Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:4][CH:3]=1.O1CCOCC1.O.[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+].NC1C=CC=CC=1>>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])[CH:6]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methyl-4′-nitro-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide was dissolved in 1,4-dioxane (10.00 mL, 0.1281 mol) and water (5.00 mL, 0.278 mol), and ammonium hydroxide (0.18 mL, 0.0045 mol) was added. To the reaction was added sodium dithionite (1.10 g, 0.00632 mol) and this mixture was stirred at 25° C. for 2 hours at which time HPLC analysis showed aniline formation. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. MS (EI) m/z=371 (M+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:21])[CH2:11][CH:12]([O:14]C2CCCCO2)[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)(O)[O-].[Na+].C1CCCCC1.C(OCC)(=O)C>C(O)(=O)C.O.O1CCCC1>[CH2:1]([S:8][C:9]1[C:10](=[O:21])[CH2:11][CH:12]([OH:14])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCSC1=CC(OC2CCCCO2)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCSC1=CC(O)CC1=O
Reaction time: 12 h
Yield: 99.2 %

Procedure:
2-n-Heptylthio-4-tetrahydropyranyloxycyclopent-2-en-1-one (80 mg) was dissolved in 5 ml of a mixture of acetic acid, water and tetrahydrofuran in a ratio of 3:1:1 and 2 ml of acetic acid, and the solution was allowed to stand at room temperature for 12 hours. The reaction mixture was neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was treated by a customary procedure to afford 58 mg (95% yield) of 2-n-heptylthio-4-hydroxycyclopent-2-en-1-one having a single spot in thin-layer chromatography (cyclohexane/ethyl acetate=4/6). The product had the following characteristics.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:23][O:24][NH:25][C:14](=[O:16])[CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][C:10]=1[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: CON
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CONC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl acetic acid (100 mg), methoxyamine hydrochloride (37.6 mg), 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg), 1-hydroxybenzotriazole (67 mg) and triethylamine (0.14 ml) in N,N-dimethylformamide (3 ml) was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=20:1), and triturated with diethyl ether-hexane to obtain N-methoxy-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]acetamide (75 mg) as colorless powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH2:34]([NH2:36])[CH3:35]>>[CH2:34]([NH:36][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33])[CH3:35]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: CCN
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Yield: 77 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ethylamine to give the title compound as a white solid (158 mg, 77%); NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.44 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.71 (br s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)[C@H](CSc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1SC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 91.4 %

Procedure:
In 300 ml of methanol is placed 10 g of 3-(o-nitrophenyl)thio-2(R)-phthalimidopropionic acid, which is catalytically reduced at ordinary temperature under atmospheric pressure, using 5% palladium-carbon as a catalyst. After the calculated amount of hydrogen is absorbed, the catalyst is removed, and the methanol is evaporated off under reduced pressure. Ether and petroleum ether are added to the residue, and the deposited yellowish crystalline powder is collected by filtration to give 8.4 g of 3-(o-aminophenyl)thio-2(R)-phthalimidopropionic acid. This product (8.4 g) is dissolved in 50 ml of dimethylformamide, and 5.5 g of diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling with stirring. After the addition is completed, the mixture is stirred for 5 minutes, and 2.28 g of triethylamine is further added dropwise under ice-cooling. The mixture is stirred under ice-cooling for 30 minutes and then at room temperature for 1 hour. Water (200 ml) is added to the reaction solution, and the mixture is allowed to stand overnight. The deposited solid is collected by filtration and dried. This product is purified by silica-gel column chromatography (dichloromethane:ethyl acetate=2:1) to give 5.4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepine-4-one as colorless prisms, melting at 202°-205° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]([C:23]1[N:24]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:25]2[C:30]([C:31](=[O:54])[C:32]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:53])(=[O:52])[NH:41][CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=1)=[CH:29][CH:28]=[C:27]([Cl:55])[CH:26]=2)=[O:22]>C1COCC1>[CH3:19][O:20][C:21]([C:23]1[N:24]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:25]2[C:30]([C:31](=[O:54])[C:32]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40](=[O:52])(=[O:53])[NH:41][CH2:42][CH2:43][OH:44])=[CH:38][CH:39]=1)=[CH:29][CH:28]=[C:27]([Cl:55])[CH:26]=2)=[O:22]
Reactant: COC(=O)c1c(Cc2ccc(S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)NCCO)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reaction time: 1 h

Procedure:
A solution of tetrabutylammonium fluoride (1 M in THF, 0.26 mL) was added to a solution of 3-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfamoyl]-benzyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (113 mg) in THF (5 mL) and the resulting mixture was stirred for 1 h. The reaction mixture was partitioned between EtOAc and water, the organic layer separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The yellow solid residue was purified by flash chromatography (DCM/MeOH, 90/10) to afford 7-chloro-3-[4-(2-hydroxy-ethylsulfamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester as an off-white powder. MS=527 [M+H]+; MP=191.5-193.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:43])[C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:22]C4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:43])[C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Yield: 22.9 %

Procedure:
A solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.047 mmol) in concentrated HCl (1 mL) and MeOH (5 mL) was stirred at RT for 1 h. The reaction was concentrated to a residue which was purified by Prep HPLC to give 5-((4-chlorophenyl) (hydroxy)methyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 23.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.47 (t, J=8.3 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.10 (dd, J=28.1, 8.2 Hz, 2H), 6.98 (s, 1H), 6.33 (d, J=7.7 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 3.95 (s, 2H), 3.45 (d, J=5.4 Hz, 2H), 3.41 (s, 3H), 1.71 (s, 2H). LCMS: [M+-OH] 539 and TR=3.084 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:14]1[C:19]([CH2:20]Cl)=[CH:18][C:17]([Cl:22])=[CH:16][N:15]=1)[CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:20][C:19]2[C:14](=[N:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[CH:8]1[CH:9]1[CH2:13][CH2:12][O:11][CH2:10]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(c1ncc(Cl)cc1CCl)C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)cnc2C1C1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl((5-chloro-3-(chloromethyl)pyridin-2-yl)(tetrahydrofuran-3-yl)methyl)carbamate (470 mg, 0.95 mmol) in anhydrous DMF (5 mL) was added with sodium hydride (115 mg, 2.84 mmol, 60% in mineral oil) in portions at 0° C. The mixture was stirred at rt for 2 h. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography column on silica gel (eluting with 10% EtOAc in petroleum ether) to afford tert-butyl3-chloro-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (285 mg, 91%) as a colorless oil. LCMS: tR=0.862 min in 5-95AB—1.5 min chromatography (MK RP-18e 25-2 mm), MS (ESI) m/z 324.9 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.47 (s, 1H), 7.83 (d, J=13.6 Hz, 1H), 5.10 (s, 1H), 4.65-4.50 (m, 1.5H), 3.95 (t, J=8.0 Hz, 0.5H), 3.85-3.67 (m, 4H), 3.03-2.87 (m, 1H), 2.15-1.65 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH3:23].[CH3:24][S-:25].[Na+].O>CN(C)C=O>[CH3:24][S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH3:23]
Reactant: C[S-]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCSC
Temperature: 80 °C
Reaction time: 1.83 h
Yield: 88.8 %

Procedure:
A suspension of 1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine (2.5 g, 7.56 mmol) in anhydrous N,N-dimethylformamide (38 mL) was heated to 80° C. to provide a light yellow solution. Sodium thiomethoxide (0.67 g of 95%, 9.07 mmol) was added in a single portion and heating was continued for 110 minutes. The resulting light brown suspension was poured into water (300 mL) with rapid stirring. A white solid precipitated. After the suspension had cooled to ambient temperature, several scoops of solid sodium carbonate were added. The suspension was chilled in an ice water bath with stirring for 1 hour. The solid was isolated by filtration, washed with cold water and then dried to provide 2.3 g of 1-[5-(methylthio)pentyl]-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine as a white powder.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH2:24][C:25]([OH:27])=[O:26])[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(-c2ccccc2)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2cc(S(=O)(=O)N(CC(=O)O)Cc3cccc(-c4ccccc4)c3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (20 mg, 0.056 mmol) in acetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (19.47 mg, 0.079 mmol) and resin-supportedBEMP (42.9 mg, 0.084 mmol). The mixture was heated in an oil bath at 90° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to give an orange residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate as an oil (26 mg, 84% yield). 1H NMR (500 MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.54-7.49 (m, 3H), 7.44-7.40 (m, 3H), 7.38 (dd, J=9.4, 5.8 Hz, 1H), 7.33 (ddd, J=6.7, 4.0, 1.2 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 4.57 (s, 2H), 3.84 (s, 2H), 2.78 (t, J=6.7 Hz, 2H), 1.80 (t, J=6.7LRMS [ESI, MNa+] m/z calcd for C30H35NO5SNa 544.21. found 544.32. To the solution of tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate (23 mg, 0.044 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.102 mL, 1.323 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated to give a reddish residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain the product as a white powder (17 mg, 82% yield). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.41 (dd, J=13.4, 5.5 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.87-6.83 (m, 1H), 4.52 (s, 2H), 3.97 (s, 2H), 2.77 (t, J=6.7 Hz, 2H), 1.79 (t, J=6.7 Hz, 2H), 1.33 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C26H26NO5S 464.15, found 464.32.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)=[O:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH:12]([OH:13])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C=C1CNCCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 232 %

Procedure:
To a solution of 16.6 g (39.1 mmol) of 3-ethoxycarbonylmethylidene-1-triphenylmethyl-4-piperidone in 150 ml of methanol, 1.48 g (39.1 mmol) of sodium borohydride were added in portions under ice cooling, followed by stirring at room temperature for 1 hour. After the reaction mixture was concentrated by evaporation under reduced pressure, 50 ml of water and 150 ml of ethyl acetate were added to the concentrate for extraction. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 16.8 g (yield: 100%) of 3-ethoxycarbonylmethylidene-4-hydroxypiperidine were obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=1[C:22]1[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=1.O>C1COCC1.CCCCCC.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[C:16]=2[C:22]2[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Reactant: Fc1ccc(S)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)COC(c2c(F)cccc2Sc2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluorothiophenol (3.64 g, 28.4 mmol) in 50 ml of dry THF at -78° C. is added n-butyllithium (17.8 ml of a 1.6M solution in hexane). After 30 minutes, 2-(2,6-difluorophenyl)-4,4-dimethyloxazoline (5.0 g, 23.7 mmol) in 10 ml of dry THF is added dropwise. The reaction mixture is allowed to warm to room temperature and then is heated to 60° C. for 5.5 hours. After cooling, the reaction mixture is poured into water and then extracted with diethyl ether. The extracts are washed with water and then brine, and dried over MgSO4 to afford the crude product. Chromatography over silica gel eluting with 10:1 hexane/ethyl acetate afforded the subtitle compound.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH:1]1([C:7]([NH:9][C:10]([Cl:18])([OH:15])[C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NC(O)(Cl)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
Next, cyclohexyl-N-(1,2,2,2-tetrachloro-1-hydroxyethyl) carboxamide 4 was synthesized as follows. A mixture of compound 3 (8.0 g, 20 mmol) and thionyl chloride (4.7 mL, 63.8 mmol, 2.2 equivalents) in dry benzene (30 mL) was heated at 80° C. in an oil bath. The initial suspension eventually became a clear solution (reaction time depends on the amount of starting materials, in this example it took about 5 hours). The mixture was stirred for an additional 30 minutes. The solvents were removed by evaporation under reduced pressure (rotovapor), and the resulting white solid was washed with hexanes and filtered, to produce the desired product 4 (7.0 g). NMR (1H, CDCl3): δ 6.59 (d, 1H), 6.30 (d, 1H), 2.19 (m, 1H), 1.89-1.19 (m, 10H).
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24]C(C6C=CC(OC)=CC=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.CC(O)=O>C1COCC1>[C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@H:23]([OH:24])[C@H:22]([CH2:27][OH:26])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.7 %

Procedure:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3.00 g, 5.90 mmol) was dissolved in THF (11.6 mL), water (11.6 mL) and AcOH (34.9 mL, 614 mmol) were added. The mixture was stirred at rt under an atmosphere of argon for 60 h. The mixture was concentrated under reduced pressure and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (2.10 g, 98%). LC/MS: Rt=1.46 min, ES+ 365 (AA standard).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCc1ccccc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-(phenyl)ethylamine to provide yellow solid 3-nitro-4-[2-(phenyl)ethylamino]quinoline, the melting point of the crude product being 174°-180° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[F:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Temperature: 80 °C

Procedure:
A mixture of 5 g (20 mmol) 1-Bromo-2-fluoro-4-trifluoromethyl-benzene, 4.6 g (24.7 mmol) n-Boc-piperazine, 106 mg (0.1 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex 2.77 g (28.8 mmol) sodium-t-butoxide and 144 mg (0.4 mmol) 2-(Dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80° C. After cooling to room temperature the mixture was treated with 15 g Isolute HM-N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation 4.54 g (63%) of the title compound as white amorphous solid; MS (m/e): 349.2 (MH+, 100%).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([NH:7][C:8]([C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=1)=[O:9])[CH2:5][CH3:6].[CH3:25]I>CS(C)=O>[CH3:25][N:7]([CH:4]([CH3:3])[CH2:5][CH3:6])[C:8]([C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=1)=[O:9]
Reactant: CI
Reactant: CCC(C)NC(=O)c1cc(-c2ccccc2)c2ccsc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 2, starting with dimethyl sulfoxide (24 cc), potassium hydroxide powder (3.6 g), N-(1-methylpropyl)-4-phenylbenzo[b]thiophene-6-carboxamide (4 g) and methyl iodide (1.6 cc). After chromatography of the residue over silica gel using a cyclohexane:ethyl acetate (50:50 by volume) mixture as the eluent and recrystallization in isopropyl ether, N-methyl-N-(1-methylpropyl)-4-phenylbenzo[b]thiophene-6-carboxamide (1.2 g), m.p. 84° C., is isolated.