Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:37]>ClCCl>[ClH:37].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH2:21])=[O:19])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a suspension of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)carbamoyl]hydrazinecarboxylate (281.8 mg, 0.65 mmol) in anhydrous dichloromethane (3.25 ml) was added 4M-hydrogen chloride dioxane solution (3.25 ml, 13.0 mmol). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was concentrated again under reduced pressure. The operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate and filtered. The filtered product was washed with ethyl acetate, and dried under reduced pressure to give the title compound (245.1 mg, quantitative) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCN(c2ccc3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3c2)CC1
Temperature: 150 °C
Yield: 26.5 %

Procedure:
{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (55 mg, 0.1 mmol), 1-methylpiperazine (13 μL, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol), (S)-BINAP (9 mg, 0.015 mmol) and cesium carbonate (46 mg, 0.14 mmol) were suspended in toluene (1.0 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 30 min. Further tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol) and (S)-BINAP (9 mg, 0.015 mmol) were added to the vial and the mixture heated conventionally at 110° C. for 24 hours. The mixture was cooled to RT, dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 3%-4% 2M ammonia in methanol/DCM) to afford the title compound as a yellow oil (15 mg, 27%). LCMS (Method B): RT=3.74 min, M+H+=566.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.[O:13]=[CH:14]C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>>[CH:14]([NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1)=[O:13]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NCCc1cn2ccccc2n1
Solvent: ClC(Cl)Cl
Product: O=CNCCc1cn2ccccc2n1

Procedure:
To a stirred solution of 2-(2-aminoethyl)imidazo [1,2-a] pyridine in chloroform chloral was added dropwise and stirring continued at room temperature for an hour. A solid precipitate was filtered off and recrystallised to give 2-(2-formamidoethyl)imidazo [1,2-a]pyridine. The 2-(2-formamidoethyl)imidazo [1,2-a]pyridine was gradually added to a slurry of lithium aluminium hydride in anhydrous tetrahydrofuran and the resultant suspension heated under reflux for 3 hours. By extracting the reaction mixture with dilute hydrochloric acid there was isolated 2-(2-methylaminoethyl)imidazo [1,2-a]pyridine dihydrochloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C:45]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:52][C:53](O)=[O:54].CCN(C(C)C)C(C)C>O.CN(C)C=O>[F:44][C:45]1[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:52][C:53]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:54]
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(F)c3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2,3-difluorophenylacetic acid (56.7 mg, 0.329 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(2,3-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (31 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (d, J=8.1 Hz, 1H) 7.85 (d, J=6.1 Hz, 1H) 7.59 (s, 1H) 7.44 (d, J=6.1 Hz, 1H) 7.32-7.41 (m, 2H) 7.26 (d, J=8.3 Hz, 1H) 7.14-7.24 (m, 2H) 6.06 (d, J=8.8 Hz, 2H) 4.33 (t, J=8.5 Hz, 2H) 4.04 (s, 2H) 3.28 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:19][CH2:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCC1CC1
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCC3CC3)nc(Cl)nc21

Procedure:
2-Chloro-6-[(cyclopropyl)methylamino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (See Example 15 for preparation), cyclopropylmethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34](O)=[O:35])[CH:27]=1.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:35])[CH:27]=1
Reactant: O=C(O)COc1cccnc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(COc1cccnc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), pyridin-3-yloxyacetic acid hydrochloride (23 mg, 0.12 mmol), WSC.HCl (23 mg, 0.12 mmol), and dry pyridine (1 mL) were mixed, and the mixture was stirred at room temperature for 4 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and hexane to give 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (41 mg, yield 91%) as yellow crystals.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:23])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1.[Br-:24].[Al+3].[Br-].[Br-].Br>>[Br-:24].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[CH3:23])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(C)c1
Agent: Br
Agent: [Al+3]
Agent: [Br-]
Product: Cc1cc(C)c([S+](c2ccccc2)c2ccccc2)c(C)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
To 38 g of diphenyl sulfoxide were added 500 ml of mesitylene and 340 g of aluminum bromide, followed by allowing a reaction to take place at 90° C. for 12 hours. After the reaction solution was cooled, a mixture of 100 ml of concentrated hydrobromic acid solution and 500 ml of ice water were poured. An aqueous layer was extracted with benzene and the organic layer was washed with water and dried over anhydrous MgSO4, followed by filtration and removal of the solvent, whereby 58 g (Yield: 80%) of diphenyl-2,4,6-trimethylphenylsulfonium bromide was obtained as white crystal.
Reaction SMILES: CC1C=CC=C2C=1C(=O)N(C1C=CC=CC=1)C(C(NC1N=CN=C3C=1N=CN3)CC)=N2.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)COC(C)(C)C.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.NC1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2.[NH2:105][C:106]1[N:114]=[C:113]2[C:109]([N:110]=[CH:111][NH:112]2)=[C:108]([NH:115][CH:116]([C:123]2[N:132]([C:133]3[CH:138]=[CH:137][CH:136]=[CH:135][CH:134]=3)[C:131](=[O:139])[C:130]3[C:125](=[CH:126][CH:127]=[CH:128][C:129]=3[CH3:140])[N:124]=2)[CH2:117][O:118]C(C)(C)C)[N:107]=1>FC(F)(F)C(O)=O>[NH2:105][C:106]1[N:114]=[C:113]2[C:109]([N:110]=[CH:111][NH:112]2)=[C:108]([NH:115][CH:116]([C:123]2[N:132]([C:133]3[CH:134]=[CH:135][CH:136]=[CH:137][CH:138]=3)[C:131](=[O:139])[C:130]3[C:125](=[CH:126][CH:127]=[CH:128][C:129]=3[CH3:140])[N:124]=2)[CH2:117][OH:118])[N:107]=1
Reactant: Cc1cccc2nc(C(COC(C)(C)C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: Brc1ncnc2nc[nH]c12
Agent: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(CO)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 68 was prepared using the general procedure described above with respect to compound 14, but 2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. The obtained 2-[1-(2-amino-9H-purin-6-ylamino)-2-tert-butoxy-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one was then dissolved in trifluoroacetic acid and allowed to stir at ambient temperature for 5 hours. Purification by LC provided the product 68 as a white solid. MS (ES): m/z 429 (M+H), 215, 206, 151. Compound 68 is shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40](OCC)=[NH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[CH2:47](N)[CH2:48][NH2:49].C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]3[NH:49][CH2:48][CH2:47][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=N)c1cnc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)c(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C3=NCCN3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-ethoxycarbonimidoylpyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) and ethylenediamine (150 μl) are dissolved in ethanol (3 ml), and the mixture is stirred under reflux for 4 hours. After cooling to room temperature, a saturated brine and ethyl acetate are added to the reaction solution. The organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=1:1→1:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (96 mg). MS (m/z): 651 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[Br:18]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 4-aminophenylacetonitrile (1.45 g, 10.9 mmol) in acetonitrile (10 mL) at 0° C. was treated with NBS (1.95 g, 10.9 mmol) in acetonitrile (10 mL) dropwise via an addition funnel. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The crude product was dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and dried (Na2SO4). Removal of the solvent in vacuo afforded the title compound (2.12 g, 92%) as a reddish solid. Mass spectrum (ESI, m/z): Calcd. for C8H7BrN2, 210.9 (M+H), found 211.0.
Reaction SMILES: [CH:1]1([C:7]2[NH:8][S:9](=[O:28])(=[O:27])[C:10]3[CH:16]=[C:15]([S:17](=[O:24])(=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=[C:13]([CH:25]=O)[C:11]=3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO.[Pd]>[CH:1]1([C:7]2[NH:8][S:9](=[O:27])(=[O:28])[C:10]3[CH:16]=[C:15]([S:17](=[O:24])(=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=[C:13]([CH3:25])[C:11]=3[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)S(=O)(=O)c1cc(C=O)c2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN(CC)S(=O)(=O)c1cc(C)c2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Yield: 0.1 %

Procedure:
3-Cyclohexyl-7-(N,N-diethylsulphamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.20 g, 0.46 mmol) was dissolved in 99% EtOH (60 ml). One small drop of concentrated hydrochloric acid was added to ensure fully hydrogenation. The mixture was hydrogenated using Pd/C (10%, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of Celite M and evaporated to dryness. The residue was dissolved in EtOAc (50 ml) and washed with water (10 ml), dried (Na2SO4) and evaporated to dryness yielding 0.18 mg (95%) of 3-cyclohexyl-7-(N,N-diethylsulphamoyl)-5-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless powder. The product was further transformed by Method F. M.p. 206-208° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[NH:6][C:7](=[O:20])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[C:5]2[C:4]([C:3]([OH:2])=[C:8]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7](=[O:20])[NH:6]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CSCCCCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1SCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.3 g (16.12 mmol) of 4-chloro-N-(4-phenylbutylthio)acetyl-anthranilic acid methyl ester are placed in 60 ml of tetrahydrofuran at 0°, and 48.3 ml of a 1-molar solution of sodium bis-trimethylsilylamide are added dropwise thereto. The mixture is then stirred for 30 minutes at room temperature. The reaction mixture is poured into 200 ml of 2N hydrochloric acid/ice and the resulting white suspension is filtered with suction and the colourless crystals are dried under a high vacuum at 60°. 7-chloro-3-(4-phenylbutylthio)-4-hydroxy-2(1H)-quinolone is obtained in the form of colourless crystals having a melting point of 176°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]([NH2:14])[CH3:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.[BH4-].[Na+].Cl.[OH-].[Na+]>CO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:14][CH:12]([C:9]1[NH:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:13]
Reactant: CC(N)c1nc(-c2ccccc2)c[nH]1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC(C)c2nc(-c3ccccc3)c[nH]2)cc1OC
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A solution of 1-(4-phenyl-1H-imidazol-2-yl)-ethylamine (0.061 g, 0.33 mmol) of Example 1, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in 5 mL of anhydrous methanol was stirred at room temperature for 1 h and then cooled to about 0-10° C. in an ice bath for 1 h. The reaction was treated carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and maintained at about 0-10° C. for 21 h. Cold 2M aqueous HCl was added dropwise (30 drops), the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The residual material was taken up in EtOAc to yield a suspension that was treated with 5 mL of cold 3M aqueous NaOH and stirred vigorously until clear. The phases were separated and the aqueous layer was extracted three times additional with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated to afford 0.11 g of (3,4-dimethoxy-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)ethyl]-amine as a light yellow oil (HPLC: 87% @ 254 nm and 66% @ 214 nm). MS (ES+) (relative intensity): 338.1 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification. The title compound may be substituted for Cpd 1d of Example 1 and elaborated to compounds of the present invention with the appropriate reagents, starting materials and purification methods known to those skilled in the art.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[NH3:13]>[Pd]>[NH2:13][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: N
Agent: [Pd]
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-hydroxy-2-adamantanone (10.2 g) in 8M ammonia (in methanol, 50 ml), 10% palladium on activated carbon (1.00 g) was added and stirred under a hydrogen atmosphere at room temperature for 15 hours. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel column chromatography (eluting solvent: chloroform alone→chloroform:methanol=9:1) to give 4-aminoadamantan-1-ol (10.2 g, E-form:Z-form=4:1). 4-Aminoadamantan-1-ol thus obtained (10.2 g) was dissolved by heating in tetrahydrofuran (50 ml), and 4M hydrochloric acid (in 1,4-dioxane, 20 ml) was added thereto, followed by stirring at room temperature for 16 hours. The precipitated solid was collected by filtration to give 4-aminoadamantan-1-ol hydrochloride (12.1 g, E-form:Z-form=4:1). The resulting E/Z mixture (9.15 g) was dissolved by heating in ethanol (450 ml) and water (35.5 ml), and stirred at room temperature for 2 days. The precipitated solid was collected by filtration to give the titled compound, i.e., E-4-aminoadamantan-1-ol hydrochloride (3.59 g) as a colorless powder.
Reaction SMILES: C(N1CC[C:12](=[O:15])[CH2:11][CH2:10]1)CC1C=CC=CC=1.NC1C=C(O)C=CC=1.[CH2:24]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(=O)CC)(=O)CC.CN(C1C=CC=CN=1)C>C(N(CC)CC)C>[OH:45][C:41]1[CH:40]=[C:39]([N:38]([CH:35]2[CH2:34][CH2:33][N:32]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:37][CH2:36]2)[C:12](=[O:15])[CH2:11][CH3:10])[CH:44]=[CH:43][CH:42]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Oc1cccc(NC2CCN(CCc3ccccc3)CC2)c1
Agent: CCC(=O)OC(=O)CC
Agent: CN(C)c1ccccn1
Agent: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1cccc(O)c1)C1CCN(CCc2ccccc2)CC1

Procedure:
As indicated in Scheme II-D above, the desired mPEGn-O-fentanyl conjugates were prepared by first reacting 1-phenethylpiperidin-4-one with 3-aminophenol under reducing conditions to thereby convert the keto functionality into an amine, i.e., by reaction with the amino group of 3-aminophenol. The product, 3-(1-phenethylpiperidin-4-ylamino)phenol, was then reacted with propionic anhydride in the presence of base (e.g., triethyl amine) and dimethylaminopyridine (DMAP) under conditions effective to form N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide. Finally, introduction of the oligomeric PEG functionality was carried out by reacting the precursor, N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide, with a molar excess of mPEGoligotosylate under coupling conditions effective to form the desired conjugates. Ratios of reactants and reaction conditions generally employed are provided in the reaction schemes above.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: Brc1ccco1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: c1ccc(-c2cn(-c3ccco3)cn2)cc1
Yield: 7.4 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-phenyl-1H-imidazole (250 mg, 1.73 mmol) and 2-bromofuran, to prepare the desired 1-(furan-2-yl)-4-phenyl-1H-imidazole (27 mg, 0.13 mmol, yield 7.4%) as a brownish solid. The HPLC purity of the final product was 99.8%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.