Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=C(F)C=1O[C:5]1[O:6][C:7]([CH3:16])([CH3:15])[C:8]([CH3:14])([CH3:13])[S:9](=[O:12])(=[O:11])[N:10]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C@@H:28]([NH:30][C:5]2[O:6][C:7]([CH3:15])([CH3:16])[C:8]([CH3:13])([CH3:14])[S:9](=[O:11])(=[O:12])[N:10]=2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OC(Oc2c(F)cccc2F)=NS(=O)(=O)C1(C)C
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A mixture of 194 mg of 2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 737 mg of (S)-1-phenylethylamine was stirred at room temperature for 16 hours and then purified in a purification laboratory by means of preparative HPLC. The combined product-containing fractions were alkalized with 25% aqueous ammonia solution and extracted three times with 30 ml of ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. This gave the product (96 mg) with a molecular weight of 310.4 g/mol (C15H22N2O3S); MS (ESI): m/e=311 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][N:23]4[C:26]([C:30]([NH:32][CH3:33])=[O:31])=[C:27]([CH3:29])[N:28]=[C:22]4[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][N:23]4[C:26]([C:30]([NH:32][CH3:33])=[O:31])=[C:27]([CH3:29])[N:28]=[C:22]4[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(C)nc2cc(Oc3ccnc4cc(OCc5ccccc5)ccc34)ccn12
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(C)nc2cc(Oc3ccnc4cc(O)ccc34)ccn12

Procedure:
The first step of the reaction was carried out according to Scheme II discussed previously to yield 7-{[7-(benzyloxy)quinolin-4-yl]oxy}-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide 111-C. Following the addition of TFA and reflux, 7-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide 111 was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[C:12]2[N:13](CC3C=CC4C(=CC=CC=4)C=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:5].BrCC1C=CC2C(=CC=CC=2)C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc2c1NC(=O)CO2

Procedure:
Synthesis of 2-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)-propionic acid methyl ester, I-67. A mixture of compound I-66 (350 mg, 1.5 mmol), 2-(bromomethyl) naphthalene (500 mg, 2.25 mmol), KI (374 mg, 2.25 mmol) and K2CO3 (310 mg, 2.25 mmol) in DMF (8 ml) and water (10 drops) was stirred at rt over night and then partitioned between dichloromethane and water. Water layer was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (4×30 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with EtOAc/hexane as the eluant to give 300 mg of compound I-67. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=S)([CH3:5])[CH3:4].[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:7](=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[NH:6]1
Reactant: CC(C)(CO)NC(=S)Nc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(=Nc2ccc([N+](=O)[O-])cc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 1-(2-hydroxy-1,1-dimethyl-ethyl)-3-(4-nitro-phenyl)-thiourea (3.25 g, 12 mmol) in THF was added 0.5 M aqueous sodium hydroxide (60.4 mL, 30.2 mmol), followed by dropwise addition of a solution of p-toluenesulfonyl chloride (2.52 g, 13.2 mmol) in THF (20 mL). The mixture was stirred at r.t. for 3 h then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give (4,4-dimethyl-oxazolidin-2-ylidene)-(4-nitro-phenyl)-amine (2.7 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:35]([O-:37])=[O:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([OH:25])[C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 82.3 %

Procedure:
12.9 g of L-proline methyl ester and 21.0 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 18.3 g of 3-hydroxy-2-nitrobenzoic acid dissolved in a mixture consisting of 360 ml of dichloromethane and 30 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 24.2 g of 1-(3-hydroxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored needle-like crystal having a melting point of 114° to 116° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]>CN(C)C=O>[OH:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: C=CCCCCBr
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCOC(=O)c1ccc(O)c(OC)c1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of vanillic acid (0.6 g, 3.56 mmol) in N,N-dimethylformamide (7 ml), diisopropylethylamine (0.93 ml, 5.35 mmol) and 6-bromohex-1-ene (0.71 ml, 5.35 mmol) were added. The reaction was stirred at 50° for 8 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 95/5 (200 ml), to n-hexane/ethyl acetate 7/3 during 2000 ml, n-hexane/ethyl acetate 3/7 (400 ml)). The product (0.59 g) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([C:24]([O:26]CC)=O)[C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:24]([OH:26])=[C:18]([CH3:17])[C:19](=[O:21])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: Cc1c(O)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Yield: 76 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (10 g, 46.5 mmol, 1 eq) and diethyl methylmalonate (16 mL, 93 mmol, 2 eq) were heated in phenyl ether (20 mL, 127 mmol) at 240° C. for 3 hours. The solution was cooled and diethyl ether (100 mL) was added. A precipitate formed which was filtered and washed with ether to give 10.5 g of the title compound as a tan solid (76%). [M+H] calc'd for C16H15N3O3, 298; found, 298.
Reaction SMILES: Br[C:2]([C@:4]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C@:6]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])=[O:3].O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:28]([C@@:4]([C@:6]([C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:10][OH:11])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
Crude 1-bromo-2,3,4-tri-benzoyl-L-ribose 21 (13.3 g, 25.3 mmol) was dissolved in acetone (150 mL) and water (5 ml, 277 mmol) at 0° C. Silver carbonate (6.28 g, 22.7 mmol) was added over 5 min. The reaction was brought to room temperature after 15 min and stirred an additional 30 min. The solids were removed by filtration and washed with acetone (100 mL) and the filtrate was concentrated in vacuo. The water was removed via azeotropic distillation with ethanol and toluene and the residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to EtOAc) to give 22 as white solid (9.8 g, 21.2 mmol, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[I-:37].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu](I)I>[I:37][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(I)ccc32)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (1.18 g, 2.08 mmol), copper iodide (I) (79 mg, 0.416 mmol) and sodium iodide (624 mg, 4.16 mmol) in dioxane (4.2 mL), N,N′-dimethylethylene diamine (89 μL, 0.832 mmol) was added at room temperature. The reaction solution was stirred for 5 hours under heating at 110° C. The temperature of the solution was brought to room temperature, and the solution was diluted with ethyl acetate, which was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting solid was washed with hexane and ethyl acetate, whereby the objective compound (995 mg, 78%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)[Cl:16]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10]([Cl:16])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C(=O)O)c1cc(Cl)cc(Cl)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 8.3 g (35.6 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid in 80 ml CH2Cl2 and 4 drops DMF 6.1 ml (71.2 mmol) oxalyl chloride was added at 0° C. and the resulting mixture stirred for 12 h After evaporation of the solvent 8.3 g (93%) 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride was obtained as a light yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([OH:25])=O)=O.Cl.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23](=[O:25])[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2[nH]cc(CCC(=O)Nc3ccccc3C(=O)O)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCc3nc4ccccc4c(=O)n3-c3ccccc3)c2c1
Yield: 39.9 %

Procedure:
To a solution of 3-(5-methoxyindol-3-yl)-N-(2-carboxyphenyl)propionamide (4.0 g, 11.8 mmol) in 50 ml of THF at room temperature was added 1,1-carbonyldiimidazole (1.92 g, 11.8 mmol). The reaction mixture stirred for one hour after which aniline hydrochloride (3.06 g, 23.6 mmol) and 25 ml of dimethylformamide were added. The reaction mixture was stirred at reflux under a drying tube for two days, allowed to cool, and concentrated in vacuo to dryness. The residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was washed (water, 1N sodium hydroxide, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. Crystallization of the product from ethyl acetate/trace methanol provided 1.86 g of 2-[2-(5-methoxyindol-3-yl)-ethyl]-3-phenyl-4-(3H)quinazolinone as a white powder: mp 220°-221° C.; EIMS: 395 (M+).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>O>[C:28]([O:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
4-(N,N-Diphenylamino)benzyl alcohol (5.94 g, 0.0216 mol), pyridine (16 mL) and acetic anhydride (11.4 mL) were mixed in a three-neck flask equipped with a condenser and addition funnel. The resulting mixture was stirred overnight at room temperature. Deionized water (50 mL) was then added and the resulting mixture stirred for 2 hours. The product was obtained by filtration, and recrystallized from hexane to yield the desired product (6.52 g, 95%). m.p. 105-6° C.; 1H NMR δ: 2.10 (s, 3H, CH3), 5.04 (s, 2H, CH2), 7.0-7.4 (m, 14H, phenyl). Analysis: Calculated for C19H17NO2: C, 79.46%; H, 6.03%; N, 4.41%. Found: C, 79.37 %; H, 5.72 %; N, 4.41%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]#[N:23].[OH:24]S(O)(=O)=O>>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:19])=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:23])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C#N)c2N)c(Cl)c1
Product: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Yield: 73 %

Procedure:
Part C: A solution of 1.64 g (4.64 mmol) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)-pyrazole in 8 mL conc. H2SO4 was stirred at room temperature for 4 hours. The reaction was quenched carefully with ice and diluted with water. The solid was collected by suction filtration, washed with water and dried to give 1.26 g (73%) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide, mp 194-196° C. Mass Spec.: (CI+) 371 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2)=[O:21]>C1COCC1>[O:31]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])[CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CCn1nc(C)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.802 g, 4.67 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (1.05 g, 2.73 mmol, 76%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.C([NH2:33])C1C=CC=CC=1.[BH4-].[Na+].Cl>>[CH2:22]1[C@H:20]([NH2:33])[C@@H:18]2[O:19][C:4]3=[C:3]([OH:25])[CH:2]=[CH:1][C:6]4=[C:5]3[C@:10]32[CH2:11][CH2:12][N:13]([CH2:14][CH:15]2[CH2:16][CH2:17]2)[C@H:8]([CH2:7]4)[C@:9]3([OH:24])[CH2:23]1
Reactant: NCc1ccccc1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: N[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 79 %

Procedure:
Chemistry. The synthesis of the newly designed NAQ analogues was achieved readily (FIG. 21, Table 8).34-38 Briefly, naltrexone underwent reductive amination with benzylamine and sodium borohydride, followed by catalytic hydrogenation in the presence of the concentrated hydrochloric acid to yield 6α-naltrexamine dihydrocholoride (6α-NTA.2HCl)39 in a total yield of 79%. A variety of substituted isoquinoline-3-carboxylic acids or its saturated counterparts (see Supporting Information) were then coupled to 6α-NTA.2HCl using EDCI/HOBt. After treating the coupling mixture with K2CO3 in methanol, the NAQ analogues were then obtained by silica gel column purification in yields ranging from 29% to 89%. Biology. In Vitro and In Vivo Pharmacological Studies. The newly synthesized NAQ analogues were first evaluated in the radioligand competition binding assay and the MOR [35S]GTPγS functional assay on OR-transfected Chinese hamster ovarian (CHO) cell membranes for their binding affinity, selectivity and MOR agonism/antagonism in vitro. They were further tested in the behavioral tail immersion assay for their functional activity in vivo. The KOR and the DOR [35S]GTPγS functional assays (in vitro) were also conducted for two selected compounds, 4 and 11. Compound 11, showing antagonism in the tail immersion assay, was then examined in the opioid withdrawal assays (in vivo). Naltrexone (NTX) was also tested as a control in all the assays. In Vitro Radioligand Binding Assay and the MOR [35S]GTPγS Functional Assay. The competitive radioligand binding assay was performed on monoclonal OR-expressed CHO cell membranes as described previously.22,29,34-38 [3H]Naloxone (NLX), [3H]naltrindole (NTI), and [3H]diprenorphine (DPN) were used to label the MOR, the DOR and the KOR, respectively. The MOR [35S]GTPγS binding assay was conducted to determine the Gi/o agonism/antagonism of each new ligand at the MOR as described previously.22,29,34-38 The results were interpreted as potency (EC50) and the relative efficacy (% Emax) of each compound to the MOR full agonist DAMGO for MOR activation. As seen in Table 8, all sixteen NAQ analogues retained sub-nanomolar to nanomolar binding affinity at the MOR.
Reaction SMILES: [OH2:1].[OH-].[Li+].Cl.[CH2:5]1[CH2:9][O:8][CH2:7][CH2:6]1>O.CO>[CH3:9][C:5]1[CH2:6][CH2:7][C@H:6]([C:7]([OH:1])=[O:8])[CH2:5][CH:9]=1
Reactant: C1CCOC1
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1=CC[C@@H](C(=O)O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Methyl-cyclohex-3-(S)-enecarboxylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (3.34 g, 13.2 mmol) in THF (25 mL), water (2.5 mL) and methanol (2.5 mL) was treated with lithium hydroxide monohydrate (2.8 g, 66.2 mmol) and warmed to 50° C. with stirring. After 1 h, the reaction mixture treated with 1M HCl (about 25 mL). The mixture was extracted with hexanes:ethyl acetate (200 mL:15 mL), dried over sodium sulfate, filtered and concentrated to 2.4 g of a white semi-solid. The residue was redissolved in hexanes:dichloromethane (100 mL, 95:5), washed with water, dried over sodium sulfate, filtered and concentrated to 1.68 g (91% yield) of (1S)-4-methyl-cyclohex-3-enecarboxylic acid as a white powder.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][NH:9][N:8]=1.N[C:16]1C(C(N)=O)=CNN=1>C(N)=O>[OH:13][C:12]1[N:14]=[CH:16][N:6]=[C:7]2[NH:8][N:9]=[CH:10][C:11]=12
Reactant: NC(=O)c1c[nH]nc1N
Agent: O=S(=O)(O)O
Solvent: NC=O
Product: Oc1ncnc2[nH]ncc12
Temperature: 145 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A suspension of 3-aminopyrazole-4-carboxamide hemisulphate (113 g.) in formamide (325 ml.) was stirred and heated to 145° C. The reaction was held at 145° C. for 5 hours. The reaction was then cooled to 30° C. and the product collected and washed with formamide (2 × 50 ml.), water (2 × 150 ml.) and acetone (2 × 100 ml.). Wt. of crude product = 79 gms. The crude product was recrystallized by dissolution in a solution made from sodium hydroxide (25 g.) in water (1200 ml.) with treatment at 25° C. with charcoal (8 g.), followed by reprecipitation by the addition of concentrated hydrochloric acid to pH 5. The product was collected and washed with cold water (2 × 300 ml.), acetone (2 × 200 ml.) and dried in vacuo at 60° C. Weight = 70 g. Yield = 80%.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(=O)C>C(O)C.[OH-].[OH-].[Pd+2]>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:22]=[N:23][CH:2]=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ccnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
9-Chloro-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (0.044 g, 0.13 mmol), prepared according to Example 377, was taken up in ethanol (5 mL) and 20% palladium hydroxide on carbon (19 mg, 0.03 mmol), and glacial acetic acid (0.2 mL) were added. The mixture was subjected to evacuation under reduced pressure and recycled with an H2 atmosphere. This process was repeated twice. Finally, the reaction was placed under an H2 atmosphere and allowed to stir at ambient temperature 2 h. At the end of this period the mixture was filtered through a pad of Celite® and concentrated in vacuo. The residue was purified by rp-HPLC (0.1% NH4OH in acetonitrile) to provide 13 mg (39% yield) of 386. MS (ESI+) m/z 296.1 (M+H+), calcd. 295.3. 1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.74 (s, 1H), 7.33 (d, J=1.1 Hz, 1H), 7.03 (d, J=5.6 Hz, 1H), 6.92 (d, J=0.9 Hz, 1H), 5.66 (dq, J=13.3, 6.6 Hz, 1H), 4.57 (td, J=7.9, 3.5 Hz, 4H), 1.38 (d, J=6.6 Hz, 6H)