Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([OH:21])[CH2:19][CH3:20])[C:3]1=[O:22].C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CC#N.CCOC(C)=O>[OH:21][CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=2)[C:3]1=[O:22])[CH2:19][CH3:20].[OH:21][C@@H:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:42])[F:41])[CH:33]=2)[C:3]1=[O:22])[CH2:19][CH3:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Product: CC[C@@H](O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (47.6 mg, 0.153 mmol) in CH3CN (2 mL) were added triethylamine (0.08 mL, 0.46 mmol), 3-trifluoromethylbenzoic acid (38 mg, 0.2 mmol), and TBTU (73.7 mg, 0.23 mmol), and the mixture was stirred for 8 h at rt. The reaction mixture was diluted with EtOAc, and washed with 1N-NaOH and water. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH-MeOH—CH2Cl2 to afford the titled compound N-(1-((1S,2R,4R)-2-((R)-1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (38.5 mg) as a solid. MS found: (M+H)+=484.3.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:7]=2[CH:6]=1)=O.[NH:15]1[CH2:19][CH2:18][NH:17][C:16]1=[S:20].C(O)(=O)C>C(O)C>[BrH:1].[Cl:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:17]4[CH2:18][CH2:19][N:15]=[C:16]4[S:20][CH:2]=3)[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: S=C1NCCN1
Reactant: O=C(CBr)c1cc2c(Cl)cccc2s1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: Clc1cccc2sc(C3=CSC4=NCCN34)cc12
Temperature: 0 °C
Yield: 66.8 %

Procedure:
A mixture of 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (2.5 g), 2-imidazolidinethione (0.88 g), acetic acid (25 ml) and ethanol (50 ml) was heated under reflux for 90 minutes, then cooled to 0° C. The resulting solid was collected by filtration and dried in vacuo at 60° C. for 2 hours to give 3-(4-chlorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[-2,1-b]thiazole hydrobromide (2.15 g) as colourless solid, m.p. 261-263° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.Cl[CH2:16][CH2:17][S:18][CH2:19][CH2:20]Cl.CC(CC)=O.CC(C)=O>C(OCC)(=O)C>[NH:10]=[C:8]1[N:7]([CH2:16][CH2:17][S:18][CH2:19][CH3:20])[C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][C:5]=2[S:9]1
Reactant: ClCCSCCCl
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Solvent: CC(C)=O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCSCCn1c(=N)sc2cc(C(F)(F)F)ccc21
Temperature: 20 °C

Procedure:
2-Imino-3(2-ethylthioethyl)-6-trifluoromethylbenzothiazoline can be obtained in the following manner: A mixture of 6-trifluoromethyl-2-benzothiazolamine (32.3 g), 2-chloroethylsulphide (18 cc) and methylethylketone (20 cc) is heated under reflux for 16 hours. After cooling to 20° C., acetone (20 cc) is added and the solution obtained is poured into a mixture of ethyl acetate (200 cc) and petroleum ether (40°-60° C., 200 cc). The precipitate obtained is filtered off, taken up in water, and made alkaline with 28% ammonia. The base is then extracted with a mixture of ethylacetate (150 cc) and cyclohexane (150 cc) and purified on a column of silica (600 g), eluting with a mixture of ethylacetate and cyclohexane (50:50 by volume). 2-Imino-3-(2-ethylthioethyl)-6-trifluoromethylbenzothiazoline (33.2 g), m.p. 50° C., is thus obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:24])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17](OCC)=[O:18])=[CH:13][CH:12]=2)[O:5]1.O1CCCC1.C(O)C>O>[CH3:9][C:8]1([CH3:10])[C:4]([CH3:3])([CH3:24])[O:5][B:6]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:12]=2)[O:7]1
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
Sodium borohydride (0.33 g) was added to a mixture of ethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-acetate (1.33 g), tetra hydrofuran (10 mL) and ethanol (10 mL). The mixture was stirred at room temperature for 4 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to afford the title compound (1.13 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12](C=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl.C(O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=CN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)nsc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
Reflux a solution of 4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinecarboxaldehyde (Tetrahedron Lett., 1993, 34, 6525–6528, 12 g, 0.045 mol), 3N hydrochloric acid and ethanol (100 mL) for 3 hours. Stir at ambient temperature for 16 hours, add water and stir with ice bath chilling while adding sodium hydroxide solution until the mixture was basic. Extract with ethyl acetate, wash the extract with water, dry (MgSO4), filter and concentrate the filtrate to afford an oil which solidified on standing to afford 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (9.2 g). React 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole under conditions as described for Example 11 to afford the title compound (0.25 g, 61% yield), LC/MS (APCI) m/e 510 (MH+), retention time 4.38 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8](N)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccccc1
Reactant: NCCCCCN
Product: NCCCCCNC(=O)c1ccccc1
Yield: 70.6 %

Procedure:
Under an argon atmosphere, 1,5-diaminopentane (25 g, 0.24 mol) and benzamide (9.9 g, 0.081 mol) were combined and heated at reflux overnight. The reaction mixture was concentrated under vacuum to remove the excess diamine. The residue was distilled at about 210° C. at 12 torr (16×102 pascals) to provide 11.8 g of N-(5-aminopentyl)benzamide as a colorless oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.O.[NH2:28][NH2:29]>C(O)C>[NH:28]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=2)=[N:29]1
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(P(c2ccccc2)c2cccc(-c3cc[nH]n3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 1.8 g (5.1 mmol) of [3-(3-dimethylamino-1-oxoprop-2-en-yl)phenyl]diphenyl phosphane and 2.6 g (51 mmol) hydrazine monohydrate in 20 ml of ethanol is heated to boil under cover gas for 3 h. After cooling of the solution to room temperature, the solvent is removed in a vacuum. The remaining colorless oily residue is recrystallized from acetic acid ethyl ester. A colorless solid is obtained (yield: >70%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4]([CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5].[BH4-].[Na+]>CO.O.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][CH:15]=1)(=[O:6])=[O:5]
Reactant: CC(C)(C)CS(=O)(=O)Cc1ccc(C#N)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CS(=O)(=O)Cc1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
Add cobalt(II) chloride hexahydrate (1.83 mg, 7.7 mmol) to a solution of 4-(2,2-dimethylpropane-sulfonylmethyl)-benzonitrile (966 mg, 3.85 mmol) in methanol (25 mL). Cool the mixture to 0° C. and stir for 15 min. Carefully add sodium borohydride (1.46 g, 38.49 mmol) in small batches, allow the mixture to warm to room temperature and stir for 2 h. Dilute the mixture with water and partition between water and chloroform. Extract the aqueous phase three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 35 min, 85:15; 50 mL/min) to give the title compound (181 mg, 49%). MS (APCI+) m/z: 256 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)c1ccccc1
Product: CON=C1C[C@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2R,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 90% purity by HPLC. MS(ESI+): m/z=456.
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].CN1C=CN=C1.[CH3:28][O:29][C:30](Cl)=[O:31].O>C(Cl)Cl>[CH3:28][O:29][C:30]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])=[O:31]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 35.4 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and the product prepared from 0.8 g N-methylimidazole and 0.9 g of methoxycarbonylchloride were reacted as a stirred suspension in 30 ml of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was dried and evaporated to give 1.2 g (33% yield) of yellow solid product, m.p. 112°-113° C., (d,l) isomer form.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[C:35]([O:39][CH3:40])(=[O:38])[CH2:36][SH:37].CN(C=O)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Yield: 15 %

Procedure:
A mixture of the title compound from Example 250 (0.26 grams), sodium hydride (0.08 grams, 60% in mineral oil), methyl thioglycolate (0.19 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with a 200 W lamp for 16 hours. The mixture was diluted with MeOH, concentrated in vacuo, diluted with CH2Cl2 and water, and washed with 1N aqueous NaOH and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo and the residue purified by preparative plate chromatography (silica gel) using 3% MeOH-CH2Cl2 to afford the title compound (0.05 grams, 15%, MH+ 534).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[CH:4][CH:3]=1.C(O)(=O)C.Br>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2ccccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Cl)c2ccccc12

Procedure:
The known compound 1-chloro-4-methoxynaphthalene is dissolved in 150 ml. of acetic acid and 150 ml. of 48 percent hydrobromic acid, and the mixture is heated at its reflux temperature for two hours. The mixture is diluted with 200 ml. of water and cooled to provide 1-chloro-4-hydroxynaphthalene as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[S:27])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(F)cc(NC(=S)c2ccccn2)c1
Yield: 92.3 %

Procedure:
N-(3,5-Difluorophenyl)-2-pyridinecarboxamide (7.00 g, 29.9 mmol) was treated with Lawesson's reagent (6.28 g, 15.5 mmol) in toluene (90 mL) at reflux temperature for 4 hours. The solvent was removed, and the residue was dissolved in dichloromethane, preadsorbed onto silica gel, and flash chromatographed (300 g of silica gel eluted with 10% ethyl acetate in petroleum ether). Recrystallization from a mixture of ethyl acetate and hexane afforded N-(3,5-difluorophenyl)-2-pyridinecarbothioamide (3.58 g, 48%) as a yellow solid, m.p. 140°-142° C. Overall yield 33%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:27][CH:26]=2)[CH:11]=1>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:27][CH:26]=2)[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice cooling 1 ml of acetic anhydride was added to a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride and 5 ml of pyridine followed by stirring at room temperature overnight. The reaction mixture was treated similarly to Example 68 to obtain 150 mg of ethyl 4-acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH:25]=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][CH:11]3[CH2:12][CH2:13][CH2:14][N:9]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[CH:29][CH:30]=2)[CH:25]=[N:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1ncc2cc(NC3CCCN(Cc4ccccc4)C3)ccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A mixture of 1-benzyl-piperidin-3-one hydrochloride (116 g, 0.52 mol, 1.2 eq) and TEA (43.5 g, 0.43 mol, 1.0 eq) in DCE (800 mL) was stirred at 30° C. for 1 hour. Then 5-amino-indazole-1-carboxylic acid tert-butyl ester (100 g, 0.43 mol, 1.0 eq) and CH3COOH (25.8 g, 0.43 mol, 1.0 eq) were added and the reaction mixture stirred for 30 min. NaBH(OAc)3 (273 g, 1.29 mol, 3.0 eq) was then added in one portion and the mixture stirred at 30° C. for 16 hours. LC-MS showed complete conversion. The reaction mixture was diluted in DCM (1 L) and the organic layer washed with saturated NaHCO3 (800 mL×3) and H2O (500 mL×3), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using (DCM:MeOH=60:1) to give the 5-(1-benzyl-piperidin-3-ylamino)-indazole-1-carboxylic acid tert-butyl ester (131 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N+:9]([O-:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)OO
Reactant: COc1cccc(Oc2cccnc2)c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1cccc(Oc2ccc[n+]([O-])c2)c1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A solution of 68 g of 3-(3-methoxyphenoxy)pyridine in 100 ml of glacial acetic acid is treated with 75 g of 40% peracetic acid in acetic acid. The mixture is stirred 16 hours at 35° C. and then is refluxed 1 hour. The mixture is cooled, 100 ml isopropanol added, and the mixture is concentrated at reduced pressure. The oily residue is dissolved in 500 ml of dichloromethane and is washed with excess cold 25% sodium hydroxide solution. The organic layer is concentrated to yield 3-(3-methoxyphenoxy)pyridine 1-oxide, m.p. 75°-77° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 2-indanone (13.47 g, 102 mmol) in anhydrous benzene (100 mL) was added to phenylmagnesium bromide (3.0 M in diethyl ether, 50.9 mL, 153 mmol) at 5° C. over 2.5 hours. The reaction was allowed to warm to room temperature over 30 minutes. The solution was cooled to 0° C. and 150 mL of water are added. The resultant mixture was diluted with 200 mL of hexanes, neutralized with 5 M HCl, and washed with brine (2×100 mL). The aqueous layer was extracted with hexanes (2×50 mL), and the combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo from the filtrate to yield a brown oil. This oil and p-toluenesulfonic acid (0.50 g) were dissolved in benzene (250 mL) in a round-bottom flask below a Soxhlet extractor containing 4 Å molecular sieves. After refluxing for 2.5 hours, the solution was filtered and cooled to 5° C. overnight. The product, a white flaky solid, was collected by filtration, and was washed with 50 mL of cold benzene. Additional product is obtained by concentrating the filtrate, cooling, and filtering the crystals (12.60 g, 64.3% yield). 1H NMR (400 MHz, 20 C, CDCl3) 7.62 (d, J=7.3 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.39 (M, 3H), 7.27 (m, 2H), 7.22 (s, 1H), 7.18 (t, J=7.4 Hz, 1H), 3.78 (S<2H). 13C{1H} NMR (100 MHz, 20 C, CDCl3): 146.3, 145.3, 143.1, 135.9, 128.6, 127.5, 126.5, 126.4, 125.6, 124.7, 123.6, 120.9, 38.9.
Reaction SMILES: O([C:3](C)(C)C)[K].[CH:7]1[C:12]2[CH2:13][C@H:14]3[N:19]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[CH2:18][CH2:17][C@:16]45[C@H:24]([C:26]([CH2:28][CH2:29][C@@:15]34[OH:30])=O)[O:25][C:10]([C:11]=25)=[C:9]([OH:31])[CH:8]=1.C(O)(=O)C.[ClH:36]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1.O>[CH2:3]=[C:26]1[C@@H:24]2[O:25][C:10]3[C:11]4[C@:16]52[CH2:17][CH2:18][N:19]([CH2:20][CH:21]2[CH2:22][CH2:23]2)[C@H:14]([CH2:13][C:12]=4[CH:7]=[CH:8][C:9]=3[OH:31])[C@:15]5([OH:30])[CH2:29][CH2:28]1.[ClH:36]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC1CCCO1
Product: C=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Methyltriphenylphosphonium bromide (MTPPB, 112.9 g) was suspended in 2-methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20-25° C., KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-25° C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10.1 g) was added over one hour at 20-25° C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1 g of Nalmefene HCl.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1.O>CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:3]3[CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:13]=2)[N:18]=1
Reactant: Oc1ccc(CN2CCCC2)cc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (2.6 g, 108.5 mmol) in DMF (300 mL) at 0° C., under N2, a solution of 4-pyrrolidin-1-ylmethylphenol (16 g, 90.4 mmol) was added slowly. After stirring at 0° C. for 30 min, 2,6-dibromopyridine (23.6 g, 99.4 mmol) was added and the resulting mixture was heated at 95° C. for 20 h. After cooling to RT, 200 mL of H2O was added and the mixture was extracted with EtOAc (3×300 mL). The combined organic layer was washed with brine (3×400 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an amber solid. This was used crude in the next step. MS m/z: 333 (M+1). Calc'd for C16H17BrN2O-333.2