Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[CH2:7]([C:9]([CH3:11])=O)[CH3:8].C([O-])(=O)C.[Na+]>O>[CH3:8][C:7](=[N:2][NH:3][C:4]([NH2:6])=[O:5])[CH2:9][CH3:11]
Reactant: NNC(N)=O
Reactant: CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC(C)=NNC(N)=O
Yield: 71.1 %

Procedure:
To a solution of semicarbazide HCl (61.2 g, 534 mmol), ethyl-methyl ketone (35 g, 0.49 mol) in water (525 mL), sodium acetate (79.7 g, 972 mmol) was added at room temperature and maintained for 18 hours. The reaction mixture was filtered, the obtained solid was washed with ether (2×25 mL) and dried at 70° C. for 20 hours to afford butan-2-one semicarbazone (45 g, 72%) as white solid. 1H NMR (CDCl3) δ 7.9 (br, 1H), 5.0-6.0 (br, 2H), 2.3 (q, 2H), 1.82 (s, 3H), 1.1 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.F[C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2)=[O:22]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:22])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(F)OC12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a mixture of (S)-methyl 2-amino-3,3-dimethylbutanoate (200 mg, 1.377 mmol) and DIEA (0.481 mL, 2.75 mmol) in DCM (2 mL) solution was add 1-adamantyl fluoroformate (334 mg, 1.515 mmol). The reaction mixture was stirred at rt overnight. The compound was purified by silica gel column chromatography (20% EtOAc/80% hexane) to give a colorless oil (358 mg, 68%) as product.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[H][H]>C(O)(=O)C.[Pd].O>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 5 °C
Yield: 91.8 %

Procedure:
72.50 kg of 14-Hydroxycodeinone is dissolved in 10% aqueous solution of acetic acid, 5% Pd/C catalyst is added, and the mixture is hydrogenated under overpressure of electrolytic hydrogen 104 to 106 kPa at temperatures 30 to 35° C. The reaction mixture is diluted with 200 l of water, filtered, the filtrate is cooled down to 5° C. and Oxycodone base is precipitated by adjusting pH with an addition of an ethanolic solution of ammonia to the value 9.2. The suspension is centrifuged, Oxycodone is washed with water and dried at 70 to 80° C. At least 67 kg (92%, purity 98.5%) of Oxycodone is obtained.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15](OCC)=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:29][C:30]([F:47])([F:46])[C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38](Cl)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1>>[CH3:21][C:11]1[NH:12][C:13]2[CH:20]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:47])([F:46])[F:29])=[CH:32][CH:33]=3)[C:15](=[O:16])[C:14]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: FC(F)(F)c1ccc(N=C(Cl)c2ccccc2)cc1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccc(C(F)(F)F)cc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(4-trifluoromethylphenyl)-benzimidoyl chloride (1.7 g, 5.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C1(=O)C=CC(=O)C=C1>CC(O)C.O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=Cc1ccco1
Agent: O=C1C=CC(=O)C=C1
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1

Procedure:
A mixture of 1,2-diamino-4-nitrobenzene (31 g, 0.2 mol) and 2-furancarboxaldehyde (25 g, 0.26 mol) in 2-propanol is treated with p-benzoquinone (24 g, 0.22 mol). The reaction mixture is heated under reflux for 2 h. The reaction solution is diluted with water to precipitate the product. After drying, the crude product weighs 46 g (100%). Recrystllization from nitromethane provides an analytical sample which melts at 228°-229° C. Anal. Calcd for C11H7N3O3 ; C, 57.64; H, 3.08; N, 18.34. Found: C, 57.55; H, 3.04; N, 18.53.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27]C(=O)C)[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:36]([CH:33]5[CH2:35][CH2:34]5)(=[O:38])=[O:37])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 28 using the procedures of Example 29 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.0 (s, 1H), 8.64 (d, 1H), 8.27 (d, 1H), 7.99 (dd, 1H), 7.85-7.76 (m, 3H), 7.65-7.62 (m, 2H), 7.54-7.45 (m, 2H), 7.33-7.27 (m, 1H), 6.59-6.57 (m, 1H), 2.95-2.93 (m, 1H), 1.04-1.02 (m, 4H); LC-MS (ESI): Calculated mass: 491.51; Observed mass: 492.1 [M+H]+ (rt: 1.659 min).
Reaction SMILES: CO.[Na].[C:4]([O:12]C)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].Cl>C1(C)C(C)=CC=CC=1>[C:17]1([C:14](=[O:16])[CH2:15][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
Methanol (0.26 ml, 6.4 mmol) and sodium (0.14 g, 6.1 mmol) were combined in xylene (60 ml) and stirred for 20 min at room temperature. Methyl benzoate (49, 2.47 ml, 19.7 mmol) and acetophenone (0.58 ml, 5.0 mmol) were added and the mixture stirred for 6 hr at 140° C. The mixture was cooled to room temperature and hydrochloric acid (10 ml, 6 N) was added and stirred for 15 min. The resulting mixture was extracted into ethyl acetate, washed twice with water, twice with saturated sodium bicarbonate and twice with water. The ethyl acetate was dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from methanol to give 0.71 g (63%) of a pink-orange solid: mp 70-71° C. [expected mp 77-78° C.]; 1H NMR: δ 6.85 (s, 1H), 7.51 (m, 6H), 7.98 (d, 4H, J=6.8 Hz); 13C NMR: δ 93.1, 127.1, 128.6, 132.4, 135.5, 185.6.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+].Cl>ClC(Cl)C>[CH2:9]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]2([CH2:25][CH2:26][OH:27])[CH:23]([CH2:1]2)[CH2:24]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[Zn]CC
Reactant: O=C(OCc1ccccc1)N1CC=C(CCO)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: ICI
Product: O=C(OCc1ccccc1)N1CCC2(CCO)CC2C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under ice-cooling, 75 ml of diethylzinc and 33.5 g of diiodomethane were added to 500 ml of dichloroethane. After further adding a solution of 6.53 g of 2-[1-(benzyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]ethanol in dichloroethane (20 ml), the resulting mixture was stirred at room temperature for 6 days. Then the reaction mixture was poured into a mixture of saturated ammonium chloride with 1 N hydrochloric acid, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.22 g of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:27])[CH2:25][NH:26][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[CH2:19]2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc(F)c(F)c1)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The chloroform (0.4 mL) solution of 3,4-difluorobenzoyl chloride (0.060 mmol) was added to the chloroform (1.0 mL) solution of the (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, and then mixed with a (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol). The mixture was stirred at room temperature for 12 hours, and filtered. The resin was washed with dichloromethane (0.5 mL). The filtrate and the washings were combined and mixed with dichloromethane (4 mL). The solution was washed with a 2M NaOH aqueous solution (0.5 mL), and then concentrated to obtain the (R)-1-(4-chlorobenzyl)-3-[{N-(3,4-difluorobenzoyl)glycyl}amino]pyrrolidine (Compd. No. 69) (7.8 mg, 38%): the purity was determined with RPLC/MS (>99%); ESI/MS m/e 408.0 (M++H, C20H20ClF2N3O2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 7-hydroxy-6-methoxyquinazolin-4-(3H)-one (8.0 g, 41.6 mmol), pyridine (7.5 ml) and acetic anhydride (63 ml) was heated at 100° C. for 4.5 hours and left to cool to ambient temperature 18 hours. The reaction mixture was poured into ice/water (400 ml) and the resultant precipitate collected by filtration and dried in vacuo. Analysis revealed that hydrolysis of the acetate group on the 4 position of the quinazoline was incomplete. The mixture was therefore treated with water (150 ml) and pyridine (0.5 ml) at 90° C. for 15 minutes. The reaction was cooled and the solid was collected by filtration, washed with water and dried in vacuo to yield 7-(acetoxy)-6-methoxyquinazolin-4-(3H)-one (7.4 g, 76% yield):
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[N:3]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([CH:4]([CH3:5])[CH3:6])=[CH:23][CH:22]=2)[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:16]
Reactant: CC(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CNN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc(-c2nn(C)c(=O)c3ccccc23)cc1
Yield: 67 %

Procedure:
Methyl hydrazine (8.05 g, 0.175 mol) was added to a mixture of 2-(4-isopropylbenzoyl)benzoic acid (40.2 g, 0.15 mol) in toluene (350 mL) and the mixture was heated to reflux for 3 hours with the removal of water with a Dean Stark trap. The reaction mixture was hot filtered through celite, the filtrate was concentrated to 125 mL and the filtrate was diluted with hexane (100 mL) and cooled. A solid was collected by filtration to afford 27.97 g (67%) of 2-methyl-4-(4-isopropylphenyl)-1-(2H)-phthalazinone, m.p. 107°-107.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH2:15])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccc2)cc1

Procedure:
The preparation took place in analogy with Example 15a), starting with 500 mg of 5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (50) and 315 μl of benzoyl chloride. The following was obtained: 51 C18H17N3O2 (307.36) MS (ESI) 308 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: Nc1ncc[nH]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a thermally controlled reaction vessel, add 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (420 g, 1.56 mol, 1.0 equiv), 2-aminoimidazole monosulfate (349 g, 1.87 mol, 1.2 equiv), N,N-dimethylformamide (2.94 L), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (722 g, 2.18 mol, 1.4 equiv), and N,N-diisopropylethylamine (869 mL, 4.98 mol, 3.2 equiv). Heat the resulting suspension to an internal temperature of 80° C. for 18 hours. Cool the reaction mixture to 10° C., pour the mixture into ice water (14 L), and stir for 90 min. Collect the solids by filtration, dry the material in air for 24 h, and in a vacuum oven at 50° C. for 24 h. Slurry the solid material in isopropanol (7 L), heat to an internal temperature of 73° C. for 3 h, and cool to 10° C. Filter the suspension to isolate the solid material. Dry the material in air for 24 h and in a vacuum oven at 55° C. for 48 h to give the title compound as an off-white solid (435 g, 83.4%). 1H NMR (DMSO-d6, 400 MHz): δ 11.84 (s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.47 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=1.7 Hz), 7.31 (dd, 1H, J=8.3, 2.0 Hz), 6.73 (s, 2H), 4.27 (d, 2H, J=5.9 Hz), 1.12 (s, 9H). MS (m/z) (35Cl/37Cl) 335/337 (M+1).
Reaction SMILES: I[C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:16]3([CH3:24])[OH:17])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[O:25])[NH:6][N:7]=[CH:8]3)[CH:3]=1.[C:26]([Cu])#[N:27]>CN(C=O)C>[C:26]([C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:16]3([CH3:24])[OH:17])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[O:25])[NH:6][N:7]=[CH:8]3)[CH:3]=1)#[N:27]
Reactant: N#C[Cu]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(I)cc3c(=O)[nH]ncc(n1)c23
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C#N)cc3c(=O)[nH]ncc(n1)c23
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of the title product from Example 19 in DMF is added CuCN/Bu4NCN and the mixture is stirred at 65° C. overnight to form the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: Ic1ccc(Oc2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.3 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (54.4 mg) was reacted with 2-(4-iodophenoxy)pyrimidine (59.2 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (53.0 mg). Thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=10/1) was used for purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][NH:22]CCC(C)C)([CH3:4])([CH3:3])[CH3:2].[C:41](=O)(O)[O-:42].[Na+].Cl>CCO>[C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1/[CH:21]=[N:22]/[O:42][CH3:41])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNCCC(C)C)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C/c1cc(NS(C)(=O)=O)ccc1C=Cc1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of the product from Example 30, Part A (35 mg, 0.070 mmol) in EtOH (2 ml) was added O-methoxylamine hydrochloride (29 mg, 0.35 mmol) and sodium bicarbonate (30 mg, 0.35 mmol). The resulting mixture was stirred at 70° C. for 2 h. To the mixture was added 1 N aq. HCl (1 ml) to give a colorless precipitate that was filtered and dried to give the title compound as a colorless solid (24 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1 H) 9.94 (s, 1 H) 8.74 (s, 1 H) 7.79-7.85 (m, 2 H) 7.76 (d, J=7.72 Hz, 1 H) 7.57-7.65 (m, 2 H) 7.32 (dd, J=8.64, 2.39 Hz, 1 H) 7.23 (d, J=2.57 Hz, 1 H) 7.18 (d, J=116.18 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.93 (s, 3 H) 3.79 (s, 3 H) 3.03 (s, 3 H) 1.38 (s, 9 H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]([NH2:37])=[S:36])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:45][C:46](=O)[CH3:47].O>C(O)C>[CH2:39]([N:20]1[C:19]([CH2:18][NH:17][C:16](=[O:43])[O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]3[S:36][CH:45]=[C:46]([CH3:47])[N:37]=3)[CH:26]=2)[C:21]1=[O:38])[CH:40]([CH3:41])[CH3:42]
Reactant: CC(=O)CBr
Reactant: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Solvent: CCO
Solvent: O
Product: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Yield: 81.9 %

Procedure:
A suspension of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.47 g, 0.8 mmol) and bromoacetone (0.22 g, 1.6 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl. acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl [2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.41 g, 82.0%) as an amorphous.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([O:20]C)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].[ClH:28]>C(OCC)C.CCOC(C)=O>[ClH:28].[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([OH:20])=[O:19])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer 79 (1.37 g, 4.61 mmol) and potassium trimethylsilanolate (0.68 g, 5.30 mmol) in diethyl ether (23 mL) was stirred at r.t. overnight. A saturated solution of hydrogen chloride in EtOAc was then added, the volatiles were evaporated to give 80, which was used without further purification in the preparation of Examples detailed below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Yield: 69.6 %

Procedure:
A mixture of 2-(4-bromophenyl)acetic acid (50 g, 0.23 mol), benzyl alcohol (26 mL. 0.25 mol) and p-toluenesulfonic acid (0.3 g) in 200 ml toluene were heated at reflux with the azeotropic removal of water (15 h). The yellow solution was washed with water (250 mL), saturated aqueous sodium bicarbonate (250 mL) and then dried (MgSO4). Concentration provided a light yellow solid that was recrystallized from cold hexanes to give benzyl 2-(4-bromophenyl)acetate (48.5 g, 0.16 mol) in 69% yield, mp. 47.5°-48° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cc(F)cc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cc(F)cc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3,5-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.14 (1H, d, J=2.8 Hz), 7.94 (2H, d, J=8.4 Hz), 7.45 (1H, dd, J=8.8, 2.8 Hz), 7.37 (1H, d, J=7.9 Hz), 7.28 (2H, d, J=8.4 Hz), 6.95 (1H, d, J=8.8 Hz), 6.58–6.68 (1H, m), 6.48–6.38 (2H, m), 5.31 (1H, dq, J=7.9, 7.0 Hz), 3.91 (3H, s), 1.49 (3H, d, J=7.0 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.