Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:18][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
12 gm (0.058 mol) of methyl 2-(4-hydroxymethyl-phenoxy)-propionate were dissolved in 60 ml of hexamethylphosphoric acid triamide, the solution was cooled to -10° C., and 4.4 ml (0.06 mol) of thionyl chloride were added dropwise thereto. The resulting mixture was stirred for 30 minutes at 0° C. and then for one hour at 10° C., and subsequently poured into water. The aqueous mixture was extracted with ether, and the extract solution was washed with water, sodium bicarbonate solution and again with water, and dried. The ether was subsequently removed in vacuo at room temperature, leaving methyl 2-(4-chloromethyl-phenoxy)-propionate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C(=O)=O.C(O)CO.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5]3[C:4]=1[C:13](=[O:17])[C:14](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2
Reactant: COc1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: OCCO
Solvent: ClCCl
Product: COc1ccc2cccc3c2c1C(=O)C3=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of 2-methoxynaphthalene (5 g, 31.6 mmol) and oxalyl chloride (11 mL, 126 mmol) in 150 mL of dichloromethane was cooled to −15° C. (CO2/ethylene glycol) under nitrogen. Aluminum trichloride (10.5 g, 79 mmol) was added slowly over 30 minutes. After 3 hours, the mixture was poured onto 100 g of ice. The layers were separated, and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solution was concentrated to afford 4.5 g of a solid. The solid was triturated with dichloromethane to give 1.24 g of the title compound as a solid, mp 218°-220° C.; 1H NMR (DMSO-d6): δ8.38 (d, 1H), 8.25 (d, 1H), 7.90 (d, 1H), 7.63 (m, 2H), 4.07 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)SC=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[O:21][C:19]([C:34]5[CH:33]=[C:32]([NH:31][C:28](=[O:30])[CH3:29])[CH:37]=[CH:36][CH:35]=5)=[CH:17][C:18]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: CC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 was reacted with 3-acetamidophenylboronic acid via General Procedure A to give the corresponding intermediate, after purification by flash chromatography, which was then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give, after purification by reverse phase HPLC, 341. MS (Q1) 455 (M+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([OH:16])(=[O:15])=O)=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=1[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([NH:21][C:22]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=3[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])(=[O:16])=[O:15])=[CH:11][C:10]([C:17]([F:19])([F:20])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NS(=O)(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 9 h
Yield: 9.8 %

Procedure:
To 2.84 g (10.2 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-sulfonic acid (i.e. the title material from Step C) in 70 mL of dichloromethane was added 1.96 g (10.2 mmol) of 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. the title compound of Step E) 1.78 mL (10.2 mmol) of diisopropylethylamine and approximately 5 mg of 4-(dimethylamino)pyridine. The reaction mixture was stirred for 9 hours, then washed with water and dried (sodium sulfate). The solvent was removed with a rotary evaporator. The residue was purified by MPLC (20–40% ethyl acetate in hexanes as eluant) to afford 0.50 g of the title compound as a foamy white solid melting at 69–72° C. 1H NMR (CDCl3) δ 0.1.12 (d, 6H), 2.32 (s, 1H), 3.85 (m, 1H), 5.96 (brd, 1H), 7.07 (s, 1H), 7.35 (m, 3H), 7.39 (dd, 1H), 7.89 (dd, 1H), 8.20 (dd, 1H), 9.26 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][C:6]1[C:5]2[C:17]3[C:18]([C:2]([CH3:1])([CH3:23])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH3:11])[CH:7]=1)=[CH:19][CH:20]=[N:21][CH:22]=3)(=[O:26])[CH3:25]
Reactant: CC(CC1CC1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)CC2CC2)cc2c1-c1cnccc1C(C)(C)O2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(3-cyclopropyl-2-propyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[N:17]4[CH:25]=[CH:26][N:27]=[C:16]4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1([CH:33]=[CH:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.N1CCCN2CCCCCC=12>CN(C=O)C>[CH:28]1([CH:33]([N:23]2[CH:24]=[C:20]([C:18]3[N:17]4[CH:25]=[CH:26][N:27]=[C:16]4[CH:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=4)[N:19]=3)[CH:21]=[N:22]2)[CH2:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: N#CC=CC1CCCC1
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cn[nH]c4)n3)cc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 55.1 %

Procedure:
7-(4-(1-Methylpiperidin-4-yl)phenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.130 g, 0.363 mmol) and 3-cyclopentylacrylonitrile (Table 1, compound g; 0.220 g, 1.81 mmol) were suspended in DMF (10 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.2169 mL, 1.451 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 66 hours. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 2-6% (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(4-(7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.096 g, 0.200 mmol, 55.19% yield). MS (apci) m/z=480.3 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccccn1
Reaction time: 1.17 h
Yield: 105.3 %

Procedure:
To a stirred solution of 1-pyridin-2-yl-ethanol (156 mg, 1.27 mmol) (Mandal, S. K. et al. J. Org. Chem. 2003, 68, 4600-4603) and Et3N (0.27 mL, 1.94 mmol) in CH2Cl2 (5 mL) was added methanesulphonyl chloride (0.11 mL, 1.29 mmol) and the solution was stirred for 70 minutes. The solution was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (2×15 mL) and brine (1×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude methanesulphonic acid 1-pyridin-2-yl-ethyl ester as a yellow oil (269 mg, 100%). 1H NMR (CDCl3) δ 1.77 (d, 3H, J=6.6 Hz), 2.94 (s, 3H), 5.79 (q, 1H, J=6.6 Hz), 7.28 (ddd, 1H, J=7.4, 7.1, 1.3 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.76 (td, 1H, J=7.6, 1.7 Hz), 8.61 (d, 1H, J=4.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(C#N)cc1F
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (2.78 g, 69.6 mmole). After 10 min, 4-benzyloxybenzyl chloride (14.85 g, 63.8 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (150 mL) and extracted with EtOAc (2×150 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (26.61 g, 97%) as a white solid: MS (ES) m/e 473 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)C.Cl.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)=[CH:30][CH:29]=1>O1CCCC1>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccc(-c2ccc(OCCCCCCCCCCCBr)cc2)c1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(=O)OCC
Yield: 84.7 %

Procedure:
First, 0.62 g of sodium ethoxide, 1.5 g of diethyl malonate, and 50 ml of dry ethanol were placed in a 100 ml flask whose content was replaced with argon. Then, 20 ml of tetrahydrofuran solution in which 4 g of 2,3-difluoro-4'-(11-bromoundecyl)oxybiphenyl was dissolved was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred under reflux for 8 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 4 g of 2,3-difluoro-4'-[12,12-bis(ethoxycarbonyl)dodecyl]oxybiphenyl (Y: 84.7%). The compound thus obtained had a purity of 99.8% by GC.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:26])=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F
Product: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F

Procedure:
4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoic acid (D5) (0.9 g) was heated at reflux in thionyl chloride (20 ml) for 2 h. The reaction mixture was evaporated to a minimum then co-evaporated with DCM (3×) to give the title compound (D6) as a white solid (1.0 g)
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[OH-].[K+].[CH3:18][CH2:19][OH:20]>CS(C)=O>[CH2:19]([O:20][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1)[CH3:18]
Reactant: CCO
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (7.06 g, 29.3 mmol) and KOH (4.26 g, 64.6 mmol) in EtOH (30 mL) and DMSO (60 mL) according to the general procedure E. Obtained as a yellow solid (4.20 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:34])[CH3:33]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]3[O:28][N:34]=[C:32]([CH3:33])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.480 mmol) of the compound from Example 63A and 71 mg (0.961 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 144 mg (62% of theory)
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]1[C:9](=[O:10])[O:8][CH:7]([CH:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[NH2:34][NH2:35]>CO>[CH2:12]([CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH:7]([OH:8])[CH2:6][CH:5]([C:9]([NH:34][NH2:35])=[O:10])[CH2:4][CH2:3][C:2]([F:1])([CH3:33])[CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reactant: NN
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (220 mg, 0.489 mmol) in methanol (5 mL) was added excess hydrazine (0.500 mL) and stirred for 18 hours. The reaction was concentrated to give the title compound (222 mg, 94%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[ClH:32].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[C:40][CH2:41][Cl:42])[CH:34]=1.[I-].[K+].O>CN(C)C=O>[ClH:42].[ClH:32].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:41][C:40]#[C:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClCC#Cc1cccnc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(CC#Cc3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.38 g) potassium carbonate (0.42 g), 3-(3-pyridyl)-2-propynyl chloride hydrochloride (1.9 ml) and small amount of potassium iodide in N,N-dimethylformamide (10 ml) was stirred for 2 hours at 40° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine dihydrochloride (0.26 g).
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: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: NCc1ccccc1
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: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:23]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:24]1[O:26][CH2:25]1>>[CH2:28]([O:27][CH2:23][C@H:24]([OH:26])[CH2:25][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@@H](O)COCc3ccccc3)cc12

Procedure:
Using the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step C of Example 1-1 and (R)— benzyl glycidyl ether as raw materials, the captioned compound was synthesized by a reaction similar to step A of Example 2-1.
Reaction SMILES: [Li].[CH2:2]([O:4][C@@H:5]1[C@:13]2([CH2:14][CH3:15])[C@H:8]([C@@H:9]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([O:24]C)[CH:18]=[CH:17][C:16]=4[C@H:10]3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:3].COCC(O)C.N>COCCOC>[CH2:2]([O:4][C@@H:5]1[C@:13]2([CH2:14][CH3:15])[C@H:8]([C@@H:9]3[CH2:23][CH2:22][C:21]4[C@H:16]([CH2:17][CH2:18][C:19](=[O:24])[CH:20]=4)[C@H:10]3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:3]
Reactant: CCO[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC
Agent: N
Agent: [Li]
Solvent: COCC(C)O
Solvent: COCCOC
Product: CCO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 1 h

Procedure:
Add 2.0 g. of lithium to a suspension of 2.0 g. of dl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene, 90 ml. of 1,2-dimethoxyethane, 100 ml. of 1-methoxy-2-propanol, and 300 ml. of ammonia while stirring. Treat with 2.0 g. of ammonium chloride and water, filter off the precipitate and add it to 80 ml. of methanol, 4 ml. of water, and 5 ml. of conc. hydrochloric acid. Stir for one hour and dilute with water. Extract the product with ether and recrystallize it successively from methanol-water and petroleum ether-ether to obtain the title substance, m.p. 95°-97°; ultraviolet peak at 244 mμ (15,900); infrared peak at 6.0 μ.