Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:9][C:10]1[CH:25]=[CH:24][C:13]2[CH:14](O)[C:15]3[C:16]([CH:21]=[CH:22][C:12]=2[CH:11]=1)=[N:17][CH:18]=[CH:19][CH:20]=3>C(O)(=O)C>[CH3:9][C:10]1[CH:25]=[CH:24][C:13]2[CH:14]([C:7]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=3)[C:15]3[C:16]([CH:21]=[CH:22][C:12]=2[CH:11]=1)=[N:17][CH:18]=[CH:19][CH:20]=3
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2O
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of uracil (1.87 g) and the product of step (iii) (3.73 g) in glacial acetic acid (30 ml) was heated at 120° C. under nitrogen for 40 hr. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated. sodium bicarbonate solution. The organic phase was separated, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 0-20% methanol in ethyl acetate.
Reaction SMILES: C([Li])CCC.Br[CH:7](Br)[CH2:8][C:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[C:32](=[O:34])=[O:33].Cl>CCCCCC.C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]=[C:10]([CH:28]([CH3:29])[CH3:30])[C:9]=2[C:8]#[C:7][C:32]([OH:34])=[O:33])=[CH:16][CH:17]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CC(Br)Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C#CC(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
30.3 ml (48.4 mmol) of a 1.6M solution of n-butyllithium in hexane were added dropwise at -70° C. to a solution of 11.5 g (24.2 mmol) of 1,1-dibromo-2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethane (Example 1a) in 70 ml of THF. The resulting solution was stirred at -70° C. for 1 h and then at room temperature for 1 h and subsequently cooled to -60° C. 10.7 g (242 mmol) of crushed dry ice were added and then the reaction mixture was slowly brought to room temperature, hydrolyzed on ice-water, acidified with dilute hydrochloric acid and extracted several times with ether. The combined organic phases were washed with saturated NaCl solution, dried over MgSO4 and evaporated. The residue was 11.0 g of the title compound which was reacted further without purification. For analytical purposes, a small amount of the crude product was purified on silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O>CCO>[N+:33]([C:29]1[CH:28]=[C:27]([C:25]2[NH:1][C:2]3[N:6]([CH:24]=2)[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=2)[C:3]=3[C:20]([NH2:22])=[O:21])[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc([N+](=O)[O-])c3)[nH]c12
Temperature: 80 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (29.4 mg, 0.1 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (24.4 mg, 0.1 mmol) in EtOH (2 mL) was stirred at 80° C. for 16 hr. The mixture was filtered to afford 5 mg of crude 2-(3-nitrophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 440.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19](O)[C@H:18]([F:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:18]([F:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Cl)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-6 using 6-chloropyridin-3-ol and cis(±)tert-butyl-3-fluoro-4-hydroxypiperidine-1-carboxylate; MS: 353.2 (M+23).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Yield: 111.9 %

Procedure:
A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (2.0 g, 7.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)propyl bromide (1.58 g, 8.1 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 3.16 grams of a semi-solid material. The crude material was firther purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 1:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 2.21 grams (78%) of a viscous yellow oil.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][CH:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.CN(C)C=O>[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: C[Si](C)(C)C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 1-bromo-3-(trimethylsilyl)-2-propyne (2.87 g., 15.0 mmol) prepared according to methods of Corey, Tet. Lett., 3963 (1973) and Miller, Syn. Comun., 2, 267 (1972) in 50 ml. of dimethylformamide is added to a mixture of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate (2.9 g., 7.65 mmol) and powdered potassium carbonate (2.65 g., 19.2 mmol) under an argon atmosphere. After stirring at 60° for a period of 2 hr. and cooling to room temperature, ether is added to the reaction mixture followed by dilute hydrochloric acid. The acidified solution is extracted with ether and the ethereal extract sequentially washed with water and brine, and then dried over magnesium sulfate. Removal of solvent under reduced pressure affords 4.72 g. of tan solid. Crystallization of this material from cyclohexane provides 3.26 g., (87% yield) of ethyl [6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate, m.p. 111.5°-113° (corr.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:19])(=[O:30])=[O:29])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: Cc1cc(C)c(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)c(C)c1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2,4,6-trimethylbenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-fluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 9-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzdiazepine is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:14]([C@@H:13]2[CH2:17][C@@H:18]([O:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:26][CH:25]=2)=[O:11])=[O:15])[CH2:32][CH2:31]1
Reactant: OCCN1CCNCC1
Reactant: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
343 mg of N,N'-carbonyldiimidazole were added to a solution of 674 mg of trans-1(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline in 14 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 275 mg of 1-(2-hydroxyethyl)piperazine in 1 ml of dry acetonitrile was then added to the mixture, and the mixture was stirred overnight at room temperature. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was mixed with an aqueous solution of sodium chloride. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 574 mg of (2S,4R)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-trimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine as an oil. The whole of the compound thus obtained was dissolved in 5.7 ml of methylene chloride, and 170 mg of 4-dimethylaminopyridine and 300 mg of 4-nitrobenzyl chloroformate were added to the solution, whilst ice-cooling. The resulting mixture was stirred at room temperature for 1 hour and then the solvent was removed by distillation under reduced pressure. 15 ml of 1N aqueous hydrochloric acid were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then made slightly alkaline by the addition of an aqueous solution of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. Following the procedure described in step 90(b)(i') above, the residue was purified to give 348 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(i) above.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][OH:18].Cl.C(O)(=O)C>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][OH:18])[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)C[N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(C[N+](=O)[O-])=NO)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-methanesulfonyl-phenyl)-2-nitro-ethanone (12.5 g, 51.4 mmol) in ethanol (100 mL), was added NH2OH.HCl (3.57 g, 51.4 mmol) and acetic acid (33 mL) at room temperature. The reaction was refluxed for 3 h and cooled to room temperature. The reaction was concentrated under vacuum and extracted with ethyl acetate (200 mL). The reaction was concentrated to afford the crude compound which was recrystallized from petroleum ether/hexane (1/3) as white crystals (10.3 g, 83.4%). 1H NMR (400 Mz, DMSO-d6) δ 12.81 (s, 1H), 8.03 (m, 4H), 5.93 (s, 2H), 3.28 (s, 3H). LCMS 259.2[M+H].
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([F:11])[CH:4]=1)#[N:2].[CH2:12](O)[CH2:13][CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:8]1[CH2:12][CH2:13][CH2:14][O:15][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2OCCCO2)c(F)c1
Reaction time: 6 h

Procedure:
4-Cyano-2-fluorobenzaldehyde (65 g, 436 mmol) and 1,3-propanediol (36.5 g, 479 mmol; 1.1 eq.) were, together with 4-toluenesulfonic acid monohydrate (1.66 g, 8.72 mmol; 0.02 eq.), initially charged in toluene (1000 ml) and stirred at boiling point on a water separator for 6 h. The reaction mixture was then washed with saturated sodium bicarbonate solution (3×300 ml) and saturated sodium chloride solution (3×300 ml). The organic phase was dried over sodium sulfate and concentrated. The title compound was obtained as a solid (92 g, quant.).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[Na].[CH3:9][O:10][C:11](Cl)=[O:12]>C1C=CC=CC=1>[CH3:9][O:10][C:11]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])=[O:12]
Reactant: O=C1CCC(=O)N1
Reactant: COC(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: COC(=O)N1C(=O)CCC1=O

Procedure:
Repeating the aforedescribed procedure in the absence of benzene solvent for the sodium succinimide-methylchloroformate reaction yields similar results.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.2 g, 24 mmol), TEA (5 mL) in dry DCM (50 mL) at 0° C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (8.4 g, 23 mmol) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of N-[[2-fluoro-5-(3-fluorophenyl)phenyl]methyl]-3-methoxy-aniline (512 mg, 1.60 mmol, 1.0 eq) in CH2Cl2 (10 mL) at −70° C. was added BBr3 (0.6 mL, 65.3 mmol, 40.8 eq). The reaction was warmed to room temperature and stirred for 1 h. The reaction was then cooled to 0° C. and quenched by addition of water. The pH of the solution was adjusted to pH 7 with aqueous Na2CO3, then extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (460 mg, 94%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:39].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:39][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.36 g), ammonium acetate (1.33 g) and acetic acid (15 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (4 mL), tetrahydrofuran (8 mL) and methanol (8 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.43 g, yield 33%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 487 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)[CH:22]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:25]1[C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][C:23]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1noc(-c2cc(Cl)ccc2C=O)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc(Cl)ccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (11 mg, 0.043 mmol) and 4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (10 mg, 0.045 mmol) in DMF (5.0 mL) is added Oxone (27 mg, 0.044 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (10 mg, 50%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH:11]=[CH:12][CH:13]([CH3:15])[CH3:14].[H][H].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:16])[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
Undernitrogen, 2.8 g of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone was dissolved in ethyl acetate and 0.14 g of 5% palladium/carbon was added thereto. The nitrogen in the reaction vessel was substituted by hydrogen and the reaction mixture was stirred at room temperature for 5 hours. After that, the reaction mixture was filtered through a Celite pad and the Celite pad was washed with 50 ml of ethyl acetate. The solution combined the filtrate with the washing solution was washed with 0.1% hydrochloric acid once, water twice and saturated brine once, subsequently. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to give 2.68 g of 4-hydroxy-6-methyl-3-(4-methylpentanoyl)-2-pyrone.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12])[CH3:6]>ClCCCl>[CH2:17]([O:16][C:15]1[C:8]([O:7][CH2:5][CH3:6])=[CH:9][C:10]([CH:11]=[O:12])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C=O)cc1OCC
Solvent: ClCCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCC
Temperature: 0 °C

Procedure:
2.13 ml of fuming nitric acid were added within 30 minutes to a solution, cooled to −30° C of 10 g of 3,4-diethoxybenzaldehyde in 185 ml of 1,2-dichloroethane. Subsequently, the reaction mixture was left to warm to 0° C. and was poured on to ice. The product was isolated by extraction. There were obtained 12.06 g of 4,5-diethoxy-2-nitro-benzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[CH:5][CH:4](CO)[CH2:3]1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(N(CC)CC)C>[C:10]([O:13][CH:4]1[CH:5]=[CH:6][CH2:7][N:2]([CH3:1])[CH2:3]1)(=[O:12])[CH3:11]
Reactant: CN1CC=CC(CO)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1C=CCN(C)C1

Procedure:
A solution of (1-methyl-1,2,3,6-tetrahydro-3-pyridyl)methanol (0.7 g, 5.5 mmol), triethylamine (25 ml), and acetic anhydride (20 ml) was refluxed for 2h. The reaction mixture was extracted with methylene chloride and pH was adjusted to 10 with aqueous sodium hydroxide. The solution was extracted with methylene chloride, which was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified on a silica gel column (Eluent: methanol/methylene chloride (1/9)) to give 1-methyl-1,2,3,6-tetrahydropyridin-3-yl acetate as an oil (Yield: 0.69 9, 70%).