Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=S(=O)(O)O
Reactant: N#CC1(N2C(=O)c3cccc(Cl)c3C2=O)CCCCC1
Solvent: ClCCl
Product: NC(=O)C1(N2C(=O)c3cccc(Cl)c3C2=O)CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution containing 300 mgs. 3-chloro-N-(1-cyanocyclohexyl)-phthalimide in 3ml. methylene chloride is added, with good stirring, 0.38 ml. concentrated sulfuric acid. After 0.5 hour, ice is added and the aqueous phase extracted with chloroform. The organic phase is washed with water, dried and evaporated to give the 1-(3-chlorophthalimido)cyclohexanecarboxamide which can be purified by recrystallization from aqueous ethanol, m.p. 193°-194°C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32]C(O)C[CH:15]3[C:14]=2[CH:13]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:15]3[C:14]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Yield: 82.7 %

Procedure:
Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200 mg, 0.52 mmol), Et3N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol) in CH2Cl2 (5 mL) and stir the reaction at room temperature for 1 hour. Dilute the solution with EtOAc and wash with H2O, saturated aqueous sodium bicarbonate and brine. Dry (Na2SO4), filter and concentrate the solution in vacuo. Purify the product by flash chromatography (10 g SiO2, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40% EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol, 83%) as a yellow oil. HRMS (FAB+) calcd for C24H28O7: 428.1835; found: 428.1833 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])([CH3:13])[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)N
Product: CC(C)NCc1cccc(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)benzonitrile and isopropyl amine. It was isolated as a yellow liquid (5.7 g, 92%).
Reaction SMILES: CC(C)=CC[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(N(CC)[C:20]1[CH:25]=[CH:24][CH:23]=CC=1)C.[CH3:28]/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>CCOCC>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][C:15]=1[C:24]([CH3:28])([CH:25]=[CH2:20])[CH3:23]
Reactant: COC(=O)c1ccc(OCC=C(C)C)cc1
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: C=CC(C)(C)c1cc(C(=O)OC)ccc1O
Temperature: 210 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
The reaction mixture of T45.1 (1.2 g, 5.0 mmol), N,N-diethylaniline (3.0 mL, 16 mmol) and N,O-bis(trimethylsilyl)acetamide (2.0 mL, 8 mmol) in a 15 mL sealed tube was heated at 210° C. for 48 hours. Ether (60 mL) was added, and the mixture was washed over HCl (3N in water, 20 mL). The organic layer was separated, and the solvent was removed. The residue was dissolved in MeOH (10 mL) and HCl (3N in water, 2 mL) and was stirred at room temperature for 30 minutes. Ether (80 mL) was added, and the mixture was washed with NaHCO3 (30 mL) and brine (15 mL). The organic layer was then dried over MgSO4. The solvent was removed, and the residue was purified by CombiFlash®silica gel column chromatography, eluent with hexane/EtOAc, 95/5 to give T45.2 (0.30 g, 25% yield). MS ESI (pos.) m/e: 221.2 (M+H)+. 1H NMR (500 MHz, CDCl3) δ ppm 8.01 (1H, d, J=2.0 Hz), 7.87 (1H, dd, J=8.4, 2.0 Hz), 6.87 (1H, d, J=8.4 Hz), 6.32 (1H, s), 6.21 (1H, dd, J=17.9, 10.5 Hz), 5.24-5.45 (2H, m), 3.90 (3H, s), 1.48 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH2:17]1[NH:22][CH2:21][CH2:20][N:19]2[CH2:23][C@H:24]([CH2:27][OH:28])[CH2:25][CH2:26][C@@H:18]12.[F-].[Cs+]>CS(C)=O>[NH2:8][C:6]1[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]3[CH2:23][CH:24]([CH2:27][OH:28])[CH2:25][CH2:26][CH:18]3[CH2:17]2)[N:7]=1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CO)CCC3C2)cc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
7-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (1 eq, see U.S. Pat. No. 6,222,035 B1), cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq.), and CsF (1-2 eq.) were dissolved in DMSO. The mixture was stirred at around 120° C. for 18 hours. The solution was then cooled to room temperature, filtered and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to give the desired, compound as a white solid. Alternatively, for scale up synthesis, the DMSO solvent was removed and the crude product was chromatographed on silica gel column using 5-10% MeOH/CH2Cl2 as eluant to afford the desired product: 1H NMR (400 Hz, CD3OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.14 (d, J=3.5 Hz, 1H), 6.63 (dd, J=3.5, 2.0 Hz, 1H), 5.99 (s, 1H), 4.26 (d, J=13.5 Hz, 1H), 4.19 (d, J=13.5 Hz, 1H), 3.83 (dd, J=10.5, 7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.04 (dt, J=12.5, 3.0 Hz, 1H), 2.95 (d, J=12.0 Hz, 1H), 2.80 (d, J=11.0 Hz, 1H), 2.62 (dd, J=12.5, 10.5 Hz, 1H), 2.22 (m, 2H), 1.98 (m, 1H), 1.86 (brd, 12.0 Hz, 2H), 1.62 (m, 1H), 1.50-1.42 (m, 2H). MS m/z: 370 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCCOc1ccccc1)c1cc(O)ccc1O
Reaction time: 12 h

Procedure:
A solution of 4-(2,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields the desired product.
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=5)[C:20]4=[O:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)C>CO.O>[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=5)[C@H:20]4[OH:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A slurry of 1-phenyl-8-[(1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (10.0 g, see example 195) in 150 ml of methanol is cooled in ice and treated dropwise with 4.5 g of sodium borohydride in 25 ml of water. The resulting mixture is stirred over a 60-hour period at room temperature under nitrogen. The reaction mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution yields the crude product. Trituration with absolute ethanol gives 8.1 g of the title compound, melting point 216°-218° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C@H:8]([NH:10][S:11]([C:14]3[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:4][N:3]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.C([O-])(O)=[O:33].[Na+]>Cl>[O:1]=[C:2]1[N:6]2[CH2:7][C@H:8]([NH:10][S:11]([C:14]3[C:15]([OH:33])=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:4][N:3]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3cccnc3Cl)CN12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3cccnc3O)CN12
Temperature: 100 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
2-Chloro-pyridine-3-sulfonic acid [(6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl]-amide (example 15) (100 mg, 0.21 mmol) was added to concentrated hydrochloric acid (10 mL, 12 M), the mixture was stirred for 24 h at 100° C. To the mixture was added sat. NaHCO3 to adjust to pH=8. Then extracted with ethyl acetate (15 mL×2), dried over anhydrous sodium sulfate and concentrated. The residue was directly purified by pre-TLC (dichloromethane:MeOH=100:1) to yield 20 mg (21%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 12.0 (bs, 1H) 8.22-8.19 (m, 1 Hz), 7.85-7.80 (m, 1H), 7.46-7.41 (m, 2H), 7.11-7.08 (m, 2 Hz), 6.49-6.41 (m, 2H), 4.09-3.91 (m, 4H), 3.63-3.61 (m, 1H), 3.04-3.01 (m, 1H), 2.22-2.20 (m, 1H), 1.64-1.62 (m, 1H); LC-MS: 459.0 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][Cl:20])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].[OH-].[NH4+:23]>CO>[ClH:20].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][NH2:23])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: C#CCOc1ccc(OCC(O)CCl)c2c1NC(=O)CC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1ccc(OCC(O)CN)c2c1NC(=O)CC2
Product: Cl
Temperature: 70 °C

Procedure:
1.0 g of 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol, and 4.5 ml of 28% ammonium hydroxide was added to the solution followed by heating at 70° C. for 10 hours. The methanol and the ammonium hydroxide were evaporated under reduced pressure, and the residue was made acidic with hydrochloric acid and washed with ethyl acetate. The aqueous layer was separated, made alkaline with sodium hydroxide, extracted with chloroform, washed with water and then dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel chromatography, and the product was converted to the hydrochloride thereof by adding methanol-hydrochloric acid. Recrystallization from methanol-diethyl ether afforded 0.5 g of 8-(2-propynyloxy)-5-(3-amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride having a melting point of 196.5°-198° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:10]=[CH:9][C:8]=1[CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.[C:29](=[O:31])=[O:30].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][C:8]1[CH:9]=[CH:10][C:11]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][C:7]=1[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: Brc1cc(COC2CCCCO2)ccc1COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(COC2CCCCO2)ccc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
n-Butyllithium (1.57 M hexane solution; 8.33 ml, 13.1 mmol) was added dropwise to a solution of 2-bromo-1,4-bis[(tetrahydropyran-2-yl)oxymethyl]benzene (3.55 g, 9.22 mmol) obtained from Example 1-(2) in tetrahydrofuran (30 ml) with stirring at −78° C. After the mixture was stirred at the same temperature for 20 minutes, carbon dioxide gas was introduced thereto for 40 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and then the reaction was stopped by addition of a saturated aqueous solution of ammonium chloride. The mixture was warmed to 0° C., and then the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to afford the residue. The residue was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=1:3) to give the title compound (1.63 g, 50% yield) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Sc1ccc(I)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1CSc1ccc(I)cc1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a stirred mixture of p-iodothiophenol (1.75 g, 7.43 mmol) and N-(tert-butoxycarbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (2.39 g, 6.75 mmol) in pyridine (12.7 mL) was added 8 N KOH (1.27 mL) at room temp, and the resulting mixture was stirred for 4 hr at the same temp. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat. NH4Cl, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.49 g (530%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 4-iodophenyl sulfide as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ (s, 9H), 1.78–2.01 (br m, 4H), 2.71 (dt, 1H), 3.32–3.49 (br m, 3H), 3.90–4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1), 7.57 (dd, J=2.0,8.3 Hz, 2H);MS(FAB)m/z 420(M++1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([O:26]C)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:4][CH:3]=1.O.[Na].Cl>O1CCCC1CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:10]([CH3:11])([CH3:12])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([OH:26])=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:28][CH:29]=1
Reactant: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccc(F)cc1)C(C3)C2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: OCC1CCCO1
Product: CC1(C)C(=O)N(C2C3CC4CC2CC(C(=O)O)(C4)C3)N1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of methyl 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate (40.0 mg, 0.100 mmol) in tetrahydrofuran-methanol (1:1, 1 mL) was added with 2M aqueous solution of sodium hydrate (1 mL) at room temperature, and the resultant was stirred at 80° C. for 30 minutes. The reaction solution was neutralized with 4M hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:2), and the title compound (24.5 mg, 63.4%) was obtained as a white crystalline powder.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)#[N:4].Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14]2)#[N:4]
Reactant: CCCCC(Br)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41.2 %

Procedure:
Sodium hydride (5 moles, 200 mg of 60% in mineral oil) was added to 5-(2-cyanophenyl)indole (4.6 mmoles, 1.0 g.) in 50 ml DMF and stirred for 45 minutes. 1-Bromo-1-(4-trifluoromethylphenyl)pentane (5 moles, 1.44 g) was added. The reaction was stirred at room temperature overnight, poured into ice water, and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 820 mg of 5-(2-cyanophenyl)-1-[1-(4-trifluoromethylphenyl)-1-pentyl]indole.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][C:22]=4[CH3:23])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([NH:16][C:14]([C:11]2[C:7]3[N:8]=[CH:9][N:10]=[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)[C:6]=3[S:13][CH:12]=2)=[O:15])[CH:18]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylphenylcarbamate (7 g, 15.93 mmol) was dissolved in DCM (80 mL), TFA (12 mL, 159.3 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the organic solvent and the remaining TFA, and water (20 mL) was added thereto. The reaction mixture was neutralized with 2.0 N NaOH solution, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(I)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(I)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 68 (0.4 g, 0.70 mmol) and pyridine hydrochloride (0.327 g, 2.83 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Yield: 95.7 %

Procedure:
To a suspension of 21 (20.0 g, 0.0735 mol; see Example 46) in 700 mL of anhydrous acetonitrile and 30 mL of anhydrous N,N-dimethylformamide was added anhydrous, powdered K2CO3 (12.68 g, 0.0918 mol) followed by benzyl bromide (13.81 g, 0.0808 mol, 9.61 mL). The mixture was stirred and vigorously refluxed for 6 hrs, cooled, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with a gradient system of 40 to 50% ethyl acetate/hexane to afford 25.50 g (96% yield) of product 40 as a pale yellow oil; TLC (silica gel; ethyl acetate/hexane: 1,1): Rf=0.35.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[C:22]([CH3:24])=[CH2:23].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:22]=[CH2:23])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: C=C(C)Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication 88/08424, 2.78 g), 2-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250°) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24](OCC)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]([CH3:40])[CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:40])[CH2:35][CH2:36]3)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(CCCN(C)C)CC3)o2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (27 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.