Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[H-].[Na+].F[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2
Reactant: NC(=O)c1ccccc1F
Reactant: Brc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1N1CCc2cc(Br)ccc21
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A slurry was prepared from 5-bromoindoline (9.85 g, 50 mmoles) dimethylsulfoxide (DMSO) (35 ml), sodium hydride (2.6 g, 50% in oil, washed with hexane, 1.1 eq). The slurry was stirred for 30 minutes. To this a solution of o-fluorobenzamide (7.9 g, 1.1 eq) in DMSO (15 ml) was added dropwise with temperature between 12°-13° C. At the end of addition the reaction mixture was stirred at ambient temperature for 4 hours, then heated up to 55° C. for 24 hours. The reaction mixture was partitioned between dichloromethane (300 ml) and water (250 ml). The aqueous phase was separated and extracted twice with dichloromethane (DCM) (150 ml). The combined DCM solution was washed twice with water (100 ml), twice with 2N HCl (100 ml), twice with brine (50 ml), dried over Na2SO4 and concentrated to a solid. Purification was on a flash chromatographic column (150 gm of silica gel) eluted with dichloromethane (DCM) (3 l). This gave 6.4 g of product (40%). Recrystallization from a small amount of ether yielded the 2-(5-bromo-indolin-1-yl)benzamide, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.C1N=CN([C:42]([N:44]2C=N[CH:46]=[CH:45]2)=[O:43])C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[F:60][C:61]1[CH:70]=[C:69]2[C:64]([C@@H](N)C[CH2:67][O:68]2)=[CH:63][CH:62]=1>C1COCC1.C(Cl)Cl>[F:60][C:61]1[CH:70]=[C:69]2[C:64]([C@@H:45]([NH:44][C:42]([NH:17][C:15]3[N:14]=[CH:13][C:12]4[C:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=5)=[N:9][N:10]([C:18]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:11]=4[CH:16]=3)=[O:43])[CH2:46][CH2:67][O:68]2)=[CH:63][CH:62]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Reactant: N[C@H]1CCOc2cc(F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(NC(=O)N[C@H]4CCOc5cc(F)ccc54)ncc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
In a vial 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (101.0 mg, 0.216 mmol) and CDI (77 mg, 0.475 mmol) were dissolved in THF (6.00 ml) before treatment with 1.0 M solution NaHMDS in THF (0.454 ml, 0.454 mmol). After stirring at RT for 1 h, a solution of (S)-7-fluorochroman-4-amine hydrochloride (97 mg, 0.475 mmol) and TEA (0.151 ml, 1.080 mmol) in THF (2.00 ml) were added. The resulting mixture was heated to 55° C. for 1 h. The mixture was cooled to RT and taken up in DCM. The organic phase was washed with saturated NaHCO3 and the aqueous phase was back-extracted with DCM (2×). The combined organic layers were dried (Na2SO4) and volatiles were evaporated in vacuo. Crude material was purified via reverse phase HPLC over a gradient of 10-90% MeCN in water with 0.1% TFA to yield (S)-1-(7-fluorochroman-4-yl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (111 mg, 0.168 mmol, 78% yield). MS ESI calc'd. for C41H33FN6O6 [M+1]+ 661, found 661.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])O[C:8](=[O:9])[CH:3]1[CH2:4][CH:5]=[CH:6][CH3:7].C1(CN)C=CC=C(C[NH2:20])C=1>C1(C)C(C)=CC=CC=1>[CH3:1][CH:2]1[C:11](=[O:12])[NH:20][C:8](=[O:9])[CH:3]1[CH2:4][CH:5]=[CH:6][CH3:7]
Reactant: NCc1cccc(CN)c1
Reactant: CC=CCC1C(=O)OC(=O)C1C
Solvent: Cc1ccccc1C
Product: CC=CCC1C(=O)NC(=O)C1C
Temperature: 200 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a 1000 ml flask replaced with nitrogen 257.4 g (1.26 mol) of allyl-bicyclo 2.2.1!hept-5-ene-2,3-dicarboxylic acid anhydride and 300 ml of xylene were charged. To the mixture was added 81.4 g (0.60 mol) of m-xylylenediamine over 1.5 hours with heating and stirring while refluxing xylene. The reaction was continued for 3 hours while separating and removing water produced by the reaction by a water separator, and then the solvent, xylene, was removed by distillation. Thereafter, the content of the flask was treated with heat at 200° C. under reduced pressure of 1 Torr for 1 hour while stirring, thus obtaining 301.8 g (yield: 99%) of the target N,N'-m-xylylene-bis(allyl-bicyclo 2.2.1!hept-5-ene-2,3-dicarboximide), of which the chemical structure is shown by the following formula 6!. This compound is hereinafter abbreviated to BANI-mX. ##STR10##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH:48]([N:53]([CH3:70])[C:54](=[O:69])[CH:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[C:49](=[O:52])[NH:50][CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[N:67]([CH:55]([C:54](=[O:69])[N:53]([CH:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.19 g; 0.783 mmol) was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazole (0.12 g; 0.861 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.900 mmol) was added and the reaction mixture was stirred 15 min at room temperature. N-[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.33 g; 0.783 mmol) and diisopropyl ethylamine (0.15 ml; 0.861 mmol) was added and the reaction mixture was stirred 12 hours at room temperature. Methylene chloride (50 ml) was added and the reaction mixture was washed with water (50 ml), sodium hydrogen sulfate (10%; 50 ml), sodium hydrogen carbonate (sat; 50 ml), water (50 ml) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.366 g of {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester. {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylene chloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reaction mixture was stirred 5 min at room temperature. Methylene chloride (25 ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodium hydrogen carbonate (s) was added until pH=8. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was lyophylised to afford 0.237 9 of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN(C)C)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride obtained in Step III as describe above (586 mg; 1.41 mmol; 1 eq), is dissolved in anhydrous DCM (15 ml). The reaction is put under nitrogen. Triethylamine (1.9 ml; 14.1 mmol; 10 eq) and N,N-dimethyl-ethane-1,2-diamine (0.17 ml; 2.82 mmol; 2 eq) are added successively and the reaction mixture is stirred at room temperature for 30 minutes. The solvents are evaporated and the crude mixture is purified by preparative HPLC, affording the title compound (68 mg; 10%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:19]([CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCOc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 4-(4′-hydroxyphenyl)benzoic acid (4 g) and 1N sodium hydroxide (41 ml) in dimethyl sulfoxide (40 ml) was heated for 30 minutes at 85° C., then treated with 4-phenoxybutyl bromide (6.42 g) and heating continued for 8 hours. After cooling, the reaction was poured into water and adjusted to pH 2 and the resulting precipitate was collected, washed with water, and dried to give 4-[4′-(4-phenoxybutyloxy) phenyl]benzoic acid (6.7 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[C:37](#N)C>O.CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:33]([CH3:37])(=[O:35])=[O:32])[N:3]=1
Reactant: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Reactant: CC#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round-bottomed flask was added (S)-4-methyl-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (170 mg, 0.406 mmol) in acetonitrile (4616 μL) and water (4616 μL). The mixture was cooled to 0° C. and Oxone® (624 mg, 1.015 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature. After 4 hours the reaction mixture was diluted with EtOAc and washed with brine (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C21H22N8O2S, 451.16; found 451.4.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:12][C:11]1[C:2]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-n2ccnc2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.17 g, 10.0 mmol) was dissolved in ethyl acetate (55 mL) and imidazole (4.09 g, 60 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and treated with SnCl2-2H2O (13.5 g, 60.0 mmol). It was heated to 70° C. for 2 h, diluted with potassium carbonate (sat. aq.) and extracted with ethyl acetate (5×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude yellow solid, which was used in the next step without further purification. [M+H] calc'd for C10H10N4O2, 219. found, 219.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][CH2:22][CH2:23][NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:23][CH2:22][F:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: FCCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(CNCCF)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-(2-fluoroethylaminomethyl)pyrrolidine (165 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (100 mg) in absolute acetonitrile (2 ml) was refluxed for an hour. After cooling, the reaction mixture was concentrated and to the residue was added acetonitrile-ether (1:1, 5 ml). The solution was allowed to stand overnight at 5° C., then the resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-ether to give the title compound (140 mg), mp 134°-138° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.C[I:27]>C1COCC1>[I-:27].[C:22]([CH2:21][CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[C:9](=[O:12])[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([NH+:2]([CH3:25])[CH3:1])[CH:11]=3)[CH2:7]2)=[CH:18][CH:17]=1)([OH:24])=[O:23]
Reactant: CI
Reactant: CN(C)c1ccc2c(c1)C(=O)N(c1ccc(CCCC(=O)O)cc1)C2
Solvent: C1CCOC1
Product: C[NH+](C)c1ccc2c(c1)C(=O)N(c1ccc(CCCC(=O)O)cc1)C2
Product: [I-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 4-[4-(6-dimethylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid (35.5 mg, 1.03 mM) obtained in Example 38 in THF (7 ml) was added with methyl iodide (1.2 ml), and the mixture was stirred at room temperature for 60 hours. The deposit was collected by filtration and dried to obtain {2-[4-(3-carboxy-propyl)-phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}-dimethyl-ammonium iodide (Compound 32) as a colored powdery substance (34.5 mg, yield: 68.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[OH:5].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>>[Br:13][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: Cc1cc(Br)cc(C(O)CCN)c1
Reactant: CCOC(=O)C(F)(F)F
Product: Cc1cc(Br)cc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Treatment of 3-amino-1-(3-bromo-5-methylphenyl)propan-1-ol with ethyl trifluoroacetate following the method used in Example 79 gave N-(3-(3-bromo-5-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a light colored oil. Yield (0.38 g, 22%, 3 steps): 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.26 (s, 1H), 7.05-7.07 (m, 1H), 4.80 (dd, J=8.8, 4.0 Hz, 1H), 3.62-3.75 (m, 1H), 3.36-3.44 (m, 1H), 2.33 (s, 3H), 1.90-2.0 (m, 2H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4.[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH:22]1([CH2:25][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
A sample of 3-methoxymorphinan-6-one hydrochloride (3.08 g, 10 mmol, prepared in Part IC), was reacted with cyclopropylmethyl bromide in the presence of sodium bicarbonate as described in Example 1D. After chromatography on Silica Gel G using 20:1 V/V chloroform-methanol, 2.5 g of the desired product was isolated as a syrup. This was converted to the hydrochoride salt to yield 2.1 g (58%) of TR-5152, mp 265°-267° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)C>[N+:20]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:15][C:14]=1[C:16]([F:17])([F:18])[F:19])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: Nc1cc(Cl)ccn1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)ccn1
Temperature: 150 °C
Yield: 16.3 %

Procedure:
To a solution of 2-amino-4-chloropyridine (2.0 g, 15.6 mmol) in N-methylpyrrolidone (16 ml) were added 5-hydroxy-2-nitrobenzotrifluoride (4.85 g, 23.4 mmol) and diisopropylethylamine (8.15 ml, 46.8 mmol), followed by stirring under a nitrogen atmosphere to heat at 150° C. for 62 hrs. The reaction mixture was cooled down to room temperature and the diisopropylethylamine was evaporated under a reduced pressure. The resultant residue was partitioned between ethyl acetate:tetrahydrofuran=1:1 (300 ml) and a 1 N aqueous solution of sodium hydroxide (100 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; heptane/ethyl acetate=1/2, ethyl acetate, then ethyl acetate/methanol=20/1). The crude product was subjected to silica gel filtration (Fuji Silysia NH) The filtrate was concentrated to give a solid, which was then suspended in diethyl ether:hexane=1:1, filtered, and dried under aeration to provide the titled compound (760 mg, 16.3%) as a brown solid.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[C:14]([CH2:16]Br)[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.[C:18](=[O:21])([O-])[O-].[K+].[K+].[I-].[K+].[CH2:26]([C:28]([CH3:30])=[O:29])[CH3:27]>>[C:28]([C:26]1[C:18]([OH:21])=[CH:15][C:5]([O:4][CH2:16][C:14]2[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([OH:4])[CH:15]=2)=[C:6]([CH2:12][CH3:13])[CH:27]=1)(=[O:29])[CH3:30]
Reactant: CCC(C)=O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(CBr)cc1OC(C)=O
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1ccc(COc2cc(O)c(C(C)=O)cc2CC)cc1O

Procedure:
A mixture of 0.75 g of 2,4-dihydroxy-5-ethylacetophenone, 1.23 goof ethyl 2-acetoxy-4-bromomethylbenzoate, 0.57 g of potassium carbonate, and a catalytic amount of potassium iodide were heated at reflux in methyl ethyl ketone overnight. The hot mixture was filtered and the filtrate concentrated to dryness. Crystallization of the residue from ethyl acetate/hexane provided 130 mg of the desired title product, m.p. 145°-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([N:27]=[C:28]=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc3ccccc23)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 1-naphthyl isocyanate (0.023 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 24 (0.039 g, 0.09 mmol, 68%) as a white powder. LCMS m/z (%)=451 (M+H79Br, 95), 453 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.58 (s, 1H), 8.32 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 7.91 (d, J=9.4 Hz, 1H), 7.75 (dd, J=2.7, 9.0 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.44-7.57 (m, 5H), 7.14 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].ClC(Cl)C.ClS(O)(=O)=O.[ClH:20].OO.[N+:23]([O-:26])(O)=[O:24]>>[Cl:20][C:4]1[C:3]([CH2:9][CH3:10])=[C:2]([Cl:1])[CH:7]=[C:6]([N+:23]([O-:26])=[O:24])[C:5]=1[OH:8]
Reactant: Cl
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(O)ccc1Cl
Agent: O=S(=O)(O)Cl
Agent: OO
Solvent: CC(Cl)Cl
Product: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Temperature: 20 °C
Yield: 78 %

Procedure:
In a 1-liter four-necked glass flask is prepared a solution mixture of 100 g of 4-chloro-3-ethylphenol and 350 g of dichloroethane. While the mixture is maintained at a temperature of 35°-45° C., 80 g of chlorosulfonic acid is added dropwise and the mixture is maintained at a temperature of 40°-45° C. for 1 hour. Next, 326 g of a 14.3% hydrochloric acid solution is added, and 68 g of a 35% aqueous hydrogen peroxide solution is added dropwise while maintaining the temperature at 40°-45° C. After the mixture is maintained at the same temperature for 8 hours, it is cooled to 20° C. After the oily layer is separated, the aqueous layer obtained is charged in a 1-liter four-necked glass flask, and 172 g of a 70% nitric acid solution is added dropwise to the aqueous a temperature of 30°-40° C. The liquid becomes turbid and turns yellowish white. The temperature is raised about 15° C. After the addition, the reaction mixture is maintained at the same temperature for 1 hour. The reaction mixture is cooled to 5° C. and filtered. The product is washed with water and dried to give 2,4-dichloro-3-ethyl-6-nitrophenol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[N+:20]([O-])=O)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.C1COCC1.[Ni]>[NH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: COc1cccc(C(=O)c2ccc(C(C)C)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C(=O)c2ccc(C(C)C)cc2)c1N

Procedure:
A solution of 6.8 g (22 mmol) (4-isopropyl-phenyl)-(3-methoxy-2-nitro-phenyl)-methanone in 90 ml methanol and 40 ml THF is hydrogenated at normal pressure and rt during 20 h in the presence of 2 g Raney nickel. After filtration and evaporation of the solvent the residue is taken up in ether and (4-isopropyl-phenyl)-(3-methoxy-2-nitro-phenyl)-methanone precipitates by the addition of saturated etheric hydrochloric acid as its hydrochloride.