Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: OC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(O)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (3000 mg; 7.22 mmol; 1 eq), is dissolved in anhydrous DCM (400 ml). The reaction is put under nitrogen. Triethylamine (5.0 ml; 36.1 mmol; 5 eq) and 4-hydroxypiperidine (3649.4 mg; 36.1 mmol; 5 eq) are added successively and the reaction mixture is stirred for 6 hours at room temperature. It is washed with water, NaHCO3 sat., brine, and dried over MgSO4, affording the title compound (3500 mg; 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:34])[C@H:13]([CH3:33])[NH:14][C:15](C(OC)=O)([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]>CO.O>[C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:34])[C@H:13]([CH3:33])[NH:14][CH:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Solvent: O
Solvent: CO
Product: COC(=O)C(CCC(=O)c1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Aqueous N-sodium hydroxide solution (6.2 ml.) was added to a solution of N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester (Example 31; 3.0 g.) in a mixture of methanol (3 ml.) and water (1.5 ml.) and the mixture was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The mixture was partitioned between water and ethyl acetate and the aqueous layer was separated, acidified to pH 5 with aqueous N-hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to dryness. There was thus obtained as residual oil N-[1-methoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][C:13]=2[CH2:24][CH3:25])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:10]2)=[C:13]([CH2:24][CH3:25])[CH:14]=1)#[CH:19]
Reactant: CCc1cc(C#C[Si](C)(C)C)ccc1C1(OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane (Intermediate 89, 240 mg, 0.69 mmol) in methanol (6 mL) was treated with potassium carbonate (10.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (190 mg, 99%) was used directly in the next reaction. 1H NMR (CDCl3) δ: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.08 (1H, s), 3.01 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz), 1.22 (2H, m), 0.92 (2H, m).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:40]=1[N:48]=[C:49]=[O:50])([CH3:38])[CH3:37].[K+].[Br-]>C(OCC)(=O)C>[CH3:38][CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:46])[CH3:47])[C:40]=1[NH:48][C:49]([N:19]([CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50])[CH3:37]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)C(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 72 h

Procedure:
A mixture of 0.50 g of the product of Example 7, 0.22 g 2,6-diisopropylphenylisocyanate and a few mL ethyl acetate was allowed to sit 3 days at room temperature. The solvent was removed and the residue chromatographed on SiO2 (70-230 mesh) using hexane/EtoAc, 1/1, as eluant. The product was obtained as a white solid. 0.33 g (46%). NMR (CDCl3) δ 0.88 (3H, t), δ 1.15 (12H, d), δ 1.21-1.26 (22H, m) δ 1.78 (2H, m), δ 2.02 (4H, m), δ 3.10 (2H, m), δ 3.47 (2H, t), δ 3.75 (6H, s), δ 3.80 (3H, s), δ 4.17 (2H, s), δ 5.35 (2H, t), δ 6.07 (1H, s), δ 6.14 (2H, s), δ 7.13-7.25 (3H, m), δ 7.72 (1H, s). IR (KBr) 3242, 2959, 2525, 1675, 1627, 1508, 1156, 1135 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: Oc1cccc(Nc2ccccn2)c1

Procedure:
3-Aminophenol (3.0 g, 27.5 mM) and 2-bromopyridine (4.34 g, 27.5 mM) were combined in acetic acid (15 mL) and heated for about 18 hours. The mixture was concentrated in vacuo and placed on a column of silica gel (150 g). The product was eluted with 3% methanol/methylene chloride to provide 1.2 g of an off white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7]>CC(O)=O>[Br:1][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([O:4][CH3:3])[C:6]=1[NH2:7]
Reactant: BrBr
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
47.64 g of bromine in 120 mL of AcOH was added dropwise to a solution of 47.64 g of 2-methoxy-4nitro-aniline in 240 ml of AcOH at 0° C. Upon addition a precipitate formed. Mixture was stirred for 30 minutes and then filtered. The precipitate was washed with satd. NaHSO3, water, and vaccum dried, giving 24 g of title compound as a bright yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[Na].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:17]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCCCl)c1
Reactant: [Na]c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: N
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCCn2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of 5-(3-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine and 0.33 g of imidazolyl sodium are heated to 50° C. in 30 ml of DMF and the mixture is stirred overnight. It is then cooled to RT, the solvent is stripped off in an RE and the mixture is treated with water, extracted 3 times with ethyl acetate and concentrated. 5-(3-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine, (Rf=0.44, silica gel, methylene chloride/methanol containing 5% of about 5N ammonia in methanol 9:1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][Cl:21])=[CH:15][CH:14]=3)[C:6]=2[CH:22]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:3]([C:23]([F:25])([F:24])[F:26])=[CH:4][C:5]2[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][Cl:21])=[CH:17][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
A solution of 1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (Example 367, step 1, 400 mg, 1 mmol) in CH2Cl2 was added MnO2 (2.7 g, 32 mmol). The mixture was stirred at room temperature for 24 h. This was directly purified by flash column chromatography eluting with hexane/ethyl acetate (4:1) to afford 350 mg (88%) of the title compound as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29][CH3:30])=[O:28])=[CH:19][N:18]=1>>[CH3:30][O:29][C:27]([C:20]1[C:21]([C:23]([F:26])([F:24])[F:25])=[N:22][C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:18][CH:19]=1)=[O:28]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Product: COC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and methyl 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylate. The reaction was heated to reflux for 16 h. The title compound was obtained as a pale-yellow solid in 20% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][C@H:27]([N:33]=[N+]=[N-])[C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[NH4+]>O1CCCC1.O>[C:20]1([CH2:26][C@H:27]([NH2:33])[C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)c1nccs1
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)c1nccs1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a 55° C. (oil bath) solution of triphenylphosphine (1.6 g, 6.3 mmol) in tetrahydrofuran (10 mL) is added (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylazide (contaminated with DPPA, 1.2 g, 5.2 mmol) as a solution in tetrahydrofuran (10 mL). The reaction mixture is allowed to stir for 2 hours at this temperature when aqueous ammonium hydroxide (14 mL) is added. Stirring at 55° C. is continued for 3 hours before the reaction mixture is stored in a −5° C. freezer overnight. The next morning, the reaction mixture is diluted with water (80 mL) and extracted twice with diethyl ether. The combined extracts are washed with 10% aqueous hydrochloric acid (70 mL). The acidic aqueous phase is cooled in an ice-water bath and then basified with 10% aqueous sodium hydroxide to pH 12. The basic phase is then extracted thrice with dichloromethane. The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide a 0.67 g (52% over 2 steps) of a slightly blond oil. MS (ES+): (M+H)=205.0
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:6]([O:15][CH2:16][CH:17]=C)=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3].CSC.Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C([BH3-])#N.[Na+]>ClCCl.CO>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][CH2:17][CH2:16][O:15][C:6]1[C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: C=CCOc1c(OC(C)C)cccc1C(=O)OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: COC(=O)c1cccc(OC(C)C)c1OCCNCc1c(C)cc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 11.2 %

Procedure:
Ozone was bubbled through a cooled (−78° C.) solution of methyl 3-(propan-2-yloxy)-2-(prop-2-en-1-yloxy)benzoate (123d, 438.1 mg, 1.75 mmol) in dichloromethane (17.5 mL) until a persistent violet-blue color was obtained (about 5 minutes). Nitrogen was bubbled into the solution for 3 minutes, causing the color to fade, then dimethyl sulfide (1.0 mL, 13.5 mmol) was added and the mixture allowed to warm to room temperature for one hour. The solvents were evaporated and the residue partitioned between sodium carbonate solution (sat., aq., 10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum to give the crude residue. This crude aldehyde was dissolved in methanol (10.0 mL) and treated with 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Cpd V, 334 mg, 1.87 mmol) at room temperature for five minutes, then sodium cyanoborohydride (332 mg, 4.50 mmol) was added and the mixture stirred at room temperature for 14.5 hours. The solvents were evaporated under vacuum and the residue partitioned between deionized water (10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (EtOH+5% NH4OH in ethyl acetate) to give methyl 2-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]amino}ethoxy)-3-(propan-2-yloxy)benzoate (123e, 76 mg, 11% yield) as a colorless glass.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH2:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[NH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:20]2[N:21]=[C:22]([NH2:29])[N:23]=[C:24]([NH:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:25]=2[N:26]=[CH:27]1)(=[O:3])[CH3:2]
Reactant: NN1CCCCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 190 h
Yield: 70.9 %

Procedure:
9-(2',3',5'-Tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-(9H)-purine (6.0 g, 14 mmol) (prepared as described by Robins, M. J. and Uznanski, B., in Nucleic Acid Chemistry (Townsend, L. B. and Tipson, R. S., eds.,) John Wiley and Sons, Inc., 1986, 3, 144) was dissolved in dioxan (100 ml). 1-Aminopiperidine (1.83 ml, 16.95 mmol) was added followed by triethylamine (2.33 ml, 18.5 mmol) and the solution was stirred for 190 hours at room temperature. The reaction mixture was filtered, evaporated and the resultant residue was purified by column chromatography on silica gel eluting with ethyl acetate/cyclohexane (3/1) to afford 2',3',5'-tri-O-acetyl-2-amino-N-(1-piperidinyl)adenosine (4.88 g, 71%) as a foam which solidified on coevaporation with methanol: m.p. 77°-79° C. 1H NMR (400 MHz, Me2SO-d6) δ2.04 (6H, s, 2' and 3'-O-acetyl-CH3), 2.13 (3H, s, 5'-O-acetyl-CH3), 4.30 (2H, m, H-5'a and H-4'), 4.40 (1H, dd, H-5'b) 6.03 (1H, d, H-1').
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[C:18]([Cl:30])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:36](=[O:37])[CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (5.0 mL) were added a solution of triethylamine (419 mg) in N,N-dimethylformamide (1.25 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 16 hrs, water was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→80/20), and recrystallized from ethanol-ethyl acetate-diisopropyl ether to give the title compound (151 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2([NH:34]C(=O)C)[CH2:31][O:30]C(C)(C)[O:28][CH2:27]2)=[CH:20][CH:19]=1.[ClH:38]>C(O)C>[ClH:38].[NH2:34][C:26]([CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:10]=[CH:11][C:12]([CH:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=3)=[CH:7][C:2]=2[F:1])=[CH:23][CH:22]=1)([CH2:31][OH:30])[CH2:27][OH:28]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C(C)C)cc4)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
N-(5-{2-[2′-Fluoro-4′-(4-isopropylphenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.24 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 75° C. for 4 hr. The reaction mixture was concentrated to dryness, and the residual solid was suspended in ethyl acetate and collected by filtration to give the title compound (141 mg) as white crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29](=O)[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Yield: 15 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopropyloxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a yellow solid (20 mg, 15%). LC/MS (Method B) 3.12 min, [M+1]+ 448.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[C:19]3[C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:24][CH3:25])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:28])=O.[Cl-].[Na+]>CS(C)=O.O>[CH3:25][O:24][C:14]1[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[C:19]=2[C:11]([C:9]2([C:26]#[N:27])[CH2:8][CH2:7][C:6](=[O:28])[CH2:5][CH2:10]2)=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1oc1ccccc12
Temperature: 135 °C

Procedure:
To a solution of 5-cyano-5-(4-methoxy-dibenzofuran-1-yl)-2-oxo-cyclohexane carboxylic acid methyl ester obtained in example 1 (7 g, 0.0185 mol) in DMSO (140 ml) and water (9 ml) was added sodium chloride (7 g, 0.119 mol) at room temperature. The reaction mass was heated to 130-140° C. for 5 hrs. Once the product is formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. 1-(4-methoxy-dibenzofuran-1-yl)-4-oxo-cyclohexane carbonitrile was isolated by column chromatography. Yield 4.2 g (71%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:30](=O)(O)[O-:31].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([O:31][CH3:30])[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccnnc3c2-c2ccnc(F)c2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2c(-c3ccc(F)cc3)nn3ccnnc23)ccn1

Procedure:
To a suspension of 7-(4-fluorophenyl)-8-(2-fluoropyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (350 mg) in methanol (2 ml) was added conc. sulfuric acid (0.32 ml) dropwise. The mixture was refluxed for 1 hour, cooled and poured into cold water. The aqueous solution was neutralized with an aqueous saturated sodium bicarbonate solution and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 7-(4-fluorophenyl)-8-(2-methoxypyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (220 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH:23]([NH2:25])[CH3:24].O>C(O)CCC>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:25][CH:23]([CH3:24])[CH3:22])[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: CC(C)N
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCNc1nc(NC(C)C)c2ccn(C)c2n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (1.6 g, 7.1 mmol) in n-butanol (10 mL) was added potassium carbonate (4.9 g, 35.5 mmol), followed by propan-2-amine (632 mg, 10.7 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 140° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and lastly dried over anhydrous Na2SO4. The volatiles were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=3/1) to yield 2-(n-propyl)amino-4-(i-propyl)amino-7-methyl-pyrrolo[2,3-d]pyrimidine (1.2 g, 75%) as a yellow solid. LCMS: (ESI) m/z=248 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=2)[C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][C:24]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(O)c2ccc(OCOC)cc2)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccc(OCOC)cc1)c1ccc(OCOC)cc1
Yield: 82.5 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 4,4'-bis(methoxymethoxy)benzhydrol (6.22 g, 32.9 mmol) and ethyl indole-2-carboxylate (10.0 g, 32.9 mmol) to give 12.9 g (yield: 89%) of the title compound.