), 2.34 (s, 3H), 2.17 (m, 1H), 1.90 (m, 1H), 1.76 (m, 2H), 1.43 (t, 3H), 1.14 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]=[C:13]2[O:27][CH3:29])=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione with sodium bicarbonate and dimethyl sulphate in acetone there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H) -pyrimidinone, m.p. 69°-71° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14](C(OC)=O)[N:13]([CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:21]1COCC1.C[Mg]Br.C([O:31][CH2:32][CH3:33])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([C:32]([OH:31])([CH3:33])[CH3:21])[N:13]([CH3:20])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: Cn1nc(Nc2cc(Cl)nn(C)c2=O)cc1C(C)(C)O
Temperature: -25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottom flask containing 119b (500 mg, 1.7 mmol) under nitrogen was added anh. THF (20 mL) and anh.toluene (5 mL) and the mixture stirred and cooled to −20 to −30° C. 3.0M methylmagnesium bromide in diethylether (1.6 mL, 4.75 mmol) was then slowly added. After the addition the reaction was allowed to slowly warm to room temp. and stir for about 3 hrs after which the reaction was quenched with 1N HCl. Concentrated to remove THF, diluted with ethyl acetate and water then adjusted the pH to ˜6-7 with 1M NaOH. Separated and extracted 2× with ethyl acetate washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography: ISCO 24 g silica, ethyl acetate/hexanes, to give 119c.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1CCCc2c(O)cccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1cccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pyridine (180 ml) solution of 5-hydroxy-1-tetralone (30.0 g), 4-dimethylaminopyridine (1.13 g) was added, and pivaloyl chloride (25.0 ml) was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was ice-cooled, and a concentrated hydrochloric acid was added thereto, followed by extracting with ethyl acetate. The extract was washed with water and saturated saline in this order, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 5:1) to thereby obtain the title compound (45.4 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([OH:7])=O.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:3][C:2]=1[Br:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)cc1Br
Temperature: 30 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of Intermediate 15 (100 g, 0.303 mol, 1.0 eq) and 4-aminopyridine (28.5 g, 0.303 mol, 1.0 eq) in DMA (1 L) was added Et3N (30.6 g, 0.303 mol, 1.0 eq), DMAP (3.7 g, 0.030 mol, 0.1 eq) and HATU (115.2 g, 0.303 mol, 1.0 eq). The reaction solution was stirred at 30° C. for 16 hrs. Solvent was evaporated under vacuum and the residue was solidified by adding DCM (600 ml) and H2O (600 ml) to give the title compound (86.1 g, 70% yield).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([OH:24])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].IC.[CH3:28]N1CCCN(C)C1=O>C1COCC1>[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([O:24][CH3:28])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CN1CCCN(C)C1=O
Reactant: COC(=O)CCc1cc(I)c(O)cc1CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)CCc1cc(I)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
A suspension of 60% sodium hydride in mineral (1.2 g) in THF (56 ml) is cooled to -20° C. and of solution of methyl 2-tert-butyldimethylsilyloxymethyl-4-hydroxy-5-iodohydrocinnamate (12.6 g), iodomethane (5 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (8 ml) in THF (20 ml) is added. The cold bath is removed, the mixture stirred for about 2 hours, and diluted with ether. The ether solution is washed with 0.1M HCl, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% ether in hexanes, to give the desired product.