Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [CH2:1]([CH:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][CH:5]([OH:15])[CH:4]1[CH3:16])[CH3:2].CC(C)=O.N1C=CCNC1.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)C>[CH2:1]([CH:3]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5](=[O:15])[CH:4]1[CH3:16])[CH3:2]
Reactant: CCC1N=C(c2ccccc2)NC(O)C1C
Agent: O=[Mn](=O)(=O)[O-]
Agent: C1=CNCNC1
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCC1NC(c2ccccc2)=NC(=O)C1C
Temperature: 35 °C
Reaction time: 20 h
Yield: 60.1 %

Procedure:
A mixture of 6.58 g (30.6 mmol) of 6-ethyl-5-methyl-4-hydroxy-2-phenyl-3,4,5,6-tetrahydropyrimidine and 300 mL of acetone was warmed to 35° C. for 1 hour to help dissolve the tetrahydropyrimidine. A cloudy solution resulted. The solution was cooled to 10° C. and 14.0 g (25.3 mmol) of potassium permanganate was added, in batches. The mixture was stirred at room temperature for 20 hours then 50 mL of absolute ethanol was added and the reaction mixture was stirred for an additional 1.25 hours. The reaction mixture was gravity filtered and the filtrate was concentrated. Ether was added to the residue and the solution was filtered again. Concentration of the filtrate left 6.0 g of a sticky white solid behind. The crude product was purified by passing through a 4 inch plug of silica gel washing with 500 mL of 40% tetrahydrofuran/60% hexane. The eluate was concentrated to yield 3.98 g (62%) 6-ethyl-5-methyl-2-phenyl-5,6-dihydropyrimidin-4-one, as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.FC1C=CC(N2CCNCC2)=CC=1.[CH:26]1([CH2:29][CH2:30][NH:31][C:32]([C:34]2[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][CH2:30][NH:31][C:32]([C:34]2[N:35]=[N:36][C:37]([N:10]3[CH2:9][CH2:8][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ccccn3)CC2)nn1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 1-pyridin-2-ylpiperazine to replace 1-(4-fluorophenyl)piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 30% yield (0.036 g). 1H NMR (300 MHz, CDCl3) δ 8.19 (m, 1H), 8.01 (m, 1H), 7.50 (m, 1H), 7.00 (d, J=9.9 Hz, 1H), 6.67 (m, 2H), 3.89 (m, 4H), 3.75 (m, 4H), 3.54 (m, 2H), 1.50 (m, 2H), 0.74 (m, 1H), 0.45 (m, 2H), 0.09 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.2, 160.2, 158.9, 147.9, 144.9, 137.8, 126.9, 113.8, 112.1, 107.2, 44.6, 39.6, 34.6, 8.67, 4.25. MS (ES+) m/z 353.6 (M+1).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18].Cl>C(O)C>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: COC(=O)NN
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CCO
Product: COC(=O)NN=C1CCC(NC(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea (4.5 g), methyl carbazate (4.0 g), 95% ethanol (150 ml) and concentrated hydrochloric acid (2 ml) is heated at reflux for an overnight period. The mixture is cooled to room temperature and the crystals are collected. The product melts at 230° C to 233° C (dec). On recrystallizing from aqueous methanol, the title compound melts at 223° C to 225° C (dec).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CS(C)=O.O>[CH2:3]([O:7][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydride with 200 mL of dimethylsulfoxide, 16.0 g (2.0 eq.) of 1-butanol was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and was concentrated to dryness under reduced pressure. The obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-butoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: S(NN=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C@H:22]([CH2:23][C@H:24]([OH:36])[C@@H:25]([O:32][CH:33]([CH3:35])[CH3:34])[CH2:26]1)[CH2:21][CH2:20]3)(C1C=CC(C)=CC=1)(=O)=O.[BH3-]C#N.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O>O.CN(C=O)C>[CH:33]([O:32][C@H:25]1[CH2:26][C@@:27]2([CH3:28])[C@@H:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:29]2[CH2:30][CH2:31][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH2:18][CH2:13]2)[CH2:23][C@@H:24]1[OH:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OC(C)C)C[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Product: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]32)C[C@@H]1O
Temperature: 110 °C
Yield: 19.1 %

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone (300 mg), NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added DMF and sulfolane (1:1, 3 mL) and the mixture obtained was heated to 110° C. for 3 h. Then additional amount of NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added and it was heated for another hour. Water was then added and the mixture was extracted with EtOAc (2×45 mL). The combined extracts were dried over Na2SO4 and the crude product obtained by removal of the solvent was purified by flash chromatography over silica gel to yield the pure 2β-isopropoxy-3α-hydroxy-5α-androstane (37 mg); TLC Rf (EtOAc:hexane 1:9)=0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Clc1ccc([C@@H]2CNc3ccccc3S2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.8 %

Procedure:
To a suspension of (R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.30 g, 0.005 mole) and triethylamine (1.66 ml, 0.012 mole) in dichloromethane (16 ml) is added dropwise a solution of chloroacetyl chloride (0.79 ml, 0.01 mole) in dichloromethane (4 ml) under ice cooling, and the mixture is stirred at room temperature for 45 minutes. After the solvent is distilled off, to the residue are added ethyl acetate and water, and the ethyl acetate layer is washed with aqueous sodium hydrogen carbonate solution, water and saline, dried over sodium sulfate and distilled to remove the solvent to give (R)-4-chloroacetyl-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.84 g) as caramel.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CN(C=O)C.CO.O>[N:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: OCc1ccccc1N1CCOCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
2-Fluorobenzaldehyde (1.0 g, 8.1 mmol) was dissolved in DMF (20 mL), morpholine (2.0 mL) and potassium carbonate (1.1 g, 8.1 mmol) were added thereto, and then the mixture was stirred at 80° C. for 2 days. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=98:2 to 60:40) to give an oily matter. The resulting oily matter was dissolved in methanol (20 mL), sodium borohydride (613 mg, 16.2 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure to give the title compound (474 mg, yield 30%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[NH:17][CH:2]=[C:3]([CH3:4])[N:16]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(CC(=N)N)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2nc(C)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A solution of chloroacetone (5.27 g, 0.057 m) in CHCl3 (90 mL) was added to a stirred suspension of 4-methoxyphenylacetamidine (28.0 g, 0.17 m) in CHCl3 (470 mL) over 1 hour. The mixture was heated at reflux for 75 minutes and then stirred at ambient temperature for 43 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oily residue was chromatographed on alumina and eluted with CHCl3 to yield 8.14 g (71%) of I; m.p. 108°-109° C. (CHCl3 -C6H14).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]2[C:9](=[O:20])[N:10]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:15])=[C:12](Cl)[N:13]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O>[CH:1]1([CH2:5][CH2:6][NH:7][C:8]2[C:9](=[O:20])[N:10]([CH2:16][C:17]([OH:19])=[O:18])[C:11]([CH3:15])=[CH:12][N:13]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(Cl)nc(NCCC2CCC2)c(=O)n1CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(NCCC2CCC2)c(=O)n1CC(=O)O
Reaction time: 4.5 h

Procedure:
5-4 (43.5 mg, 0.145 mmol) was added to a stirred solution of potassium hydroxide (85% by weight, 25.4 mg, 0.384 mmol) in water (2.1 mL). After degassing the resulting solution with nitrogen, 10% Pd/C (22 mg) was added and the mixture was stirred under a hydrogen filled balloon. After 4.5 h, the mixture was filtered through celite, washing the cake with water. The filtrate was acidified with 3N KHSO4 and evaporated in vacuo. The solids were extracted with 10% methanol/chloroform (30 mL), removing the undissolved inorganic solids by filtration and the filtrate was evaporated in vacuo to give 5-5 as a glass: 1H NMR (CD3OD): selected signals δ 2.21 (d, J=1.1 Hz, 3H, CH3), 6.59 (q, J=1.1 Hz, 1H, pyrazinone-5).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH:17]=O)=O)(=O)C.[NH3:19]>CCO>[CH3:16][O:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[N:8]=[C:6]([CH2:5][OH:4])[N:19]=[CH:17]2
Reactant: COc1ccc(NC(=O)COC(C)=O)c(C=O)c1
Reactant: N
Solvent: CCO
Product: COc1ccc2nc(CO)ncc2c1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
The solution of 2-(2-formyl-4-methoxyphenylamino)-2-oxoethyl acetate (5 g, 0.02 mol) and ammonia (6.8 g, 0.4 mol, 20 eq) in EtOH (30 mL) was reacted under a high pressure (30 psi) at 135° C. for 5 h. After cooling to room temperature, the solvent was evaporated in vacuum. The residual aqueous solution was extracted with DCM (100 mL×3). The combined extracts were dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude product was purified by chromatography (eluting with DCM/MeOH=100/1) to give (6-methoxyquinazolin-2-yl)methanol (4.1 g, yield: 90%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8, 3.2 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 5.34 (t, J=6.4 Hz, 1H), 4.72 (d, J=6.4 Hz, 2H), 3.91 (m, 3H); ESI-MS: m/z 191.1 ([M+1]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([OH:12])=[C:6]2[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]3[CH2:25][N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][C@@H:21]23)=[CH:15][N+:14]=1[O-])#[N:2].P(Cl)(Cl)Cl>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([OH:12])=[C:6]2[C:13]1[N:14]=[CH:15][C:16]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]3[CH2:25][N:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][C@@H:21]23)=[CH:17][CH:18]=1)#[N:2]
Reactant: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(-c4c(O)[nH]c5ccc(C#N)cc45)[n+]([O-])c3)[C@@H]2C1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(-c4c(O)[nH]c5ccc(C#N)cc45)nc3)[C@@H]2C1

Procedure:
The titled compound was prepared in analogy to example 4.2 starting from 2-(5-cyano-2-hydroxy-1H-indol-3-yl)-5-(((3aS,6aS)-5-(ethoxy-carbonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)methyl)pyridine 1-oxide (100 mg) and phosphorus trichloride (123 mg). The obtained crude product was used without further purification in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1cc(F)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Difluorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([SH:22])[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([S:22][CH2:20][CH3:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCS
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(SCC)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
52 mg of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, Example D-20c, was dissolved in 2 ml of ethanethiol and heated in a sealed tube at 70° C. for 24 h, and 100° C. for 48 h. The resultant solution was concentrated under vacuum and the residue (54 mg) was purified by chromatography on silica gel using a gradient of 0 to 20 percent ethyl acetate in hexanes to elute the product. 25 mg of product was obtained; MS (+): m/z 306.06 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: COC(=O)c1cnc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (170 mg, 0.43 mmol) from Example 61, Step B in methanol (5 mL) was added 5N sodium hydroxide (0.20 mL, 1.0 mmol). The reaction was stirred at rt for 20 h and was then acidified with 2N hydrochloric acid and extracted twice with methylene chloride. The organic layer was washed with a portion of brine, dried over sodium sulfate, and concentrated in vacuo to give 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid as a white solid. HPLC/MS: 378 (M+1), 380 (M+3); Rt=3.65 min
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br.O>CN(C=O)C>[N+:1]([C:4]1[C:5]2[O:11][CH2:20][CH2:19][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1OCCO2
Temperature: 110 °C
Yield: 62.2 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (11 g, 0.071 mol) in N,N′-dimethylformamide (500 mL) was added potassium carbonate (29 g, 0.0.213 mol) followed by 1,2-dibromoethane (14.7 g, 0.078 mol). The mixture was heated at 110° C. for 2 hours. After cooled to room temperature, the mixture was poured into water and then extracted with ether. The organic phases were combined and dried over anhydrous sodium sulfate, filtrated and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to afford the product 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (8 g, yield 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.48-7.50 (dd, 1H, J=1.6 Hz, 8.4 Hz), 7.09-7.12 (dd, 1H, J=1.6 Hz, 8.4 Hz), 6.88-6.92 (t, 1H, J=8.4 Hz), 4.40-4.42 (m, 2H), 4.34-4.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cccc(-c2nn(CCN3CCOCC3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
A mixture of 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-morpholinoethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 9.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH3:17][CH:16]([NH:19][CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CC(C)N
Reactant: COCCc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COCCc1ccc(OC[C@@H](O)CNC(C)C)cc1

Procedure:
A solution of 290 mg of (+)-4-(2-methoxyethyl)-phenyl glycidyl ether of Example 1 in 6.2 ml of dried ethanol containing 1.84 ml of isopropylamine was heated at reflux for 3 hours after which the sovents were removed by evaporation The resulting oil was dissolved in 10 ml of methylene chloride and the solution was extracted with 10 ml of 0.2N HCl which was then washed twice with 10 ml of methylene chloride. The acid layer was made basic with 3 ml of 2N NaOH and the product was extracted with 10 ml of methylene chloride. The methylene chloride extract was dried over Na2SO4 and the solvent was evaporated to obtain a sticky solid. The product was crystallized from hexane to obtain 260 mg of (-)metoprolol having a [α]D25 =-5.46° (c=1.01 in ethanol) and melting at 42-45° C. (±)-metoprolol melting at 49-51° C., prepared chemically was, as expected, optically inactive. The pmr and mass spectra of (-)-metoprolol (FIGS. 2 and 3) and (±)-metoprolol (not shown) were consistent with the required structure and were indistinguishable from the pmr spectrum of (±)-meto prolol (melting at 48.5-50.5° C.) extracted from a commercial sample of metoprolol tartrate.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21].O.[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][O:18][CH2:19][C:20]([F:23])([F:21])[F:22]
Reactant: CCOC(=O)c1nc2ccccc2n(COCC(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2ccccc2n(COCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.9 %

Procedure:
1.5 g (4.54 mmol) of ethyl 2-oxo-1-[(2,2,2-trifluoroethoxy)methyl]-1,2-dihydroquinoxaline-3-carboxylate and 0.28 g (6.81 mmol) of lithium hydroxide monohydrate were dissolved in a solvent mixture of ethanol (30 mL) and water (30 mL), and the solution was stirred for 2 hours at room temperature. The reaction solution was concentrated to a half the original volume, and then water was added to the residue. The mixture was acidified using 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated, to obtain 2.4 g (yield: 53%) of 2-oxo-1-[(2,2,2-trifluoroethoxy)methyl]-1,2-dihydroquinoxaline-3-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:23]([O:22][C:16]1[CH:15]=[C:14]([C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[O:13])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH3:24]
Reactant: CCOc1cc(C(O)c2ccc(OC)c(OCC)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c(OCC)c2)ccc1OC
Yield: 84.8 %

Procedure:
To a stirred solution of bis-(3-ethoxy-4-methoxy-phenyl)-methanol (8.80 g, 26.5 mmol) in CH2Cl2 (30 mL) at room temperature was added activated MnO2 powder (11.51 g, 132 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed at least 98% conversion occurred. The black suspension was filtered through a Celite pad, concentrated in vacuo to give bis-(3-ethoxy-4-methoxy-phenyl)-methanone as an off-white solid (7.42 g, 85% yield): 1H NMR (CDCl3) δ 1.49 (t, J=7 Hz, 6H, 2CH2CH3), 3.96 (s, 6H, 2OCH3), 6.89-6.92 (m, 2H, Ar), 7.16 (q, J=7 Hz, 4H, 2CH2CH3), 7.35-7.42 (m, 4H, Ar). The product was used in the next step without further purification.