Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[S:30]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]3[N:31]=[C:29]([NH:28][CH2:27][CH2:26][CH:22]4[CH2:23][CH2:24][CH2:25][N:21]4[CH3:20])[S:30][CH:2]=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: CN1CCCC1CCNC(N)=S
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCCCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCCC1CCNc1nc(C2(c3ccc(Cl)cc3)CCCCC2)cs1
Temperature: 50 °C

Procedure:
A solution of 2-chloro-1-[1-(4-chloro-phenyl)-cyclohexyl]-ethanone (144.8 mg, 0.53 mmol) and sodium iodide (80 mg, 0.53 mmol) in acetone (4 mL) was stirred at room temperature for 10 min. Next, [2-(1-methyl-pyrrolidin-yl)ethyl] thiourea (100 mg, 0.71 mmol) was added. The resulting mixture was heated at 50° C. overnight. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (3×20 mL). The extracts were combined, and dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The crude was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (95:5) to give {4-[1-(4-chloro-phenyl)-cyclohexyl]-thiazol-2-yl}-[2-(1-methyl-pyrrolidin-2-yl)-ethyl] amine, 95, as an oil (150 mg, 70%). 1H (CDCl3, 300 MHz) δ 7.30-7.21 (m, 4H), 6.02 (s, 1H), 5.67 (s, 1H), 3.67-1.52 (m, 24H) ppm; 13C (C6D6, 75 MHz) δ 22.9, 23.5, 26.9, 29.4, 30.8, 36.7, 40.8, 43.2, 46.4, 57.4, 64.9, 101.2, 128.7, 129.4, 132.0, 146.8, 160.1, 169.5 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCCc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)O)ccc32)cc1
Product: CCCCc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)Nc4ccccc4OCCCC(=O)O)ccc32)cc1

Procedure:
224 mg of compound 36 was obtained in a similar manner to those described in the Examples 1 and 2 using 513 mg of ethyl 4-(2-aminophenoxy)butyrate and 400 mg of 3-[1-(4-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[F:25])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]>C(O)C.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])=[C:2]([F:1])[CH:14]=2)=[C:17]([F:25])[CH:18]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(N)cc2F)cc1F
Reaction time: 19 h

Procedure:
A mixture of methyl 2-(2-fluoro-4-(2-fluoro-4-nitrophenoxy)phenoxy)propanoate (6.5 g, 0.018 mole) in ethanol (150 ml) containing 5 percent palladium on charcoal (0.5 g) as catalyst was subjected to hydrogenation (initial pressure equals 50 psi) on a Parr apparatus. After 19 hours, the excess hydrogen was removed and nitrogen was bubbled through the liquid mixture. This mixture was filtered through celite and the ethanol removed by distillation. A slightly yellow oil weighting 5.8 grams (98 percent) resulted. NMR spectroscopy (1H, 19F) and infrared (I.R.) spectroscopy confirmed the structure as one being consistent with the desired product. It was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=[O:38].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][C@@H:17]5[O:38][C@@:18]65[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]6)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3C[C@@H]4O[C@@]45CCCC[C@@H]5[C@H]32)cc1
Temperature: 0 °C
Reaction time: 168 h

Procedure:
20 g of the diketal prepared in Example 1 c) are dissolved in 200 ml of methylene chloride. 0.1 ml of pyridine are added, the whole is cooled to 0° C., and 0.9 ml of hexachloroacetone is added. 9.2 ml of a 30% aqueous hydrogen peroxide solution are then added dropwise. The whole is stirred at room temperature for 7 days and then saturated sodium thiosulphate solution is cautiously added to the reaction solution with gentle cooling. The aqueous phase is removed and extracted repeatedly with methylene chloride and the organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product is purified by chromatography on silica gel with a mixture of ethyl acetate and hexane. 16.6 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5α,6α-epoxy-oestrane are obtained in the form of a white foam.
Reaction SMILES: C1(C)C=CC=CC=1.C([Al](CC(C)C)CC(C)C)C(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.[OH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[C:41](OCC)=[O:42]>C(Cl)Cl>[OH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[C:41]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:42]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Reactant: COc1ccc(N)cc1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cnc3ccccc3c2O)cc1
Reaction time: 6 h

Procedure:
230 ml of a toluene solution of triisobutyl aluminum were added with stirring at 8°-10° C. over 30 minutes to a mixture of 61.5 gof p-anisidine in one liter of anhydrous methylene chloride and then 21.7 gof ethyl 4-hydroxy-3-quinoline-carboxylate [described in J.A.C.S., Vol. 68 (1946), p. 1264] were added to the mixture in small portions. The mixture was refluxed for 20 hours and was evaporated to dryness. The residue was taken up in a mixture of 500 g of ice and 500 ml of aqueous 6 N hydrochloric acid and the mixture was stirred for 6 hours and vacuum filtered. The recovered product was washed with water until there were no chloride ions in the wash water, dried at 100° C. and was crystallized from acetic acid to obtain 23.54 g of 4-hydroxy-N-(4-methoxyphenyl)-3-quinoline-carboxamide melting at >260° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C.C(O)C>[CH2:1]([NH:4][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCNCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 130.8 %

Procedure:
Propylamine (4.13 g) was slowly added to 4-hydroxybenzaldehyde (11.2 g, 91.80 mmol) in 50 mL of isopropanol at ambient temperature. The reaction was stirred for 1 hour and then cooled in an ice bath to 0° C. The imine was then reduced with sodium borohydride (1.74 g, 46 mmol) for 1 hour. The reaction was diluted with 100 mL of ethanol and acidified with acetic acid. The resulting solid was filtered and recrystallized from ethanol/isopropanol to give 15.1 g (99%) of the title compound. TLC (3:1 ethyl acetate/ethanol, trace triethylamine) Rf =0.37.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:3]=1[CH:4]=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][CH2:26][C:27]#[N:28]>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][C:26]1[C:27]([NH2:28])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[CH:8][CH:9]=2
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1ccc(N2CCOCC2)cc1C=O
Product: COc1cccc(F)c1Cc1cc2cc(N3CCOCC3)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-morpholin-4-ylbenzaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8]OC2C=CC=CC=2)=[CH:5][CH:4]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:1]=[CH:3][CH:4]=[CH:5][C:6]=2[OH:7])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCc1ccc(OCOc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1ccc(Oc2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 135.1 %

Procedure:
710 mg of 2-(4-ethylphenoxy)methoxybenzene 70 are dissolved in 5 ml absolute dichloromethane. 0.6 ml of boron tribromide (1 M dichloromethane) is added dropwise, and the solution stirs for 6 h. Further BBr3 is added and the mixture is stirred until the reaction is almost complete according to LCMS. The solution is brought into ice-water, the organic phase is separated off, and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is dried, evaporated to dryness and purified by chromatography. 450 mg of the desired product are obtained. C14H14O2 (214.27) MS (ESI): 215.10 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](O)=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O:16][C:17](=N)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C>CO>[CH2:18]([C:17]1[O:16][C:7]2[CH:6]=[CH:5][C:4]([CH2:8][C:9]([OH:11])=[O:10])=[CH:3][C:2]=2[N:1]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=N)OCC
Reactant: Nc1cccc(CC(=O)O)c1O
Agent: Cl
Solvent: CO
Product: CCCCCc1nc2cc(CC(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (3-aminohydroxy-phenyl)-acetic acid (4.65 g, 27.8 mmol) in methanol (79 ml) was treated with hexanimidic acid ethyl ester hydrochloride (5.00 g, 27.8 mmol) and stirred for 14 hours at RT. The solvent was evaporated in vacuum and the residue purified by silica gel chromatography (eluent: DCM/methanol 10/1). Crystallization from Cyclohexane/n-pentane provided the title compound as colorless crystals. mp: 58.2/57.1° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:37]([CH3:44])([CH3:43])[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C(O)C>[Cl:3][C:4]1[N:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([O:23][CH:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:21][CH2:22]3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:37]([CH3:44])([CH3:43])[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Yield: 84 %

Procedure:
653 mg of ethyl 2-[3-chloro-6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 6 ml of ethanol; 1.97 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 4.5 by the addition of 1 N hydrochloric acid. Acetone was added; the crystal precipitated was collected by filtration, washed with water-acetone (5:1) and dried to yield 465 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Cl>>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nc[nH]n1
Reactant: ClCc1ccccc1Cl
Product: Nc1ncn(Cc2ccccc2Cl)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 2-chloro benzyl chloride. The title compound was obtained as a colorless oil (Yield=11%). MS ISP (m/e): 209.0 & 211.0 (100 & 44) [(M+H)+].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(Cl)nc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)nc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-chloropyridine-3-carbaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 504.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1)=[O:20].[F:35][C:36]([Si](C)(C)C)([F:38])[F:37].Cl>C1COCC1>[F:35][C:36]([F:38])([F:37])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1)[OH:20]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(-c2ccccc2C=O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccccc2C(O)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
Tetrabutylammonium fluoride (5.3 μl, 1.0 M solution in tetrahydrofuran) was added to a solution of 5-(2-formyl-phenyl)-pyridine-2-carbonitrile (110 mg, 0.53 mmol) and trifluoromethyltrimethylsilane (120 μl, 0.81 mmol) in 5 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 140 mg of 5-[2-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-pyridine-2-carbonitrile, yield 95%.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7](O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH:7]1[C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc2c(c1)OCCC2O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)OCCC2Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
7-Cyano-4-chromanol (8.0 g, 46 mmol) was dissolved in CH2Cl2 (120 mL) and cooled to 10° C. SOCl2 (5.0 mL, 70 mmol) was added, the reaction was warmed to RT and stirred overnight. The reaction was concentrated in vacuo and azeotroped with CH2Cl2 (2×50 mL). The residue was dissolved in EtOAc (500 mL), washed with saturated NaHCO3 (250 mL), and with brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH2:24]>[Pd].C(O)=O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH-:24].[NH4+:2]
Reactant: O
Agent: [Pd]
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: O=CO
Product: [NH4+]
Product: [OH-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Pd/C Catalyst was filtered off and ammonium hydroxide was used for the oxycodone base precipitation (˜60 mL) at temperature less than 15° C. Precipitated product was washed with water (2×75 mL) and dried on filter giving 28.07 g of oxycodone base. The oxycodone base was transferred into 250-mL RBF with Pd/C catalyst (0.59 g) and water (120 mL). Formic acid (4.36 mL) was added (pH 2.1) and stirring continued for 45 minutes at 50-60° C. The reaction mixture was cooled to ambient temperature, catalyst was filtered off, and oxycodone base was isolated with ammonium hydroxide addition to the filtrate at temperature lower than 20° C. Drying on filter provided 29.51 g of the oxycodone base (2nd crude, Lot O).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([O:17][CH3:18])[CH:13]=[CH:12][C:11]=1[C:19](=[O:23])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(O)C>[Cl:16][C:15]1[C:10]([Cl:9])=[C:11]([C:19](=[O:23])[C:20](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][CH3:22])[CH:12]=[CH:13][C:14]=1[O:17][CH3:18]
Reactant: CCCC(=O)c1ccc(OC)c(Cl)c1Cl
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=Cc1ccccc1)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
To a mixture of benzaldehyde (19.4 g., 0.183 mole) and 2',3'-dichloro-4'-methoxybutyrophenone (42.2 g., 0.183 mole) in absolute ethanol (350 ml.) a 20% sodium hydroxide solution (35.9 ml.) is added dropwise with stirring. The mixture is stirred for 22 hours. The white solid product that separates is collected and air dried. Yield 55.6 g. (91%), m.p. 127°-130° C.
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]1[O:26][CH2:25]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]([OH:26])[CH2:25][S:4][CH:1]([CH3:3])[CH3:2])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: CC(C)S
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)SCC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Isopropylmercaptan (0.93 ml) and triethylamine (1.39 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (2.11 g) as obtained in Example 1-A) in methanol (100 ml), and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 1.66 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[S:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:19]2)=[CH:14][CH:13]=1)([OH:11])(=[O:10])=[O:9].[C:31]([OH:34])(=O)[CH3:32]>>[CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:1][C:2]1[C:21]2[C:22](=[O:23])[N:18]([C:15]3[CH:14]=[CH:13][C:12]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:17][CH:16]=3)[NH:19][C:20]=2[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31](=[O:34])[CH:32]=1
Reactant: CC(=O)O
Reactant: O=c1cc(Nc2ccccc2)[nH]n1-c1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(-c2ccccc2)c2[nH]n(-c3ccc(S(=O)(=O)O)cc3)c(=O)c12

Procedure:
1-(4-Sulfophenyl)-3-anilinopyrazolin-5-one triethylamine salt (8.6 g) and 3.5 g of ethyl acetacetate were added to 50 ml of glacial acetic acid and refluxed with heating for 8 hours, and then the reaction solution was concentrated to about 1/3 of the volume. Isopropanol (80 ml) was added thereto to deposit crystals which was then recrystallized from methanol to obtain 3.5 g of 4-methyl-7-phenyl-2-(4-sulfophenyl)pyrazolo[3,4-b]pyridine-3,6-dione triethylamine salt. These crystals (3 g), 0.9 g of glutacondialdehyde dianil hydrochloride, 1.3 ml of triethylamine, 1.1 ml of acetic anhydride and 20 ml of N,N-dimethylformamide were mixed and stirred at room temperature for one hour and then at 50° C. for 2 hours. The reaction solution was cooled to room temperature and a solution of 1.8 g of potassium acetate in 10 ml of methanol, followed by one hour stirring. The deposited crystals were recovered by filtration and recrystallized from a methanol-water mixed solvent (methanol/water=3/1) to obtain 1.1 g of Compound 33 as dark bluish, green crystals. Melting point 300° C. or more, λmaxCH3OH =767 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19](I)[C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33].O>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([C:32]#[N:33])[C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: COc1ccc2c(c1I)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1C#N)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 190 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53c, 300 mg, 0.568 mmol) in NMP (8 mL, dry) was added CuCN (152 mg, 1.705 mmol) at room temperature. The resulting mixture was stirred at 190° C. for 3 hours. The mixture was cooled to room temperature and H2O (20 mL) was added to the mixture. The mixture was diluted with EtOAc (5×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over Na2SO4, and concentrated under vacuum to give a residue, which was purified by column chromatography (petroleum ether/EtOAc, 3:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile (53d, ˜0.568 mmol, 100%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cncc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cncc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-fluoropyridin-3-yl)oxy]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.33 (1H, d, J=2.3 Hz), 8.23 (1H, d, J=2.3 Hz), 8.11 (1H, d, J=2.7 Hz), 7.95 (2H, d, J=8.2 Hz), 7.45 (1H, dd, J=8.7, 2.8 Hz), 7.38–7.25 (1H, m), 7.30 (2H, d, J=8.2 Hz), 6.95 (1H, td, J=8.9, 2.3 Hz), 6.91 (1H, d, J=8.7 Hz), 5.38–5.25 (1H, m), 3.90 (3H, s), 1.50 (3H, d, J=6.9 Hz).