Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and p-anisidine (60 mg, 0.39 mmol). The title compound was obtained as a solid (42 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.43 (1H, s), 9.00 (2H, s), 8.67 (1H, s), 7.56 (2H, m), 6.94 (2H, m), 3.73 (3H, s). MS m/z: 454.08, 456.02 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)O)[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([CH2:13][CH:14]=[CH:15][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[N:12]=1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC=Cc1ccc(O)cc1
Yield: 28.6 %

Procedure:
4-[3-[2-(2-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-hydroxypropyl]phenol (110 mg, 0.296 mmol) and p-toluene-sulfonic acid monohydrate (17 mg, 0.092 mmol) were refluxed in toluene (2 mL) for 20 hours. After the starting compounds diminished, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to give the desired compound (30 mg) as white crystalline product (yield 28%).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:21](=[O:43])[N:22]([C@H:32]4[CH2:37][CH2:36][C@H:35]([O:38][CH2:39][C:40](=O)[CH3:41])[CH2:34][CH2:33]4)[C:23]4[N:24]([N:29]=[CH:30][N:31]=4)[C:25]=3[CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)[NH:3]1.Cl.[NH2:45][O:46][CH3:47].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:47][O:46]/[N:45]=[C:40](\[CH3:41])/[CH2:39][O:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([N:22]2[C:21](=[O:43])[C:20]([CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:4]4[NH:3][C:2](=[O:1])[O:6][N:5]=4)=[CH:14][CH:15]=3)=[C:25]([CH2:26][CH2:27][CH3:28])[N:24]3[N:29]=[CH:30][N:31]=[C:23]23)[CH2:37][CH2:36]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC/C(C)=N/OC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.095 g), (aminooxy)methane hydrochloride (0.041 g) and pyridine (5 mL) was stirred at 80° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.07 g, 70%).
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:30][N:31](C)[CH:32]=O>>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([N:31]([CH3:32])[CH3:30])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCCOc1cc(C(=O)N(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of 4-benzyl-3-n-butoxy-5-sulfamylbenzoic acid (3.6 g), thionyl chloride (20 ml) and N,N-dimethylformamide (0.1 ml) is refluxed for 1 hour and is then evaporated in vacuo. The resulting crude 4-benzyl-3-n-butoxy-5-sulfamylbenzoyl chloride is dissolved in methylene chloride (30 ml), and the resulting solution is during about 15 minutes added dropwise to a stirred mixture of dimethylamine (10 ml; 40% in water) and methylene chloride (20 ml), keeping the temperature at 0°-5° C. by external cooling. After stirring for an additional 2 hours at 22°-25° C., the mixture is washed with water and the organic layer is separated and dried in the presence of magnesium sulphate. Filtration followed by evaporation in vacuo yields crude 4-benzyl-3-n-butoxy-5-sulfamyl-N,N-dimethylbenzamide. After recrystallization from benzene it is obtained with a melting point of 199°-201° C.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[CH3:14][C:15]1[N:19]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:18]=[N:17][CH:16]=1>>[CH3:14][C:15]1[N:19]([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:18]=[N:17][CH:16]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1ccccc1N=C=S
Product: Cc1cncn1CCCn1c(=S)[nH]c2ccccc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.276 g, 1.43 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.198 g, 1.43 mmol) as described above.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH:14]1([C:17]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: [I-]
Product: CCOC(=O)c1ccc(C(=O)C2CC2)cc1

Procedure:
Intermediate i-3a was prepared from 4-ethoxycarbonylphenyl zinc iodide and cyclopropanecarbonyl chloride following the above procedure as described for intermediate i-1a. m/z (ES) 219 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.17 (d, 2H, J=8.5 Hz), 8.08 (d, 2H, J=8.4 Hz), 4.44 (q, 2H, J=7.1 Hz), 2.71 (m, 1H), 1.45 (t, 3H, J=7.1 Hz), 1.31 (m, 2H), 1.13 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:11]N(CCCCCCC)CC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].C(Cl)(=O)C.[C:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1)(=[O:28])[CH3:27]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:27][C:26]([C:29]1[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=1)=[O:28])[CH3:2]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CCCCCCCN(CC)CN(CC)CCCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCCCCCCN(CC)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The Bis(ethylheptylamino)methane (0.95 g, 3.2 mmol) of Preparation 15 in 8 ml of tetrahydrofuran (THF), under nitrogen, is cooled in an ice bath and treated dropwise over 2 min with 0.23 ml (0.25 g, 3.2 mmol) of acetyl chloride; the mixture is stirred 15 min in the cold and 45 min at ambient temperature. The mixture is cooled in an ice bath and a solution of N-(4-acetylphenyl)methanesulfonamide, as described in Preparation 1, (dried by azeotrope from carbon tetrachloride then benzene) (0.68 g, 3.2 mmol) in 10 ml of THF is added dropwise over 5 min. It is stirred in the cold for 1 hr then at room temperature for 72 hrs. The solvent is removed in vacuo (bath <30° C.) and the residue partitioned between cold diluted HCl and ether. The layers are separated and the aqueous layer is extracted with additional ether (4×50 ml). The pooled ether extract is washed with cold diluted HCl. The aqueous layers are combined and brought to pH 8.5 with saturated NaHCO3. This is extracted with ethyl acetate (3×75 ml). The pooled ethyl acetate extract is washed with brine, dried (Na2SO4), acidified with excess ethereal HCl and concentrated to give a mixture which includes the title compound that can be used without further purification.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[N:9]([O-])=O.[Na+].Cl.FC(F)(F)[C:16]([O:18]C(=O)C(F)(F)F)=[O:17]>O>[N:9]1([C:16]([O-:18])=[O:17])[N+:1]2[CH2:8][CH2:7][CH2:6][C:2]=2[CH:3]([OH:5])[O:4]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=N[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C([O-])N1OC(O)C2=[N+]1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of L-Proline (1000 mg, 8.69 mmol) and sodium nitrite (845 mg, 12.2 mmol) in water 2.00 mL) cooled to 0° C. was slowly added concentrated hydrochloric acid (1.0 mL, 11.6 mmol). The reaction mixture was allowed to warm to room temp and stirred overnight. The reaction mixture was diluted with water and extracted with MTBE, dried over sodium sulfate and concentrated in vacuo. The crude residue was then taken up in toluene (4.00 mL) and cooled to 0° C. Trifluoroacetic anhydride (1.81 mL, 13.0 mmol) was then added and the reaction was stirred overnight at room temp. The reaction mixture was concentrated in vacuo, adsorbed onto silica and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound as a brown oil (0.807 g, 74%)1H NMR (400 MHz, CDCl3) δ 4.43 (t, J=7.6 Hz, 2H), 2.96-2.86 (m, 2H), 2.85-2.73 (m, 2H). LC-MS (ESI): m/z=127.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:12]([CH3:11])[CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN1CCCC(CO)C1
Reactant: N#Cc1cnc(N)cc1F
Product: CN1CCCC(COc2cc(N)ncc2C#N)C1

Procedure:
From intermediate 21 and racemic (1-methylpiperidin-3-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.33 min; ESI-MS 247.2 [M+H]+.
Reaction SMILES: C[C:2]1[C:16]([C:17](O)=[O:18])=[CH:15][C:5]2[N:6]([CH3:14])[C:7]([CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.Cl.[CH3:28][C:29]1[N:33]=[C:32]([C@H:34]([NH2:36])[CH3:35])[O:31][N:30]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:3]2[C:4]3[N:8]=[C:7]([CH2:9][C:10]([OH:13])([CH3:11])[CH3:12])[N:6]([CH3:14])[C:5]=3[CH:15]=[C:16]([C:17]([NH:36][C@@H:34]([C:32]3[O:31][N:30]=[C:29]([CH3:28])[N:33]=3)[CH3:35])=[O:18])[CH:2]=2)=[CH:25][CH:24]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1c(C(=O)O)cc2c(nc(CC(C)(C)O)n2C)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3nc(CC(C)(C)O)n(C)c3c2)n1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a mixture of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1-methyl-1H-benzimidazole-6-carboxylic acid (122 mg, 0.236 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (46.3 mg, 0.283 mmol), 1-hydroxy-7-azabenzotriazol (3.21 mg, 0.024 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (79 mg, 0.412 mmol) was added DMF (0.471 mL) followed by triethylamine (0.099 mL, 0.707 mmol). Reaction heated at 50° C. for 30 min. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (87.4 mg): LC-MS [M+1]=452.4; 1H NMR (500 MHz, CHCl3-d): δ 7.94 (2H, m), 7.90 (1H, s), 7.77 (1H, s), 7.20 (1H, d, J=7.73 Hz), 7.15 (2H, t, J=8.51 Hz), 5.66-5.59 (1H, m), 5.47 (1H, s), 3.78 (3H, s), 3.02 (2H, s), 2.39 (3H, s), 1.74 (5H, d, J=7.14 Hz), 1.35 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][C:15]([OH:23])=[C:16](C(OCC)=O)[N:17]=[C:12]2[CH:11]=[N:10]1.[OH-].[Li+].C1C(=O)N([Br:33])C(=O)C1>O.CC#N>[Br:33][C:16]1[C:15](=[O:23])[NH:14][C:13]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: CCOC(=O)c1nc2cnn(-c3c(F)cccc3F)c2nc1O
Reactant: O=C1CCC(=O)N1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of ethyl 1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate (1.27 g, 3.70 mmol) in 2.5 mL of water and 2.5 mL of CH3CN at RT was added lithium hydroxide (209 mg, 8.72 mmol), and the resulting mixture was warmed to 60° C. for 0.5 h. The reaction mixture was cooled with an ice bath, and NBS (1059 mg, 5.95 mmol) was added in small portions. The reaction mixture was stirred at RT for 0.5 h, then partitioned between a saturated solution of NaHCO3 and EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated to afford 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (1210 mg, 93.3% yield) a a brown amorphous solid. This crude material was used without further purification. MS (ES+): 327.0/329.0 (M+H)+.
Reaction SMILES: C1C=[CH:3][NH+:4]=[CH:5]C=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C:13]([C:19]([F:22])([F:21])[F:20])([CH:17]=[CH2:18])[CH2:14][CH2:15]O.CC1C=CC(S(C[N+:34]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>C(Cl)Cl.O1CCCC1>[CH3:12][C:13]([C:19]([F:22])([F:21])[F:20])([CH:17]=[CH2:18])[CH2:14][C:15]1[N:34]=[CH:3][NH:4][CH:5]=1
Reactant: c1cc[nH+]cc1
Reactant: C=CC(C)(CCO)C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(C)(Cc1c[nH]cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
PCC (15.4 g, 71.4 mmol) was added to an ambient temperature solution of 3-methyl-3-(trifluoromethyl)pent-4-en-1-ol (4.0 g, 23.8 mmol) in methylene chloride (100 mL). After stirring at ambient temperature for 1.5 h, celite was added and the reaction stirred vigorously for 10 min. The reaction mixture was filtered through celite and concentrated in vacuo. TosMIC (9.3 g, 47.6 mmol) followed by potassium tert-butoxide (cat.) were added to a solution of crude residue in tetrahydrofuran (50 mL). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated in vacuo. Ammonia (7 N in methanol) (50 mL) was added to the crude residue. After stirring at 100° C. overnight, the reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 10% aqueous sodium hydroxide and methylene chloride. The aqueous phase was extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded 4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCC(CNC(=O)OC(C)(C)C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CCCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 370 ml of an ethanolic suspension containing 37.0 g of ethyl 6-(t-butoxycarbonylamino)-5-phenylhexanoate [prepared as described in step (b) above] were added 79 ml of water containing 8.8 g of sodium hydroxide. The reaction mixture was stirred for 1 hour at room temperature and then the solvent was distilled off under reduced pressure. The residue was mixed with ethyl acetate and water, and the aqueous layer was adjusted to a pH value of 3 by the addition of concentrated hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave quantitatively 6-(t-butoxycarbonylamino)-5-phenylhexanoic acid as a syrupy substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].[C:42](OC(=O)C)(=[O:44])[CH3:43].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([C:42](=[O:44])[CH3:43])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), potassium carbonate (84 mg, 0.6 mmol) in DMF (5 mL) was added acetic anhydride (0.3 mL) at −15° C. The mixture was slowly warmed to room temperature and stirred for 30 min. The reaction mixture was added 30 mL of water. The solid was collected to give 100 mg of 312. Yield=62%. 1H NMR (CDCl3, 400 MHz): δ8.03 (s, 1H), 7.51-7.46 (m, 1H), 7.19-7.00 (m, 4H), 6.50 (d, J=8.8 Hz, 1H), 4.19 (t, J=4.4 Hz, 2H), 3.66-3.65 (m, 2H), 3.07 (t, J=4.8 Hz, 2H), 0.93-2.89 (m, 2H), 2.13 (s, 3H), 2.03 (s, 2H), 1.29-1.24 (m, 6H). ESI-MS: m/z=537 [M+H+]
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:32]([O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([OH:44])[CH:37]=1)[CH3:33].[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[CH2:54][CH2:55]O>C1COCC1>[CH2:32]([O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH2:55][CH2:54][C:48]2[CH:49]=[CH:50][C:51]([Cl:53])=[CH:52][C:47]=2[Cl:46])[CH:37]=1)[CH3:33]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 10 g (38.3 mmol) of triphenylphosphane in 100 ml of THF were added 6.7 g (3.83 mmol) of DEAD over 5 min at room temperature. After 30 min at room temperature, 5 g (25.5 mmol) of 3-hydroxy-4-methoxybenzoic acid ethyl ester and 4.87 g (25.5 mmol) of 2-(2,4-dichlorophenyl)ethanol were added and the mixture was stirred at room temperature for 12 h. The solvent was removed and the residue was separated by chromatography to give 3.6 g (38%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:19][C:11]3=[N:12][CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>CN1CCCC1=O>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[CH:7]=[C:6]([C:8]2[NH:19][C:11]3=[N:12][CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccnc(Cl)c3)nc2c1
Reactant: COCCCN
Solvent: CN1CCCC1=O
Product: COCCCNc1cc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)ccn1
Yield: 33.6 %

Procedure:
1.20 g (4.35 mmol) 2-(2-Chloro-pyridin-4-yl)-6-nitro-3H-imidazo[4,5-b]pyridine in 12 ml dry N-methylpyrrolidone (NMP) and 1.18 g (13 mmol) 3-methoxypropylamine were heated to 200 C in a closed vessel in a microwave reactor for 30 min. The solvent was removed under vacuum and the residue dissolved in a mixture of 20 ml ethyl acetate and 30 ml 5% aqueous HCl. The HCl phase was separated and brought to alkaline pH by addition of conc. ammonia. The alkaline aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried. Evaporation and chromatography of the residue on silica in ethyl acetate/methanol mixtures gave 480 mg of the title product.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=2[O:18][CH3:19])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@H:29]1[OH:37]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=2[O:18][CH3:19])[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@H:29]1[OH:37])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COc1ccc(OC)c2c1CCNC2Cc1ccccc1
Reactant: O=C(Br)CBr
Product: COc1ccc(OC)c2c1CCN(CC(=O)N[C@H]1c3ccccc3C[C@H]1O)C2Cc1ccccc1

Procedure:
prepared by reaction of 1-Benzyl-5,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].CCC[CH2:9][CH2:10][CH2:11][CH3:12].[CH3:13]C(C)=O>>[C:1]([O:5][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])(=[O:4])[CH:2]=[CH2:3].[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Reactant: CCCCCCC
Reactant: CC(C)=O
Product: C=CC(=O)O
Product: C=CC(=O)OCC(C)CC

Procedure:
Non-limiting further examples of pressure sensitive adhesives useful with the present invention include those adhesives described in U.S. Pat. No. Re. 24,906 (Ulrich); U.S. Pat. No. 2,973,826; U.S. Pat. No. Re. 33,353; U.S. Pat. Nos. 3,389,827; 4,112,213; 4,310,509; 4,323,557; 4,732,808; 4,917,929; and 5,296,277 (Wilson et al.) and European Publication 0 051 935, the disclosures of which are incorporated by reference herein. A presently preferred adhesive is an acrylate copolymer pressure sensitive adhesive formed from a 90/10 weight percent monomer ratio of 2-methylbutyl acrylate/acrylic acid in a 65/35 heptane/acetone solvent system (39-41% solids) and having an inherent viscosity of about 0.7-0.85 dl/g.