Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[CH2:26][CH3:27])=[CH:9][C:8]=1[CH3:28])([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:5]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[CH2:26][CH3:27])=[CH:9][C:8]=1[CH3:28])([OH:3])=[O:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cc(C)c(OC(C(=O)OC)c2cccc(Cl)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cc(C)c(OC(C(=O)O)c2cccc(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a magnetically stirred solution of 0.280 g (0.56 mmol) of the product of Step D in 4.0 mL methanol was added 0.5 mL of a 5.0N solution of sodium hydroxide and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH=6 with 1.0N hydrochloric acid and then concentrated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.238 g (87%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: CN
Reactant: Cc1ccc(OCCCCl)cn1
Solvent: CO
Product: CNCCCOc1ccc(C)nc1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
The 3-chloro-1-(6-methyl(3-pyridyloxy))propane (2.78 g, 18.3 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH was adjusted to 1 with 10% HCl solution and impurities were extracted with chloroform (4×25 mL). The pH of the aqueous phase was raised to 7 with 10% NaOH solution and other impurities were extracted with ether (4×30 mL). The aqueous layer was basified to pH 11 with 10% NaOH solution and extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.224 g (45.3%) of an oil.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>O>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:15])([CH3:14])[C:4]([OH:16])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Cc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 3-(4-fluorophenyl)-2,2-dimethylpropionic acid ethyl ester (10.0 g, 44.6 mmol, see Part 1 of Example 25a) and a solution of sodium hydroxide (25 g) in water (110 mL) was heated at reflux for 18 h and cooled to room temperature. The solution was stirred on an ice bath and acidified with concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The residue was stirred with dichloromethane and filtered, and the filtrate was concentrated to provide an off-white solid (7.60 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:20])[C:9]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([C:21]([OH:23])=O)[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:24]1([NH:30][C:21]([C:4]2[CH:3]=[C:2]([Br:1])[C:7]3[N:8]([CH3:20])[C:9]([NH:11][C:12]4[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=4[Cl:18])=[N:10][C:6]=3[CH:5]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)cc(Br)c21
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)NC3CCCCC3)cc(Br)c21

Procedure:
Prepared analogously to example 3c from 7-bromo-2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid, cyclohexylamine, TBTU and TEA in DMF.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1)#[N:9]
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ccon3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(-c2cccc(F)c2)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ccon3)ccc12
Temperature: 120 °C
Yield: 20.4 %

Procedure:
A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (INTERMEDIATE WWWW, 95.3 mg, 0.216 mmol), (3-fluorophenyl)boronic acid (60.5 mg, 0.432 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.219 mg, 5.40 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (8.19 mg, 10.81 μmol), and potassium phosphate (138 mg, 0.649 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (983 μl) and water (98 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 2.5 h at 120° C. Additional portions of (3-fluorophenyl)boronic acid (60.5 mg, 0.432 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (8.19 mg, 10.81 μmol), and potassium phosphate (138 mg, 0.649 mmol) were added. The vial was heated for an additional 30 min at 150° C. The mixture organic layer was separated, and the aq. layer was diluted with 0.5 N aq. HCl and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-4% MeOH/DCM) to give a light-yellow solid. The material was taken up in DCM, sonicated, and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide (22.04 mg, 0.044 mmol, 20.37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.93 (br. s., 1H), 8.82-8.64 (m, 3H), 8.19 (d, J=5.7 Hz, 1H), 8.01-7.83 (m, 3H), 7.71-7.55 (m, 3H), 7.49-7.33 (m, 2H), 6.50 (d, J=1.7 Hz, 1H), 3.81 (s, 3H). m/z (M+H) 501.0 (M+H)+.
Reaction SMILES: CO[CH:3]([O:7][CH3:8])N(C)C.O[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=C[C:11]=1[C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>C1C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:17](=[O:18])[C:11]3[CH:10]=[CH:15][C:14]([OH:16])=[CH:13][C:3]=3[O:7][CH:8]=2)=[CH:21][CH:22]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Solvent: c1ccccc1
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Yield: 85 %

Procedure:
Another known approach used for the synthesis of formononetin is the general method involving the addition of one carbon to 2-hydroxydeoxybenzoins and their cyclization to form isoflavones. The method introduced by Andrew Pelter (Pelter, Andrew, et al., Synthesis, 5:326 (1976)) involves the reaction of 2-hydroxydeoxybenzoins with N,N-dimethylformamide dimethylacetal (dimethoxydimethyl aminomethane) (two equivalents) in dry benzene. Refluxing a mixture of 2,4-dihydroxy-4'-methoxydeoxybenzoin with N,N-dimethylformamide dimethyl acetal in dry benzene for 4 hours gave formononetin in 85% yield. However, the use of the expensive reagent, N,N-dimethylformamide dimethyl acetal and dry benzene as solvent makes this an unattractive method for the commercial production of formononetin.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=O)=O>C1COCC1.O>[NH2:15][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:3][N:2]([CH3:17])[CH3:1])[CH2:6][NH:7]2)=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1Cc2ccc(N)cc2NC1=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(N)ccc2C1
Yield: 95.9 %

Procedure:
To a suspension of N,N-dimethyl-7-amino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (450 mg) in THF (15 ml) was added Borane-THF complex (1M, 12 ml) under ice-cooling. The reaction mixture was heated under reflux for one hour. The reaction mixture was diluted with water (2 ml) under ice-cooling and concentrated. The residue was dissolved in methanol (12 ml), which was heated under reflux with 6N hydrochloric acid (4 ml) for 3 hours. After cooling, the reaction mixture was made basic and extracted with combined solution of THF and ethyl acetate. The organic layer was dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate to ethyl acetate/methanol=20:1) to obtain the entitled compound (380 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][CH2:22][N:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:9][C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][CH2:22][N:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A solution of 30 (1.56 g, 2.08 mmol) in MeOH (21 mL) was degassed with argon for 10 min followed by the addition of 10% Pd/C (400 mg). The mixture was then stirred under an atmosphere of hydrogen for 3 h. The mixture was filtered through glassfiber filter paper and the filtrate was concentrated under reduced pressure to give crude 31 (1.37 g, 100%) as a colourless liquid that was used without purification: 1H NMR (400 MHz, acetone-d6): δ 1.40 (bs, 9H), 1.44-1.46 (m, 27H), 1.52 (bs, 4H), 1.66-1.83 (m, 4H), 3.06 (bt, J=5.6, 2H), 3.22-3.32 (m, 10H), 3.94 (s, ½ of 2H, rotomer A), 3.97 (s, ½ of 2H, rotamer B), 5.98 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4](=[O:15])O[C:6]2=[O:14].[F:16][C:17]1[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]2[C:18]=1[C:19]([OH:37])=[C:20]1[C:25](=[C:26]2[OH:34])[C:24](=[O:35])[CH2:23][CH2:22][C:21]1=[O:36].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].Cl>>[F:13][C:8]1[C:7]2[C:3](=[C:4]([OH:15])[C:22]3[C:21](=[O:36])[C:20]4[C:25]([C:24](=[O:35])[C:23]=3[C:6]=2[OH:14])=[C:26]([OH:34])[C:27]2[C:18](=[C:17]([F:16])[C:30]([F:31])=[C:29]([F:32])[C:28]=2[F:33])[C:19]=4[OH:37])[C:2]([F:1])=[C:10]([F:11])[C:9]=1[F:12]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C1CCC(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1c2c(c(O)c3c(F)c(F)c(F)c(F)c3c2O)C(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O
Temperature: 280 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
4,5,6,7-tetrafluoroisobenzofuran-1,3-dione (2) (5.75 g, 26.1 mmol), 5,6,7,8-tetrafluoro-9,10-dihydroxy-2,3-dihydroanthracen-1,4-dione (1) (9.84 g, 31.3 mmol), aluminum chloride (1.53 g, 11.5 mmol), and sodium chloride (10.0 g, 171 mmol) were added to a 200-mL SUS autoclave and heated for 1 hour at 280° C. After completion of the reaction, cooling to room temperature was carried out and the reaction mixture was then introduced into dilute hydrochloric acid and was stirred for 1 hour at 100° C. The mixture was then filtered and the residue was washed with methanol, dichloromethane, toluene, and ether in the sequence given. The resulting solid was vacuum dried to give 11.5 g (85% yield) 1,2,3,4,8,9,10,11-octafluoro-5,7,12,14-tetrahydroxypentacen-6,13-dione (3).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].Br[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:27][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Temperature: 82.5 °C
Reaction time: 1.25 h

Procedure:
The compound of example 390 (3 g, 0.0084 mol), 2-bromo-5-nitropyridine (1.95 g, 0.0096 mol) and Pd(dppf)Cl2: CH2Cl2 (0.196 g, 0.00024 mol) were taken in DMF (100 mL) under an argon atmosphere. To this reaction mixture, 2M solution of Na2CO3 (2.55 mg, 0.0241 mmol, 12 mL) was added. The reaction mixture was stirred at 80-85° C. for 1 to 1.5 h. After completion of the reaction, water was added and the product obtained was extracted with ether. The combined ether layers were washed with brine and dried over anhydrous Na2SO4 or anhydrous MgSO4. The solvent was evaporated and the product obtained was purified by flash chromatography to obtain the title compound
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:8]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:9](=[O:11])[CH:10]=1
Reactant: COCCOCCBr
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOCCOC)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and 1-bromo-2-(2-methoxyethoxy)ethane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (1% MeOH/CH2Cl2 as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a pale yellow oil (41%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.43 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.3, 1.9, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.44 (d, J=1.3 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.61 (t, J=5.2 Hz, 2H), 3.54-3.50 (m, 2H), 3.43-3.39 (m, 2H), 3.22 (s, 3H), 1.32 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C19H22FIN2O5 (M+) 504.0558, found 504.0552.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 19 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-phenylpropanoyl chloride to afford the title compound (15 mg, 19%). 1H-NMR (δ, ppm, DMSO-d6): 2.61 (t, 2H, CH2, J=8.0 Hz), 2.89 (t, 2H, CH2, J=8.0 Hz), 6.45 (d, 1H, HPy,5, J=6.0 Hz), 6.82 (d, 1H, Harom, J=8.0 Hz), 7.16-7.44 (m, 8H, Harom), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 10.02 (s, 1H, NHamide), 11.16 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z[M+H] calcd for C21H19N4O3: 375.1457; found: 375.1469.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[Br:20]Br>ClCCl>[Br:20][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH:2]([OH:1])[C:7]([CH3:8])([CH3:9])[O:6][C:5]=2[CH:10]=1
Reactant: BrBr
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 4 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30 mL). Purification by flash chromatography using 1% methanol in dichloromethane as the eluant and recrystallization from dichloromethane/hexanes gave the product, 3.87 g (78%), as a colorless solid: mp 200°-202° C.; IR(KBr): 3442, 2942, 1616, 1571 and 1488 cm-1 ; MS: m/z 360 (MH+); 1H NMR(CDCl3): δ 1.29 (s, 3H), 1.46 (s, 3H), 1.82 (m, 4H), 2.51 (m, 2H), 3.12 (m, 1H), 3.27 (m, 1H), 3.46 (d, J=5.0 Hz, 1H, exchanges with D2O),3.78 (d,d, J=9.0 Hz, J=5.0 Hz, 1H, simplifies to d, J=9.0 Hz, with D2O), 5.74 (d, J=9.0 Hz, 1H) and 7.58 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C([O:14][C:15](=O)[CH:16]([CH:18]=O)[CH3:17])C>C(O)C>[CH3:18][C:16]1[C:15](=[O:14])[N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:17]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: NNCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: Cc1c[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.9 g of 3,4-dichlorobenzylhydrazine were added dropwise to a solution of 7.5 g of α-formylpropionic acid ethyl ester in 50 ml of ethanol. After stirring overnight at room temperature, the solvent was distilled off in vacuo and the solid residue was recrystallized from ethanol.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:39][CH2:38][C:26]3([C:31]4[S:32][C:33]([Cl:35])=[CH:34][C:30]=4[C:29]([F:37])([F:36])[CH2:28][O:27]3)[CH2:25][CH2:24]2)[C:19]([CH3:40])=[N:18]1>O1CCCC1>[Cl:35][C:33]1[S:32][C:31]2[C:26]3([CH2:25][CH2:24][N:23]([CH2:22][C:20]4[C:19]([CH3:40])=[N:18][N:17]([C:12]5[C:11]([C:10]6[O:5][N:4]=[C:1]([CH3:2])[N:3]=6)=[CH:16][CH:15]=[CH:14][N:13]=5)[CH:21]=4)[CH2:39][CH2:38]3)[O:27][CH2:28][C:29]([F:36])([F:37])[C:30]=2[CH:34]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cccnc2-n2cc(CN3CCC4(CC3)OCC(F)(F)c3cc(Cl)sc34)c(C)n2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of acetamide oxime (154 mg, 2.1 mmol) in 7 mL tetrahydrofuran, are added under argon 139 mg of grinded 4A molecular sieves and sodium hydride (2.1 mmol; 84 mg as 60% in mineral oil). The mixture is allowed to stir for 30 min at 50° C. After cooling to room temperature, 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester (309 mg, 0.6 mmol) is added and then the mixture is heated at 50° C. for 40 min. Quenched after cooling with water and extracted with dichloromethane. After drying the organic phase with magnesium sulfate and evaporation of the solvent, the residue is diluted in methanol and purified using a 5 g SCX cartridge. The resulting residue is further purified by semipreparative reverse phase HPLC_MS using a XBridge column (Sum, 19×100 mm) and a gradient between 60 and 80% of B in A in 5 min at flow 25 mL/min (basic conditions A: ammonium bicarbonate 20 mM pH9 and B: acetonitrile) to give 71 mg of the title compound. MS (m/z): 533 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11]1[N:12]([CH3:29])[C:13](=[O:28])[C:14]2[C:15](=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[CH:19]=2)[N:16]=1)([CH3:9])[CH3:8].O.[OH-].[NH4+]>CN(C=O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]2[CH:19]=[C:14]3[C:13](=[O:28])[N:12]([CH3:29])[C:11]4[N:16]([CH2:6][C:7]([CH3:9])([CH3:8])[N:10]=4)[C:15]3=[N:17]2)=[CH:22][CH:23]=1
Reactant: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN1C(=O)c2cn(Cc3ccc(Br)cc3)nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Thionyl chloride (67 mL, 922 mmol) is added dropwise to a solution of 6-(1-hydroxy-2-methylpropan-2-ylamino)-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (134 g, 330 mmol) in DMF (800 mL). The reaction mixture is stirred at room temperature until the reaction is complete. The mixture is poured into cold water, and then adjusted to pH 8-9 with ammonium hydroxide aqueous solution. After filtration, the obtained solids are washed with water, and then dried under vacuum to give 118 g of product (yield: 92%). MS (ESI) 388.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[C@@:10]([OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3]>C(OCC)(=O)C>[CH3:3][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: COc1cccc([C@@]2(O)CCCC[C@@H]2CN(C)C)c1
Solvent: CCOC(C)=O
Product: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Temperature: -2.5 °C
Reaction time: 2 h

Procedure:
A reactor vessel is charged successively with cis-Tramadol base hydrate (crude) 200 Kg and ethyl acetate 300 l and the contents of the vessel heated to 50° l C. until all solids are in solution. The vessel is then cooled to −5 to 0° C. and the product crystallises. Stirring is continued for two hours and the product is then centrifuged and washed with cold ethyl acetate, 2×25 l. Approximately 165-175 Kg (moist) of cis(+/−) Tramadol base hydrate are obtained from this procedure.