Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:3]1[C:2]([Cl:1])=[C:7]([C:8]#[N:9])[C:6](=[C:5]([Cl:12])[C:4]=1[Cl:13])[C:10]#[N:11]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2-c2ccccc2)c(Cl)c1C#N

Procedure:
To a 250 mL flask, 4.8 g of tetrachlorophthalonitrile, 4.3 g of biphenyl-2-ol, 5 g of potassium carbonate (K2CO3) and 55 mL of acetonitrile are added, followed by heating for 12 hours while refluxing. After completion of the reaction, 30 mL of ethyl acetate is added and filtered to remove the solvent. To the obtained solid, a suitable amount of dichloromethane is added to dissolve the solid, followed by adding hexane for crystallization. The obtained solid is filtered and dried under vacuum to obtain a compound, 4-[(biphenyl-2-yl)oxy]-3,5,6-trichlorophthalonitrile. The second step reaction may be represented by Reaction Scheme 2:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C1COCC1.[Ni]>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CN2CCCCC2)cc1

Procedure:
To a solution of 0.22 g (1.0 mmol, 1.0 eq.) of 1-(4-nitrobenzyl)piperidine (I-27) in 20 mL of THF was added ˜30 mg of Raney Nickel. The reaction mixture was stirred under at room temperature under 1 atm. of hydrogen for 12 h. The reaction mixture was through Celite® and the solvent removed in vacuo to provide 4-(piperidin-1-ylmethyl)benzenamine (I-28).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].C(Cl)(Cl)Cl>CO>[CH:3](=[N:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[OH:4])[C:5]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:11]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@H](N)Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To millimols) suspension of 0.43 g. (1.4 millimoles of bis(salicylaldehydate)copper in 10 ml. methanol was added dropwise a solution of 1.1 g. (3.0 millimols) of (R)-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol {[α]D +42.3° (c 1.1, chloroform)} in 10 ml. of methanol. The addition was carried out under thorough stirring at room temperature. The period of the addition was one hour and the reaction mixture was stirred for another one hour. The resulting solids were collected by filtration, washed with methanol and dried under reduced pressure to give a mononuclear complex of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol as grayish blue crystals. Yield, 0.75 g. (58%), [α]546, +860° (c 0.065, benzene), melting point: 205° - 206° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:16][CH2:15][C:14]([F:21])([F:13])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Temperature: 75 °C
Reaction time: 108 h

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and imethylphosphoric acid triamide (2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization from ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20](=O)[CH:21]=[O:22]>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:20]/[CH:21]=[O:22])=[CH:5][CH:4]=1
Reactant: O=CC=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C/C=N/Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 4-fluorophenylhydrazine hydrochloride (1 g, 6 mmol) in THF (20 mL) is treated with DIPEA (3 mL, 18 mmol). Then oxalaldehyde (40% in water, 0.89 g, 6.0 mmol) in THF (10 mL) is added dropwise in an ice-bath. After the addition, the mixture is stirred at RT for 30 min, quenched with water, and extracted with EtOAc. The organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated to afford the crude title compound (0.97 g, 97% yield). MS (m/z): 167 (M+H).
Reaction SMILES: COC([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:9][CH2:8][C:7]2([CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]2)[C:6]1=[O:17])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH:5]2[CH2:9][CH2:8][C:7]3([CH2:10][O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14]3)[C:6]2=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC2(COC(C)(C)OC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1(C)OCC2(CCC(Cc3ccc(Cl)cc3)C2=O)CO1
Temperature: 25 °C

Procedure:
After adding toluene (1 mL) in 2-(4-chlorobenzyl)-8,8-dimethyl-1-oxo-7,9-dioxaspiro[4.5]decane-2-carboxylic acid methyl ester (10.0 g, 0.0273 mol), the mixture was suspended in a 0.5 M sodium hydroxide solution (27.3 mL, 0.0273 mol×0.5 mol) and reacted at 110° C. The reaction was continued by adding a 0.5 M sodium hydroxide solution (27.3 mL, 0.0273 mol×0.5 mol) every 2 hours (for three times total), and heating and stirring were performed for total of 9 hours. Following the completion of the reaction, the mixture was allowed to cool to room temperature and then subjected to extraction using toluene. The organic layer was washed with saturated brine solution, and then dried using anhydrous sodium sulfate. Thereafter, the dried product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5]Br.[C:7]12([C:17]([OH:19])=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>>[Br:5][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:17]([OH:19])=[O:18])([CH2:14]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A two-neck round bottom flask was connected to a reflux condenser, to which aluminum chloride (AlCl3, 7.15 mmol) was injected, followed by cooling at −5° C. in argon environment. Then, bromine (Br2, 66 mmol) was added thereto, followed by stirring for 15 minutes. 1-adamantanecarboxylic acid (5.5 mmol) was added to the reaction mixture at a time, followed by stirring for 1 hour with maintaining the temperature at −5° C. The reaction mixture was then additionally stirred for 48 hours with raising the temperature slowly to room temperature. Upon completion of stirring, ice water was poured to the mixture to terminate the reaction. Excessive bromine was de-colored by adding sodium pyrosulfite. The de-colored reactant was extracted by using chloroform. The extracted organic layer was dried over sodium sulfate, followed by concentration under reduced pressure to give the target compound (5.016 mmol, 92.83%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (1.6 M, 101 mL) was added dropwise to stirring anhydrous tert-butanol (200 mL) under nitrogen in a room temperature water bath. After 0.5 hours, 4-chloro-3-nitrobenzoyl chloride (10.0 g) was added, and the dark solution was stirred for 1.5 hours at room temperature. The reaction was evaporated under vacuum, and the residue was crystallized from hexane to yield the title compound as an orange solid. Mp: 66°-67° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O.[Pd]>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)s1
Yield: 96.1 %

Procedure:
A mixture of 5-bromo-thiophene-2-carbaldehyde (2.0 g, 10.5 mmol), phenylboronic acid (1.7 g, 11 mmol), K2CO3 (8.7 g, 62.8 mmol) and 10% Pd/C (0.56 g) in isopropanol/H2O (1:1, 40 mL) was refluxed for 5 h. The reaction mixture was filtered through a pad of Celite. After the isopropanol was removed, the product was collected on a filter, washed with hexane and dried in vacuo to yield the title compound (1.9 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:14]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)cccc1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of 2,6-difluorobenzoic acid (1.58 g, 10.0 mmol) and SOCl2 (1.1 ml, 15 mmol) were refluxed at 80° C. for 1 hr. Two drops of DMF were added and reflux continued for 15 min. to dissolve any remaining solid. Excess SOCl2 was evaporated in vacuo to give 2,6-difluorobenzoyl chloride as a light yellow oil.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:20][CH:21]=1
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1

Procedure:
A 50% aqueous solution of hydroxylamine (13.25 mL, 225 mmol) was added at once into a solution of tert-butyl N-(4-cyanobenzyl)-N-methylglycinate (11.70 g, 45 mmol) in EtOH (75 mL).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:14]3OCC[O:15]3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(#N)C>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Sc2cccc(C3OCCO3)c2)cc1
Agent: Cl
Solvent: CC#N
Product: O=Cc1cccc(Sc2ccccc2)c1
Reaction time: 18 h

Procedure:
Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (0.3 g, 1.1 mmol) and acetonitrile (8.0 ml) add a solution of hydrochloric acid (1N, 2.0 ml). After 18 hours, concentrate in vacuum to remove most of the acetonitrile, dilute with water and extract with ether. Combine the organic extracts and wash once with saturated sodium bicarbonate, then with brine. Dry (Na2SO4) the organics, filter, and concentrated to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=O)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CCOC(C)=O.Cl>C(Cl)Cl.CO>[CH3:11][C:9]1[S:10][C:6]([CH2:4][OH:3])=[C:7]([CH3:12])[N:8]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(C)c(CO)s1
Temperature: -78 °C
Reaction time: 14 h

Procedure:
A 3-neck 100 mL round-bottom flask under N2 atmosphere was charged with ethyl-2,4-dimethylthiazole-5-carboxylate (1.85 g, 10 mmol ) in anhydrous CH2Cl2 (20 mL). The mixture was cooled to −78° C. 22 mL of di-isobutylaluminum hydride (1.0 M in CH2Cl2) was added dropwise via syringe. The reaction was allowed to warm to room temperature slowly and stirred for 14 h. TLC (1:1 Hexane/EtOAc) showed no starting material. The reaction was cooled to 0° C. MeOH(2 mL) and then 1 M HCl (10 mL) were slowly added. The bath was removed and the reaction stirred for 20 min. Extract with Et2O (3×10 mL). Wash the combined organic layers with brine (10 mL). Dry over MgSO4, filter and remove solvent under vacuum. Yield: 1.363 g (95%), orange oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](OCC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(CO)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
A solution of ethyl 2,4-dimethyl-1,3-thiazole-5-carboxylate (5.0 g) in THF (50 ml) was added dropwise to a solution of aluminum lithium hydride (1.1 g) in THF (150 ml) under ice-cooling. After stirred at room temperature for 4 hours, water (1.1 ml), 15% sodium hydroxide solution (1.1 ml) and water (3.3 ml) were added thereto, and the mixture was stirred for 10 minutes. The mixture was filtered with Celite, and washed with methanol. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/2) to give (2,4-dimethyl-1,3-thiazol-5-yl)methanol (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([Cl:10])=[CH:4][N:3]=1.C[N+](C)(C)C.COP(C)(=O)O>P(OC)(OC)(OC)=O.[Zn]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)c(Cl)c1Cl
Agent: COP(C)(=O)O
Agent: C[N+](C)(C)C
Agent: [Zn]
Solvent: COP(=O)(OC)OC
Product: Clc1cnc(Cl)c(Cl)c1
Yield: 77.8 %

Procedure:
By the method described in Example 1, 11.0 g (0.05 mol) of 2,3,4,5-tetrachloropyridine, 4.4 g (0.065 gram atom) of zinc dust (96.5%) and 24.7 g (0.135 mol) of the tetramethylammonium salt of methanephosphonic acid monomethyl ester in 90 ml of trimethyl phosphate are reacted to obtain 7.1 g (78% of theory) of 2,3,5-trichloropyridine, m.p. 47°-47.5° C., which contains, according to gas-chromatographical analysis, 97.6% of 2,3,5-trichloropyridine, 0.4% of 2,3,4,5-tetrachloropyridine and 1.4% of unknown products.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(O)C>[CH2:18]([NH:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NCc1ccccc1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10 mmol) in iPrOH (40 mL) and DIPEA (1.55 g, 12 mmol) was added a solution of benzylamine (1.28 g, 12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.5 g, yield: 68%) as a white solid. H NMR (300 MHz, CDCl3) δ 8.35 (br s, 1H), 7.20-7.38 (m, 5H), 6.35 (s, 1H), 4.52 (s, 2H); MS (ESI): 220 [M+H]+.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C([O-])(O)=O.[Na+]>[C:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a suspension of morphine (0.5 g, 1.75 mmol) in saturated NaHCO3 solution (25 mL), acetic anhydride (0.5 mL, 5.25 mmol) was added dropwise and allowed to stir for 3 hours. Progress of the reaction was monitored by TLC and after the completion; reaction mixture was extracted 6 times with dichloromethane. Dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get solid 3-acetylmorphine. 0.34 g (59% yield). GC-MS, 1H and 13C NMR confirmed the structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc2nccn12
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
To a chilled solution of 5-chlorothiophene-2-carboxylic acid (0.16 g, 1.0 mmol) in EtOAc (3 mL) and DMF (1 drop) was added neat oxalyl chloride (92 μL, 1.05 mmol). The reaction mixture was stirred cold for 2 hr and concentrated in vacuo to give crude 5-chlorothiophene-2-carbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A solution of 44.8 g of 1-bromo-4-methoxybenzene in 700 ml of THF is cooled to −78° C., 168 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise and the mixture is then stirred at −78° C. for 30 minutes. The solution of 45.3 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise and the mixture is stirred at −78° C. for 2 hours. The reaction mixture is poured into 400 ml of saturated NH4Cl solution and extracted with ether, the organic phase is washed with water, with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. 48.6 g of the expected product are obtained after crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:24][CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN1CCN(CCCO)CC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 3-(4-methylpiperazin-1-yl)-propan-1-ol. LC/ESI-MS: m/z=351 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[S:11][CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=1)([CH3:9])[CH3:8].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C1COCC1.CCOCC>[OH:16][CH2:15][C:13]1[N:14]=[C:10]([CH:7]([CH3:9])[CH3:8])[S:11][CH:12]=1
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CO)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 10 ml (10 mmol) of lithium aluminum hydride in toluene was diluted in a dry flask under N2 atmosphere with 75 ml of THF. The resulting mixture was cooled to 0° C. and treated dropwise with a solution of 3.96 g (20 mmol) of ethyl 2-isopropyl-4-thiazolecarboxylate in 10 ml of THF. After addition, the solution was stirred at 0° C. for 3 h, diluted with ether, and treated with a small amount of aqueous Rochelle's salt. After stirring, the slurry was filtered, washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 2.18 g (69%) of the desired compound, Rf 0.58 (4% methanol in chloroform). 1H NMR (CDCl3) δ 1.39 (d, J=7 Hz, 6 H), 2.94 (br, 1 H), 3.31 (heptet, J=7 Hz, 1 H), 4.74 (s, 2 H), 7.04 (s, 1 H). Mass spectrum: (M+H)+ =158.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.CS(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Cl)ccnc2cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinoline (WO98/13350A1)(2.0 g, 6.67 mmol) in TFA (13 mL), was added methansulfonic acid (0.95 mL, 13.3 mmol). The mixture was heated to reflux for 3 h. After cooling to RT, the mixture was concentrated in vacuo. The resulting residue was diluted with ice/H2O and neutralized with cold 1N NaOH to a pH of 7. The resulting precipitate was stirred for 1 h at RT, filtered, and dried under high vacuum to give the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 210 (M+1). Mass Calc'd for C10H8ClNO2: 209.0.