Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].N12CCCN=C1CCCCC2.[NH2:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[NH:30][C:31]2[CH:47]=[CH:46][C:34]([O:35][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=3)=[CH:33][CH:32]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide (45 g, 0.1319 mol) was refluxed in N,N-dimethyl formamide (100 ml) with 1,8-diazabicyclo[5.4.0]undec-7-ene (24.67 ml, 0.1649 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (32.07 g, 0.1319 mol) for 24 hours and cooled to room temperature. The reaction mass was quenched in water (1000 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water to remove DMF traces. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (1000 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (52 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH2:12][Cl:11])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: OCCCl
Reactant: Oc1cccc2[nH]ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydrofuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3×100 ml) and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine, (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]2=[N:21][O:20][N:19]=[C:18]2[CH:22]=1)[CH3:2]
Reactant: Oc1ccc2nonc2c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Temperature: 90 °C
Yield: 26.2 %

Procedure:
A mixture of 5.5 g (29.4 mmol) 2-chloro nicotinic acid ethyl ester, 4.0 g (29.4 mmol) 5-hydroxybenzofurazan and 20.1 g (61.7 mmol) cesium carbonate in 125 ml dry dimethylformamide was heated at 90° C. for five days. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined; washed successively with sodium bicarbonate solution, water, and brine; then dried (Na2SO4); and concentrated in vacuo to give a solid. Recrystallization from diethyl ether/pentane gave 2.2 g (26%) solid.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[C:16]([O-])([O-])(OCC)[CH3:17]>CCCCCC>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([C:16]([CH3:17])=[N:2][N:1]=3)[N:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1ncc(-c2ccc(F)cc2)nn1
Solvent: CCCCCC
Product: Cc1nnc2ncc(-c3ccc(F)cc3)nn12

Procedure:
A mixture of 3.09 g. of 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine and 35 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled, poured into hexane and the solid is collected, and washed with ethanol giving the desired product as a brown solid, m.p. 147°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH:19]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[C:20]([NH2:22])=[NH:21].[OH-].[Na+]>CO.O>[N:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][C:23]=1[N:19]=[C:20]1[NH:22][C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:22][C:20](=[N:19][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[NH:21][C:10]2([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:21]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccc(F)cc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 4,4'-difluorobenzil (1.0 g, 4.06 mmol) and 2-guanidinobenzimidazole (0.6 g, 3.4 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (750 mg, 79% yield). MS (ESI) m/z 561 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:18].[C:19](OC)(OC)(OC)[CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCl
Yield: 60.5 %

Procedure:
Using the general method of Example 1 Part D, N4-(5-chloropentyl)quinoline-3,4-diamine (˜20.4 mmol) was cyclized using trimethyl orthobutyrate (3.6 g, 24.5 mmol) in the presence of pyridine hydrochloride (˜0.1 g). The crude product was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 3.9 g of 1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a light green solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)/[C:12](=[N:19]/[NH:20][C:21]([O:23]C(C)(C)C)=O)/[C:11](C(OCC)=O)=[CH:10]2)=[N:6][CH:7]=1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][NH:20][C:21](=[O:23])[C:11]3=[CH:10]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Br)cn2)c2ccccc2/c1=N/NC(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(Br)cn3)cc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl (4Z)-1-[(5-bromopyridin-2-yl)methyl]-4-[(tert-butoxycarbonyl)hydrazono]-1,4-dihydroquinoline-3-carboxylate (2.86 g, 5.70 mmol) was dissolved in toluene (30 mL), treated with hydrochloric acid (0.950 mL, 12 N aqueous, 11 mmol, 2 equiv) and placed into an oil bath preheated to 100° C. for 3 hours. The mixture was cooled to ambient temperature. The mixture was filtered and the yellow solid was collected and washed with toluene (2×10 mL), providing the titled compound.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C.O>[C:26]1([N:32]2[C:10]3[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[CH:4]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cnn2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (Step A, 2.1 g, 8.3 mmol) was dissolved in 100 mL methanol, and water (50 mL) was added followed by the addition of sodium carbonate (0.53 g, 5.0 mmol) and phenyl hydrazine hydrochloride (1.43 g, 9.9 mmol). Finally, acetic acid (1 mL) was added and the resulting mixture was stirred at rt for 1 h. The mixture was made basic by adding saturated aq. sodium bicarbonate (ca. 20 mL) and the methanol was removed on a rotary evaporator. The resulting mixture was extracted with methylene chloride (3×40 mL) and the combined extracts were dried over anhyd. sodium sulfate, filtered, and concentrated to afford the crude product. Purification by flash chromatography on silica gel using 20% ethyl acetate in hexanes as the eluant afforded fractions containing the desired product. Concentration of the combined fractions afforded the desired product b as a yellow oil (1.63 g, 66%). 1H NMR (400 MHz, d3-MeOD): δ 7.73 (s, 1H), 7.60-7.47 (m, 5H), 4.37 (s, 2H), 3.57 (t, J=6.1 Hz, 2H), 3.17 (t, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:9])(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:25])=[O:26])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])(=[O:3])[CH3:2]
Reactant: CCCCCN(CCOC(C)=O)C(=O)C(CCC(=O)OCc1ccccc1)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCN(CCOC(C)=O)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 47.3 %

Procedure:
To a solution of benzyl 4-[N-(2-acetoxyethyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoate (0.40 g) in acetic acid (5 ml) was added 10% Pd-C (0.05 g), and the mixture was hydrogenolyzed at atmospheric pressure and ambient temperature for 48 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (10:1) to give 0.16 g of 4-[N-(2-acetoxyethyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid as oil. ##STR28##
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.S(=O)(=O)(O)O.[F:17][C:18](I)([F:20])[F:19].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:18]([F:20])([F:19])[F:17]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(N)c(C(F)(F)F)c(=O)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
0.16 g (1.0 mmol) of 6-amino-1,3-dimethyluracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 6-amino-1,3-dimethyl-5-trifluoromethyluracil (19F-NMR yield: 95%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 6-Amino-1,3-dimethyl-5-trifluoromethyluracil was obtained as a white solid (0.20 g, yield: 95%) by column chromatography.
Reaction SMILES: OC(C1C=C2C(=CC=1)C=C(C(OC)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[OH:44][C:45]([C:73]1[CH:74]=[C:75]2[C:80](=[CH:81][CH:82]=1)[CH:79]=[C:78]([C:83](O)=[O:84])[CH:77]=[CH:76]2)([C:49]1[N:50]=[CH:51][N:52](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:53]=1)[CH:46]([CH3:48])[CH3:47].Cl.[CH:87]([O:90][NH2:91])([CH3:89])[CH3:88]>>[OH:44][C:45]([C:73]1[CH:74]=[C:75]2[C:76](=[CH:81][CH:82]=1)[CH:77]=[C:78]([C:83]([NH:91][O:90][CH:87]([CH3:89])[CH3:88])=[O:84])[CH:79]=[CH:80]2)([C:49]1[N:50]=[CH:51][NH:52][CH:53]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)ON
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: Cl
Product: CC(C)ONC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.77 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with O-isopropylhydroxylamine hydrochloride (420 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.46 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH2:12]([O:14][C:15](=[O:23])[C:16](=[CH:19]OCC)[C:17]#[N:18])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:23])[C:16]([C:17]#[N:18])=[CH:19][NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:13]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
3,4-dimethoxyaniline (30.6 g, 200 mmol) was diluted with toluene (80 mL) and to the resultant solution was added ethyl(ethoxymethylene)cyanoacetate (33.8 g, 200 mmol). The resultant reaction was heated to 100° C. and allowed to stir at for 1 hour, then heated to 125° C. and allowed to stir for 15 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo to provide a crude residue, which was recrystallized from EtOAc to provide 2-cyano-3-(3,4-dimethoxyphenylamino)acrylic acid ethyl ester as a tan solid (40.0 g, 72%). mp 166-170° C.; MS (ES+) m/z 277.2 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:3].[H][H]>O=[Pt]=O.C(O)C>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:1]
Reactant: CN(C)CC1C=C(c2ccc(Cl)cc2)c2ccccc2O1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)CC1CC(c2ccc(Cl)cc2)c2ccccc2O1
Yield: 55.2 %

Procedure:
2-(N,N-Dimethylaminomethyl)-4-(4'-chlorophenyl)-3-chromene (0.36 g) and Adams catalyst (PtO2) (5 mg) in ethanol (30 ml) was hydrogenated at atmospheric pressure. When hydrogen uptake was complete (4 hours) the catalyst was removed by filtration and the solution evaporated to give an oil which was chromatographed on alumina using chloroform as eluant. The eluate was evaporated to give, after trituration with petroleum ether (40°/60°) the title compound (200 mg) as a white solid, mp 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc2nc(N3CCN(C)CC3)oc12

Procedure:
5-Chloro-7-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (0.55 ml) was added dropwise to the solution and then the mixture was stirred with heating for 3 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-7-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (270 mg).
Reaction SMILES: [C:1]([O:4][OH:5])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:12][CH:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15]>O.CCOCC.C(Cl)(Cl)Cl>[Cl:12][CH:13]([CH2:17][CH3:18])[C:14]([O:5][O:4][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCC(Cl)C(=O)OOC(C)=O
Temperature: -3 °C
Yield: 49.5 %

Procedure:
To 9.5 g. (0.05 moles) of 40% peracetic acid in 20 cc. H2O was added 3.2 g. (0.03 moles) of anhydrous sodium carbonate. The mixture was chilled to -3° C. with stirring and 7.1 g. (0.05 moles) of 2-chlorobutyryl chloride in 30 cc. chloroform added over a period of 8 minutes. After a total of 40 minutes at -3° to -6° C., ether and water were added. The organic phase was separated, washed once with cold 1% KOH solution, once with ice water, and once with cold saturated salt water. The concentrated material weighed 8.2 g., including 2.0 g. of dimethyl phthlate. Product A.O. analysis: theory, 8.14 found, 4.81; 59.1% pure; 49.5% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][OH:11])=[CH:4][C:3]=1[O:12][CH3:13].[H-].[Na+].I[CH3:17]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:17])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OC)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under cooling in an ice water bath, to a solution of (4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide (960 mL) was added sodium hydride (60% oily; 24.7 g), and the mixture was stirred for 10 minutes. To this iodomethane (41.7 mL) was dropped. Thereafter, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (2.5 L), and extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate (4:1), 121.3 g of a title compound was obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cccc(Br)n1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of 2-bromo-6-methylpyridine (302 mg, 1.76 mmol) an 10 mL THF at −78° C., was added a solution of lithium diisopropylamide (1.8 M in heptane/THF/ethylbenzene, 1.07 mL, 1.93 mmol). The bright orange/red mixture was treated with iodomethane (0.20 mL, 3.2 mmol). The mixture was stirred at −78° C. for 10 min, then was removed from the ice bath and stirred 30 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford 157 mg of Intermediate 163.1 as a colorless oil. LCMS (2 min gradient) RT=1.26 min, 186.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[C:43]([O:51][C:52](=[O:54])[CH3:53])=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45](O)=[O:46])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[C:43]([O:51][C:52](=[O:54])[CH3:53])=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[O:46])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(N4CCOCC4)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
4-Morpholinoaniline (0.214 g, 1.203 mmol), triethylamine (0.122 g, 1.203 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.203 g, 1.203 mmol) were added to a methylene chloride solution (40 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.150 g, 0.401 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.109 g, 0.203 mmol, 51%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)COCCOCCO
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A suspension of tert-butyl 3-(2-(2-(benzyloxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (48) (13 g, 37 mmol) and 10% Pd/C (1.3 g) in EtOH (92 mL) were placed under 5 bar of H2 pressure (isolated system), and stirred for 16 h. The mixture was filtered through celite and the filtrate concentrated in vacuo to afford tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)-2,2-dimethylpropanoate (49) (8.2 g, 85%) as a colourless oil: m/z 285 (M+Na)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 3.73-3.69 (m, 2H), 3.66-3.58 (m, 6H), 3.44 (s, 2H), 2.37 (t, J=6.2 Hz, 1H), 1.43 (s, 9H), 1.14 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:20])C>S(=O)(=O)(O)O>[OH:20][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC(F)(F)C(F)F)cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2,3-dimethyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine-1-oxide (2.6 g) in acetic anhydride (8 ml), concentrated sulfuric acid (2 drops) was added; and the solution was stirred at 110° C. for 4 hours and then concentrated. The resulting residue was dissolved in methanol (20 ml) and a solution of sodium hydroxide (1.2 g) in water (5 ml) was added, after which the mixture was stirred at room temperature for 30 minutes. After concentration, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was evaporated, after which the resulting residue was applied on a silica gel (50 g) column, eluted with chloroform-methanol (10:1) and then recrystallized from isopropyl ether to give 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3-tetrafluoropropoxy)pyridine as yellow crystals (melting points: 67°~68° C.).