Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[N:41]1([CH:27]2[CH2:28][CH2:29][N:23]3[N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:12]5[CH:13]=[C:9]([Cl:8])[N:10]=[CH:11]5)=[C:15]([O:39][CH3:40])[CH:16]=4)[N:38]=[C:24]3[CH:25]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:26]2)[CH2:44][CH2:43][CH2:42]1
Reactant: C1CNC1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(N2CCC2)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (50 mg, 0.107 mmol, from example 137) was added to a mixture of azetidine (6.11 mg, 0.107 mmol), and sodium cyanoborohydride (1.0M in THF, 428 μL, 0.428 mmol) in ethanol (0.535 mL). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (18.7 mg, 27% yield) as a TFA salt. LC-MS (M+H)+ 508.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.63 (1 H, d, J=3.7 Hz), 7.89-7.98 (1 H, m), 7.31-7.38 (1 H, m), 7.07-7.22 (5 H, m), 7.01 (2 H, dd, J=8.5, 4.9 Hz), 4.92 (2 H, d, J=4.6 Hz), 4.64-4.77 (1 H, m), 4.42 (2 H, br. s.), 3.98-4.10 (1 H, m), 3.66-3.97 (5 H, m), 2.58-2.90 (2 H, m), 2.14-2.44 (4 H, m).
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>CN(C=O)C.CC(=O)OCC.O>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:39][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(Cl)c3)sc21
Temperature: 65 °C
Yield: 59 %

Procedure:
To a mixture of 6-bromo-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (100 mg, 0.23 mmol), K2CO3 (159 mg, 1.15 mmol) in DMF (3 mL) was added 3-chlorophenol (90 mg, 0.70 mmol). The reaction was heated at 65° C. for 1 h, cooled to RT then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography and eluted with PE/EA (5:1) to give 6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (65 mg, 58.6% yield) as a yellow oil. LCMS: MH+ 479 and TR=1.836 min.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)#[N:2].C([Sn]([N:28]=[N+:29]=[N-:30])(CCCC)CCCC)CCC.Cl>COCCOC.CO>[NH:28]1[C:1]([CH2:3][C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[N:2][N:30]=[N:29]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(CC#N)cc1
Agent: Cl
Solvent: COCCOC
Solvent: CO
Product: CCOC(=O)c1ccc(Cc2nnn[nH]2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Ethyl 4-cyanomethylbenzoate (approximately 8 g) was dissolved in DME (10 ml). The solution was added tris(n-butyl)tin azide (5 ml) and the resultant solution was stirred and heated at 85° C. overnight. The solution was cooled to room temperature. The cooled solution was diluted with methanol then acidified with 1N hydrochloric acid. The acidified mixture was stirred for one hour then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:12][O:13][C:14](=[O:29])[C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:24]=O)=[C:19]([CH3:26])[CH:18]=1.OOS([O-])=O.[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]([C:15]([CH3:28])([CH3:27])[CH2:16][C:17]1[CH:18]=[C:19]([CH3:26])[C:20]([C:24]2[NH:1][C:2]3[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[C:21]([CH3:23])[CH:22]=1)=[O:29]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.6 g of 3,4-diaminobenzenoic acid was stirred in 120 ml of DMF at room temperature. It was treated with 12.4 g of 3-(4-formyl-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (the intermediate A in Example 1-62) followed by an addition of a slurry of 15 g of Oxone in 60 ml of DMF. The reaction was stirred at room temperature for 3 h and 60 mL of water was added and the pH was adjusted to 6. Additional 150 mL of water was added and the resulting precipitates were collected by filtration. The collected precipitates were washed with water and dried under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc(F)cc1C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide in THF (100 mL) was added 1M phenylmagnesium bromide in THF (124.12 mL, 124.12 mmol). The reaction was stirred from −78° C. to ambient temperature over 3.5 h and then cooled again to −78° C. Additional 1M phenylmagnesium bromide in THF (62.06 mL, 62.06 mmol) was added and the reaction stirred at −78° C. for another hour. The reaction was then diluted with CH2Cl2 (500 mL) and quenched with saturated ammonium chloride solution (300 mL). The layers were separated and the organic one washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (3-8% MeOH/CH2Cl2) yielded (2-amino-5-fluorophenyl)(phenyl)methanone as a yellow solid. 1H NMR (CDCl3, 400 MHz) 7.63 (m, 2H, ArH); 7.55 (m, 1H, ArH); 7.47 (m, 2H, ArH); 7.15 (m, 1H, ArH); 7.08 (m, 1H, ArH); 6.70 (m, 1H, ArH); 5.91 (s, NH2); MS (Electrospray): m/z 216.1 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](=[NH:9])[NH2:8])[CH2:3][CH2:2]1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21]>C1(C)C=CC=CC=1>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:25]([OH:26])=[N:9][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:20]=1[OH:21]
Reactant: N=C(N)C1CCOCC1
Reactant: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Solvent: Cc1ccccc1
Product: Oc1nc(C2CCOCC2)nc(O)c1-c1nc2ccccc2s1

Procedure:
A solution of oxane-4-carboximidamide (160 mg, 1.25 mmol, 1.00 equiv), and 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate (366 mg, 1.25 mmol, 1.00 equiv) in Toluene (3 mL) was heated for 3 h at 110° C. in an oil bath. After concentrated under reducing pressure, 460 mg (crude) of the title compound was obtained as a white solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 330.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].C[O-].[Na+].[O:42]1CCC[CH2:43]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([O:42][CH3:43])[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, sodium methoxide/tetrahydrofuran was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5 to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 404.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH2:30][CH2:29][CH2:28]1)#[N:24].C(/C=C\C1(CNC(=O)OC(C)(C)C)CCCC1)#N.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:23]([CH2:25][CH:26]([C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:30][CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)NCC1(/C=C/C#N)CCCC1
Agent: CC(C)(C)OC(=O)NCC1(/C=C\C#N)CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (355 mg, 1.12 mmol) and tert-butyl (1-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (1-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg, 1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60° C. for 2.5 hours. The ACN was removed in vacuo and the resulting residue was purified by flash column chromatography (eluting with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:6]2)[CH3:2].C1COCC1.CCO.O.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:14])([F:15])[F:16])[C:7]([C:17]([OH:19])=[O:18])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
A 15 mL single-neck round bottom flask was charged with ethyl 6-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.238 g, 0.932 mmole), THF:EtOH:H2O (7:2:1 by volume, 3 mL), and aqueous NaOH (0.41 mL of 2.5 N aq solution, 1.026 mmole). The reaction was stirred at RT under nitrogen for 3 days and was concentrated in vacuo (high vacuum) to yield a semi-solid. The semi-solid was dissolved in H2O, washed with diethyl ether, and sparged with nitrogen with gentle warming. The resulting organic solvent-free aqueous phase was acidified with concentrated HCl with stirring providing a slurry. The slurry was vacuum filtered yielding a white solid. The solid was dried on high vacuum yielding the title compound as a white powder (0.178 g, 70%): mp 145-149° C. LCMS m/z 273.15 (M+H). HRMS m/z 271.0600 (M−H, C13H10F3O, Cald'd 271.0577). 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.30 (d, 1H, J=2.0 Hz), 7.27 (d, 1H, J=8.3 Hz), 6.94 (d, 1H, J=8.3 Hz), 5.77 (q, 1H, J=7.0 Hz), 2.61 (q, 2H, J=7.5 Hz), 1.21 (t, 3H, J=7.5 Hz).
Reaction SMILES: O=[C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:15]=2)[O:10][C:4]2([CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH2:3]1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:4]2([CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:3]/[C:2]/3=[N:29]/[C:30]#[N:31])[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC2(CCOCC2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Yield: 80.8 %

Procedure:
A solution of 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (170 mg, 0.53 mmol) and TiCl4 (403 mg, 2.12 mmol) in anhydrous DCM (5 mL) was heated at 50 under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (198 mg, 1.06 mmol) was added and the mixture was heated at 60 for another 30 mins. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (Z)—N-(6-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-ylidene)cyanamide (147 mg, crude), which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:25])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1.[O:26]=[C:27]1[CH2:32][S:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1>CO.C(Cl)Cl>[CH3:25][C:4]1([CH2:3][NH:2][CH2:37][C:35]2[CH:34]=[CH:33][C:30]3[S:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=3[N:36]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CN)C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2c1
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of the HCl salt of 4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (50 mg) in MeOH (2 mL) and DCM (2 mL) were added NaHCO (130 mg, 1.6 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (30 mg, 0.18 mmol). After 24 h at 25° C., NaBH (10 mg, 0.27 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (20 mg) as a brown oil: LC/MS (ES) m/e 503 (M+H) 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (m, 3H), 2.9-2.5 (m, 6H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3cc(OC)ccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(-n3cc(C(=O)O)c4ccccc43)ccnc2c1
Yield: 72.3 %

Procedure:
0.504 g (12 mmol) of lithium hydroxide monohydrate and 20 cm3 of water are added to 1.3 g (3.91 mmol) of 3-methoxycarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole dissolved in 20 cm3 of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water (pH=10). The resulting aqueous solution is washed with 50 cm3 of ethyl acetate and adjusted to pH 6 with N hydrochloric acid. The resulting precipitate is filtered off and then it is rinsed with three times 20 cm3 of water and twice 20 cm3 of isopropyl ether and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. to give 0.9 g of 3-carboxy-1-(7-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M+•).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28]C(Cl)(Cl)Cl)Cl.O[N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)ON4C(=O)c5ccccc5C4=O)cc3)c2cc1OC
Yield: 13.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-hydroxy-1,3-isoindolinedione (42 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (11 mg, yield 12%).
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:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:17]1[CH:15]([CH2:14][N:13]2[C@@H:8]3[CH2:7][C:6]4[CH:1]=[CH:2][C:3]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:4]5[O:19][C@H:18]6[C:20]([CH2:22][CH2:23][C@:9]3([OH:24])[C@:10]6([C:5]=45)[CH2:11][CH2:12]2)=[O:21])[CH2:16]1
Reactant: BrCc1ccccc1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 60 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of naltrexone (2.5 g, 7.3 mmol) and benzylbromide (1.5 g, 8.8 mmol) in DMF (25 mL) was added potassium carbonate (2.8 g, 20 mmol). The mixture was stirred for 12 hrs at 60° C., then cooled and diluted with water. The resulting oily product was extracted with EtOAc. The extract was washed with water dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (hexane-EtOAc, 3;2) to afford 3-benzylnaltrexone (4) (2.3 g, 74%). 1H NMR (CDCl3) δ 0.15(2H, m, H-20β, H-21β), 0.56(2H, m, H-20α, H-21α), 0.87(1H, m, H-19), 1.58(1H, dd, J=12.3 Hz, 2.4 Hz, H-15), 1.64(1H, dt, J=13.5 Hz, 2.4 Hz, H-8), 1.89(1H, d, J= 13.5 Hz, H-8), 2.13(1H, dt, J=12.3 Hz, 2.4 Hz, H-15), 2.30(1H, dt, J=12.3 Hz, 2.4 Hz, H-16), 2.40(3H, m, H-7, H-18), 2.55(1H, dd, J=18.3 Hz, 6.0 Hz, H-10), 2.69(1H, dd, J=12.3 Hz, 2.4Hz, H-16), 3.03(2H, m, H-7, H-10), 3.18(1H, d, J=6.0 Hz, H-9), 4.70(1H, s, H-5), 5.20(1H, d, J=12.0 Hz, Bz CH), 5.29(1H, d, J=12.0 Hz, Bz CH), 6.56(1H, d, J=7.2 Hz, H-1), 6.71(1H, d, J=7.2 Hz, H-2), 7.25-7.60(5H, m, Bz aromatic H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[F:32][C:33]1[CH:46]=[CH:45][C:36]2[C:37]([CH2:40][CH2:41][CH2:42][CH2:43]Cl)=[N:38][O:39][C:35]=2[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:43][CH2:42][CH2:41][CH2:40][C:37]3[C:36]4[CH:45]=[CH:46][C:33]([F:32])=[CH:34][C:35]=4[O:39][N:38]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Reactant: Fc1ccc2c(CCCCCl)noc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(C(CN2CCN(CCCCc3noc4cc(F)ccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
0.37 g of 1-[2-(4-Fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine obtained in Example 2 (4) was dissolved in 4.0 ml of dimethylformamide, and 0.19 g of N-ethyldiisopropylamine and 0.31 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)butyl chloride were added, followed by stirring at 120° C. for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.22 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)butyl]piperazine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH2:10][CH3:11])[CH:3]=1)[NH:9][N:12]=[CH:8]2.[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([CH3:8])[CH:7]=1)[NH:9][N:12]=[C:10]2[CH3:11]
Reactant: CCc1cc(Br)cc(C)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(Br)cc2cn[nH]c12
Product: Cc1n[nH]c2c(C)cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %
Yield: 33 %

Procedure:
A solution of 4-bromo-2-ethyl-6-methylbenzenamine (3.21 g, 15 mmol) in acetic acid (50 mL) was stirred for 3 hours before addition of a 2 M solution of sodium nitrite (11 mL, 22.5 mmol). The resulting mixture was stirred overnight at room temperature. The solution was concentrated and the solid was dissolved in EtOAc and washed with saturated aqueous NaCl (3×). The organic extract was dried over Na2SO4, filtered and concentrated. the crude material was purified by Biotage chromatography (40M, 15-30% EtOAc/heptane) to provide 5-bromo-7-ethyl-1H-indazole (1.11 g, 33%) and 5-bromo-3,7-dimethyl-1H-indazole (0.84 g, 25%).