Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1>[O:29]=[C:13]1[C:9]2([CH2:12][CH2:11][CH2:10]2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:3][CH:4]=2)[C:15](=[S:16])[N:14]1[C:17]1[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cc1C(F)(F)F
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(Oc4ncccn4)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 50 mg, 0.12 mmol), 2-chloropyrimidine (17 mg, 0.15 mmol), and cesium carbonate (60 mg, 0.18 mmol) in anhydrous THF (1.2 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and water was added. The aqueous was extracted with EtOAc (3×), the organics combined and washed with brine, dried (MgSO4) and concentrated. Purification by column chromatography on silica gel eluting with 0 to 60% EtOAc/hexanes provided 30 mg of 5-(8-oxo-5-(4-(pyrimidin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.78 (d, 1H), 8.73 (d, 2H), 7.48 (dd, 4H), 7.35 (t, 1H), 2.72-2.61 (m, 2H), 2.54-2.42 (m, 2H), 2.10-1.93 (m, 1H), 1.69-1.52 (m, 1H). LCMS [M+1]+ 497.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:30]1([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)[CH:31]=[CH:32][C:33]([NH:36][C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:38])=[CH:34][CH:35]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 513.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:17]([O-])=O)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]>C(O)C.[Pd]>[CH3:20][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN2C(=O)CN(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CCN2C(=O)CN(C)C

Procedure:
A solution of N,N-dimethyl-2-[6-(methyloxy)-5-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (0.16 g, 1.72 mmol) in absolute ethanol (50 mL) was maintained under 45 psi H2(g) with catalytic 10% Pd/C for 12 hours. The catalyst was removed by vacuum filtration through a celite pad and rinsed with methanol. The filtrate was concentrated under reduced pressure and dried under high vacuum to provide 1-[(dimethylamino)acetyl]-6-(methyloxy)-2,3-dihydro-1H-indol-5-amine. This was then carried forward without any further purification. ESIMS (M+H)+=250.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C([CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)C>CN(C)P(N(C)C)(N(C)C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:20]2[CH2:19][CH2:23][CH2:22][CH2:21]2)=[O:32])=[CH:30][CH:29]=1
Reactant: OCCCCCCCCCCCCCCBr
Reactant: CCC1CCCN1C(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(c1ccc(NCCCCCCCCCCCCCCO)cc1)N1CCCC1

Procedure:
A solution of 10 g. of 14-hydroxytetradecyl bromide and 10.8 g. of ethyl 1-(4-aminobenzoyl)pyrrolidine in 75 ml. hexamethylphosphoramide is heated at 110° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed in portions with 100 ml. 50% ethanol-water. After drying the product is crystallized from ethanol to yield 1-[4-(14-hydroxytetradecylamino)benzoyl]pyrrolidine as a white solid.
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH2:7].[CH3:8][C:9]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:10](=O)[CH2:11][C:12]#[N:13].[OH-].[Na+]>O>[CH3:8][C:9]([C:10]1[CH:11]=[C:12]([NH2:13])[O:6][N:7]=1)([CH3:23])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: NO
Reactant: CC(C)(COC1CCCCO1)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(COC1CCCCO1)c1cc(N)on1
Temperature: 25 °C

Procedure:
Hydroxyamine sulfate (0.729 g, 4.439 mmol) is added to a stirred solution of 4,4-dimethyl-3-oxo-5-(tetrahydro-pyran-2-yloxy)-pentanenitrile (2 g, 8.878 mmol) and sodium hydroxide (0.764 g, 19.1 mmol) in water (20 mL). The reaction mixture is stirred at reflux for 18 hours. After this time, the reaction mixture is cooled to room temperature and extracted with ethyl acetate. The organic layers are combined and washed with brine, dried (Na2SO4), filtered and concentrated to yield the title compound, m/z 157 [M+H+−84]. 1H NMR (400 MHz, DMSO-d) δ ppm 1.17 (6H, d), 1.45 (4H, br), 1.58 (1H, br), 1.68 (1H, br), 3.26 (1H, d), 3.4 (1H, br), 3.59 (1H, d), 3.68 (1H, br), 4.5 (1H, br), 4.88 (1H, s), 6.43 (2H, s).
Reaction SMILES: I[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CN(C)C=O>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:12]#[N:13])=[CH:4][CH:5]=1)[CH2:10][CH3:11]
Reactant: [C-]#N
Reactant: CCCc1ccc(CI)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Under argon condition, 1-(iodomethyl)-4-propylbenzene (73.6 mg, 0.283 mmol) was dissolved in 1 mL of well-dried N,N-dimethylformamide (dry DMF) and then sodium cyanide (NaCN; 27.7 mg, 0.566 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 3 mL of water and the mixture was extracted with diethyl ether (3 mL×3). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 41.0 mg (0.257 mmol, 91%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH2:32]([NH2:35])[C:33]#[CH:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:35][CH2:32][C:33]#[CH:34])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: C#CCN
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 47, 5-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by propargylamine to give 5-chloro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+](=[CH2:22])=[N-]>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:22])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)cc1

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:8]=1[CH2:16][CH3:17])C>C1COCC1.[OH-].[Na+].O>[C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([CH2:6][CH2:5][C:4]([OH:18])=[O:3])=[C:8]([CH2:16][CH3:17])[CH:9]=1)#[N:15]
Reactant: CCOC(=O)CCc1c(C)cc(C#N)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1CCC(=O)O
Yield: 84 %

Procedure:
A solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid ethyl ester (55.0 g, 224 mmol) in THF (220 mL) and 1N aq. NaOH solution (220 mL) is stirred at rt for 2 before it is diluted with water (200 mL) and extracted with DCM (2×200 mL). The aqueous phase is added to 32% aq. HCl solution (50 mL) at 15-30° C. A precipitate forms. The solid material is collected, washed with water and dried under high vacuum to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (40.87 g) as pale brown crystals; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.30-2.39 (m, 5H), 2.67 (q, J=7.3 Hz, 2H), 2.87-2.94 (m, 2H), 7.47 (s, 2H), 12.30 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:14])=[O:13])=[N:6][C:7]=1[S:8]([OH:11])(=[O:10])=[O:9].Cl.[CH3:16]O>O1CCOCC1>[CH3:16][O:13][C:12]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([S:8]([OH:11])(=[O:9])=[O:10])[N:6]=1)=[O:14]
Reactant: Cc1ccc(C(=O)O)nc1S(=O)(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(S(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-methyl-6-sulfo-pyridine-2-carboxylic acid (0.8 g, 3.69 mmol) in methanol (20 mL) was added 4 N hydrogen chloride in dioxane (8 mL). The mixture was stirred overnight at room temperature. Undissolved solid was filtered off, and the filtrate was concentrated to give the product as yellow solid 0.5 g; MS (EI): m/e=232.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:12])=[CH:9][N:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CCCCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: CC(C)(C)N
Solvent: CCO
Product: C=CCCCCNC(=O)c1cnc(OCC(O)CNC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates method for preparing the compounds of the present invention. In this example a mixture containing 12 g. (0.037 mole) of 1,2-epoxy-3-[5-(hex-5-enylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the ethanol solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for two hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-t-butylamino-3-[5-(hex-5-enylaminocarbonyl)thiazol-2-yloxy]propan-2-ol, m.p. 80°-81° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, isoamyl nitrite is added dropwise to a mixture of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-pyridyloxy]acetate, copper (I) chloride, copper (II) chloride, and acetonitrile at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is poured into 2% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-pyridyloxy]acetate (compound a-118).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13]C(=O)C(F)(F)F)[CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 84 %

Procedure:
To a stirred solution of Intermediate 2 (2.97 g) in methanol (15 ml) and water (5 ml) was added potassium carbonate (5.53 g). The mixture was stirred at 22° C. for 18 h before the methanol was removed in vacuo. Water (25 ml) was added and the mixture extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with water (5 ml) and saturated aqueous sodium chloride solution (10 ml) before drying over sodium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 75:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless oil (1.85 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.BrN1C(=O)CCC1=O.[NH2:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[OH:34].CN(C)C1C=CC=CC=1>Br.O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH2:7]([CH:8]1[C:9](=[O:11])[NH:24][C:25]2[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=2[O:34]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(O)CCc1ccccc1
Agent: Br
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1Nc2cc([N+](=O)[O-])ccc2OC1Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
A mixture of 12.0 g of 3-phenylpropionic acid, 25 ml of thionylchloride and 8 ml of carbon tetrachloride are heated at 70° C. for 45 minutes. Then, 10.7 g of N-bromosuccinimide, 40 ml of carbon tetrachloride and 6 drops of 48% hydrobromic acid are further added thereto, and the mixture is heated for 1 hour. After cooling, insoluble materials are filtered off, and the filtrate is condensed to dryness. The residue is dissolved in 20 ml of tetrahydrofuran, and the mixture is added dropwise to 120 ml of a tetrahydrofuran solution containing 12.3 g of 2-amino-4-nitrophenol and 14.5 g of N,N-dimethylaniline under ice cooling. After stirring at room temperature for 40 minutes, the mixture is evaporated to remove the solvent. Water is added to the residue, and the mixture is extracted with ethyl acetate, dried and evaporated to remove the solvent. Then, the residue is dissolved in 200 ml of acetone. 41.4 g of potassium carbonate are added thereto, and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into water. Crystalline precipitates are collected by filtration, washed with water, dried and recrystallised from a mixture of ethyl acetate and n-hexane to give 12.25 g of 2-benzyl-6-nitro-3-oxo-1,4-benzoxazine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 125 °C
Yield: 91.4 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-chlorophenylboronic acid (0.489 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate in hexanes) to afford: 6-(3-chlorophenyl)pyrimidin-4-amine (0.47 g, 2.286 mmol, 91% yield) as a yellow solid. LCMS R.T.=1.45; [M+2H]+=208.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].COC(OC)OC>ClCCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[N:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: COc1ccc(C=NCC(OC)OC)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (2.42 g, 10 mmol), aminoacetaldehyde dimethylacetal (1.08 g, 10 mmol), and trimethylorthoformate (2.5 mL) were mixed in 1,2-dichloroethane (10 mL) at room temperature and stirred×2 hours. The solvent was removed in vacuo to give (3-benzyloxy-4-methoxy-benzylidene)-(2,2-dimethoxy-ethyl)-amine as a viscous oil, which was dissolved in diethyl ether (10 mL).
Reaction SMILES: CC[C@H]([C@H](CN(C)C)C)C1C=CC=C(O)C=1.[ClH:17].[CH3:18][N:19]([CH3:35])[CH2:20][C@H:21]([CH3:34])[C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(O)[CH2:23][CH3:24].S(Cl)([Cl:38])=O>>[ClH:38].[Cl:17][C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)([CH2:23][CH3:24])[C@@H:21]([CH3:34])[CH2:20][N:19]([CH3:35])[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CC[C@@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Agent: Cl
Product: CC[C@@](Cl)(c1cccc(OC)c1)[C@@H](C)CN(C)C

Procedure:
According to the '737 patent, tapentadol is prepared by the reaction of (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with thionyl chloride to produce (−)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride, followed by subsequent removal of the ‘Cl’ substituent by treatment with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride, to produce (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride. The (−)-(2R,3R)-[3-(3-methoxy phenyl)-2-methylpentyl]-dimethylamine hydrochloride is then converted to (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol (tapentadol) by reacting with concentrated hydrobromic acid at reflux.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:4]=1[NH:5][C:6]1[C:7]([C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])=[CH:8][N:9]([CH3:13])[C:10](=[O:12])[CH:11]=1>C1COCC1>[F:2][C:3]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:4]=1[NH:5][C:6]1[C:7]([C:14]([NH2:1])=[O:15])=[CH:8][N:9]([CH3:13])[C:10](=[O:12])[CH:11]=1
Reactant: N
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Conc. NH3 solution (0.5 ml) was added to 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (0.33 g, 0.6 mmol) in THF (10 ml) and the solution stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue dissolved in 5% EtOAc/MeOH. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated to give crude 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinearboxamide which was then recrystallised (EtOAc/Hexane) (0.11 g, 84%); m.p. (EtOAc/Hexane) 285-288° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.14 (s, 1H), 8.32 (s, 1H), 7.86 (br s, 1H), 7.43 (br s, 1H), 7.31 (t, J=8.4 Hz), 1H), 7.16 (dd, J=11.8, 1.1 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.38 (d, J=1.1 Hz, 1H), 3.34 (s, 3H), 2.32 (s, 3H). LCMS (ACPI−) 274 (100%). Anal. Calcd for C14H14FN3O2: C, 61.1; H, 5.1; N, 15.3. Found C, 61.0; H, 5.2; N, 15.4.