Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH2:1]([C:4]1[N:9]=[C:28]([CH3:29])[N:11]2[N:12]=[C:8]([CH3:10])[N:7]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)(OCC)OCC
Product: CCCc1nc(C)n2nc(C)nc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
6 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are heated to 90° C. for 5 hours in 100 ml of triethyl orthoacetate. The mixture is then evaporated under vacuum and the residue is taken up in 75 ml of formic acid. The solution obtained is heated to reflux for 5 hours, the formic acid is then evaporated off under vacuum and the residue is crystallised in an ether/pentane mixture to give 5 g of 7-n-propyl-2,5-dimethyl-8-[(2'-cyano-4biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 132° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(O)C>[Pd].C(N(CC)CC)C>[C:5]1([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
4-(4-Chlorophenyl)pyrrole-2-carboxylic acid (0.6 g.) was hydrogenated over 200 mg. of 5% Pd/C in 50 ml. of ethanol for approximately 16 hours at 50 p.s.i. An additional 200 ml. of catalyst and 1 ml. of triethylamine was added and hydrogenation continued for 3 hours at 50 p.s.i. The catalyst was recovered by filtration, and the mother liquor concentrated to dryness to yield 4-phenylpyrrole-2-carboxylic acid [400 mg., m.p. 226°-228° C. (dec.), m/e 187]. For analysis, the product was rectystallized from acetone/hexane [240 mg., m.p. 227°-229° C. (dec.)].
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:24][CH3:25])=[O:11])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (80 g) in ethanol (3.2 () was added dropwise conc. sulfuric acid (160 ml) over a period of 0.5 hour and the mixture was stirred for 2.5 hours at ambient temperature. Evaporation of ethanol gave a residue which was poured into ice-cold water (2.4 () and extracted with chloroform. The extract was washed with water and brine successively and evaporated to dryness to give ethyl 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate which was recrystallized from diisopropyl ether (87.05 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:14])[C@@H:10]([NH2:13])[CH2:11][OH:12])=[CH:5][CH:4]=1.[C:15]1(C)[CH:20]=CC=C[CH:16]=1.O>CC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[O:14][C:15]([CH3:20])([CH3:16])[NH:13][C@H:10]2[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: Cc1ccccc1
Reactant: CSc1ccc([C@H](O)[C@@H](N)CO)cc1
Solvent: O
Solvent: CC(C)=O
Product: CSc1ccc([C@@H]2OC(C)(C)N[C@H]2CO)cc1

Procedure:
A stirred mixture of enantiomerically pure (+)-thiomicamine (100 g; 0.469 mol), toluene (920 ml) and acetone (100 ml) was heated at reflux for 18 hours beneath a Dean Stark trap: a mixture of toluene, water and acetone (11 g) was collected. The solvent (200 ml) was distilled at ambient pressure and then under vacuum (internal temperature 80° C.) to give compound 7 (118.6 g) as residue.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:21])[CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[CH2:26][S:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:22])[CH2:10][C:11](=[O:21])[NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]2=3)=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(N)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(NS(=O)(=O)Cc2ccccc2Cl)cc1
Yield: 21.5 %

Procedure:
By using 1-(4-aminophenyl)-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (65 mg, 0.22 mmol), and 2-chlorobenzylsulfonyl chloride (74 μL, 0.33 mmol), the title compound (23 mg, yield 13%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[CH:9](OCC)(OCC)OCC>>[NH:6]1[C:3]([C:4]#[N:5])=[C:2]([C:7]#[N:8])[N:1]=[CH:9]1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCOC(OCC)OCC
Product: N#Cc1nc[nH]c1C#N

Procedure:
In another 5-step synthesis, diaminomaleonitrile can be reacted with triethyl orthoformate to give the imidazole-4,5-dinitrile which, after alkylation with dimethyl sulfate, hydrolysis and partial decarboxylation by heating in acetic anhydride, gives the compound of the formula Ia (R1 =CH3, X1 =COOH).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:32][O:33][C:34]1[C:35]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:44]=2[CH2:53]Br)=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:53][C:44]3[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:43]=3[C:35]3[CH:36]=[C:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one) (46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3 mL) was added. NaHMDS (296 μL of a 1M solution in THF, 0.296 mmol) was added and the reaction was stirred for 5 min. At this time, 2′-(bromomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl methyl ether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2 mL). After 30 min, the reaction was quenched with saturated NH4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The organic layer was washed with water (15 mL), and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}4-methyl-1,3-oxazolidin-2-one. Rf=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H), 3.25-3.74 (m, 4H), 2.88 (m, 1H), 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[CH2:22][C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:21]1[C:20]2[CH:22]=[CH:12][CH:13]=[CH:14][C:19]=2[CH:18]=[CH:17][CH2:16][C:15]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CC=Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 100 g of m-chloroperbenzoic acid in 1 l of chloroform at 0° C. is added dropwise 100 g of α-tetralone in 250 ml chloroform. After 5 days of stirring at room temperature the reaction mixture is treated carefully with 1 l sat. NaHCO3 and stirred for 1/2 hour. The organic layer is separated, washed with 500 ml of water and solid NaHCO3 until no evolution of gas. The organic layer is separated washed with sat. NaHCO3 and water and dried (MgSO4). After filtering and concentrating to dryness it is vaccum distilled to obtain low melting material which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[NH4+:12]>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 1.3 %

Procedure:
3 g (1 mol equiv.) 5-Chloro-thiophene-2-sulfonyl chloride was dissolved in 30 mL acetonitrile and cooled to 0° C. Dropwise, 6.5 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 2.49 g (91%) 5-chloro-thiophene-2-sulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J=4.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.79 (br.s., 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(C1C=CC=C(CC=C)C=1[OH:24])C=C.C1(O)C=CC=CC=1.C(N(CC)CC)C>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCc1cccc(CC=C)c1O
Solvent: Oc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Triethylamine (4 ml) and 4-toluenesulfonyl chloride (3.80 gm, 0.02 mol) were diluted with 1,2-dichloromethane (50 ml) and 2,6-diallylphenol (3.48 gm, 0.02 mol), dissolved in 1,2-dichloromethane (10 ml), was added drop wise to the phenol-triethylamine solution at room temperature and then refluxed for 1 hr. The reaction mixture was cooled, washed with water and dried over MgSO4, filtered and evaporated to give 4-toluenesulfonic acid: 2,6-diallylphenyl ester as an oil. Purification was carried out via filtering a hexane solution of the ester through silica gel. MS m/z 328 (M+ calcd for C19H20O3S=328). H NMR (300 MHz, CDCl3) d 2.50 (s, 3, CH3), 3.25–3.35 (d, 4, CH2), 4.95–5.10 (m, 4, CH2 vinyl), 5.75–5.90 (m, 2, CH, vinyl), 7.10–7.25 (m, 3, aromatic), 7.85–7.95 (m, 2, aromatic). Oxidation of product as described in Example 1 gave 4-toluenesulfonic acid 2,6-di(2,3-epoxypropyl)phenyl ester. MS m/z 360 (M+ calcd for C19H20O5S=360. H NMR (300 MHz, CDCl3) d 2.45–2.55 (m, 2, CH2 epoxypropyl), 2.50 (s, 3, CH3), 2.35–2.95 (m, 6, CH2 epoxypropyl), 3.21–3.35 (m, 2, CH epoxypropyl), 7.25–7.45 (m, 5, aromatic), 7.85–7.95 (d, 2, aromatic).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>C(O)C.C1CCCCC=1.[Pd]>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[NH2:15]
Reactant: Cc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1ccc(N2CCN(C)CC2)cc1N
Temperature: 80 °C

Procedure:
To a solution of 1-methyl-4-(4-methyl-3-nitro-phenyl)-piperazine (9.0 g, 38.29 mmol) in ethanol (100 mL) and cyclohexene (7 ml), Pd/C 10% (1.5 g) was added. The mixture was heated at 80° C. for 6 hours. The Pd was filtered from the reaction and the solvents were removed from the filtrate under reduced pressure. The crude was diluted with DCM and treated with HCl in dioxane; the precipitate was collected and washed with diethyl ether to give the final compound as a brown solid in quantitative yield.
Reaction SMILES: C([O:4][C:5]1[C:21]([O:22]C(=O)C)=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:10])=[O:8])(=O)C>CO.N>[OH:4][C:5]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:10])=[O:8]
Reactant: CC(=O)Oc1cccc(C(=O)N(N)C(=O)OC(C)(C)C)c1OC(C)=O
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N(N)C(=O)c1cccc(O)c1O
Reaction time: 24 h

Procedure:
[2,3-bis(Acetyloxy)benzoyl]hydrazinecarboxylic acid, t-butyl ester (25 g) was dissolved in 100 ml of methanol containing 6 g of ammonia. After standing over 24 hours at 0° C., the solvent was removed in vacuo and the residue stirred with 100 ml of ice water yielding (2,3-dihydroxybenzoyl)hydrazinecarboxylic acid, t-butyl ester as beige crystals, 17.8 g; melting point 158°-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH3:13][N:12]([CH3:14])[C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[NH:1][C:27]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[C:27]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(NCc2ccccc2N)cc1
Reactant: CCCCCCCN=C=O
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1CN(C(=O)NCCCCCCC)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of N-(2-aminobenzyl)-N',N'-dimethyl-1,4-phenylenediamine (0.6 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.4 g) and the mixture was stirred overnight while returning slowly to room temperature. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) to give 1-(4-dimethylaminophenyl)-1-[2-(3-heptylureido)benzyl]-3-heptylurea as a non-crystallizable solid (0.55 g, 44%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCC1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCCC1

Procedure:
Oxalyl chloride (139 μL; 1.64 mmol; 3 eq.), Intermediate 33 (120 mg; 0.55 mmol; 1 eq.), Intermediate 2 (120 mg; 0.55 mmol, 1 eq.) and DIEA (2834; 1.64 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:39]([CH3:41])[CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:24]2)[O:12]1>CCO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:39]([CH3:41])[CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24]2)[O:12]1
Reactant: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10% Pd—C (70 mg) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}(propan-2-yl)amino)cyclobutyl]propanoate (790 mg, 1.40 mmol) in EtOH (20 ml) and stirred under an atmosphere of hydrogen for 18 hours at RT. A further aliquot of 10% Pd—C (70 mg) was added and the reaction was continued stirring under hydrogen for 4 hours. This was filtered and evaporated in vacuo, and then evaporated from DCM (2×20 ml) to give 680 mg (quant.) of a white foamy solid; MS (ESI+) for C23H34N6O5 m/z 475.20 [M+H]+; HPLC purity 100% (ret. time, 1.11 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.29 (d, J=16.3 Hz, 1H), 7.97 (d, J=16.2 Hz, 1H), 6.86 (s, 2H), 6.05 (dd, J=4.3, 1.7 Hz, 1H), 5.66-5.43 (m, 1H), 5.00 (ddd, J=19.3, 6.3, 3.2 Hz, 1H), 4.30 (s, 1H), 3.47-2.85 (m, 2H), 2.60 (ddd, J=38.8, 24.1, 13.5 Hz, 2H), 2.19 (ddd, J=14.7, 11.9, 7.1 Hz, 2H), 2.07-1.94 (m, 2H), 1.81 (dd, J=65.1, 6.9 Hz, 3H), 1.66-1.46 (m, 5H), 1.45-1.22 (m, 4H), 1.00 (d, J=6.4 Hz, 3H), 0.89 (dd, J=12.2, 6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C)=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[Cl-].[Al+3].[Cl-].[Cl-].Cl.ClCCl>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(F)c2c1CCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCc2c(O)ccc(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 8-fluoro-5-methoxytetralone (Owton, W. M. J. Chem. Soc., Perkin Trans. 1 (1994), 2131-2135) (7.0 g, 36 mmol) in 1,2-dichlorethane (150 mL) was treated with aluminum chloride-(21 g, 157 mmol), refluxed for 3.5 hours, cooled to ambient temperature, poured carefully into 4M HCl (500 mL), stirred for 16 hours, treated with dichloromethane (400 mL) and thoroughly shaken. A black solid was removed by filteration through Celite®. The dichloromethane layer was isolated, combined with the black solid and extracted with 5% sodium hydroxide solution (3×150 mL). The combined sodium hydroxide extracts were acidified with 4M hydrochloric acid and the resulting solid was collected by filtration to provide the desired product as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1.[OH-:22].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[NH:7][C:6](=[O:22])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1
Reactant: Fc1ccc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Yield: 77.9 %

Procedure:
To a tetrahydrofuran solution (200 mL) of 2,4-dichloro-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine (21.0 g, 63 mmol) synthesized in Reference Synthesis Example 1, 1 M sodium hydroxide aqueous solution (128 mL, 128 mmol) was added at room temperature and the resultant solution was stirred for 1 day. To the reaction solution, 1 M sodium hydroxide aqueous solution (32 mL, 32 mmol) was added and the resultant mixture was stirred for 6 hours. To the reaction solution, 1 M sodium hydroxide aqueous solution (19 mL, 19 mmol) was further added and the resultant solution was stirred for 2 hours. After completion of the reaction, pH of the reaction solution was adjusted to 4 by adding 1 M hydrochloric acid. After removing impurities, the resultant mixture was concentrated under reduced pressure to obtain a solid. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.2 g, yield 79%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:17][CH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:12]=[CH:13]1)(=[O:25])[CH3:24]
Reactant: Nc1nc(NCC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)C1

Procedure:
A solution of (%)-cis-4-(2 amino-6-(cyclopropylmethylamino)-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 7 (0.30 g, 1 mmol), acetic anhydride (0.204 g, 2 mmol), N,N-dimethylaminopyridine (0.005 g, 0.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature under nitrogen overnight. H2O (1 mL was added and the solution allowed to stir an additional hour, then concentrated under high vacuum. The residual oil was partitioned between saturated sodium bicarbonate solution (5 mL) and chloroform (3×50 mL). The combined chloroform extracts were dried (MgSO4), solvent evaporated and residue chromatographed on silica gel. Title compound was eluted with 4% methanol-chloroform; foamed from ethanol under high vacuum (0.330 g, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[C:11]([C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[N:17][CH:18]=1)#[N:12].N1C(C)=CC=CC=1C>COCCOC>[Br:1][C:2]1[C:3](=[O:10])[N:4]=[C:5]([CH3:9])[NH:6][C:7]=1[NH:12][CH2:11][C:13]1[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[N:17][CH:18]=1
Reactant: Cc1nc(O)c(Br)c(Cl)n1
Reactant: N#Cc1cncc(CN)c1
Solvent: Cc1cccc(C)n1
Solvent: COCCOC
Product: Cc1nc(=O)c(Br)c(NCc2cncc(C#N)c2)[nH]1
Temperature: 90 °C
Yield: 31 %

Procedure:
A stirred suspension of 5-bromo-6-chloro-2-methyl-4-pyrimidinol (1.57 g, 7.04 mmol), 5-cyano-3-aminomethylpyridine (1.03 g, 7.74 mmol), and 2,6-lutidine (2.00 mL, 17.4 mmol) in 1,2-dimethoxyethane (7.0 mL) was heated at 90° C. for 15 hours. Solvent was removed in vacuo, and the residue was suspended in water. The white precipitate was isolated by filtration with aqueous rinse, and then recrystallized from methanol/diethyl ether to afford crude product (922 mg, 41%). The crude product was adsorbed onto silica gel. The product was eluted with 4:1 ethyl acetate:hexane (150 mL) followed by methanol (300 mL). The methanol eluant was concentrated in vacuo, and the residue was recrystallized from methanol/diethyl ether to give the title compound in analytically pure form (705 mg, 2.20 mmol, 31% yield): mp 260.0°-260.5° C.; Rf 0.51 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ11.0 (s, 1H), 8.88 (d, J=1.69 Hz, 1H), 8.77 (d, J=1.64 Hz, 1H), 8.16 (s, 1H), 7.34 (t, J=6.14 Hz, 1H), 4.60 (d, J=6.00 Hz, 2H), 2.16 (s, 3H); IR (KBr) 3280 (NH), 2620-3000 (CH), 2230 (CN), 1645, 1605, 1585 (C=C, C=N); UV (MeOH)λ275.5 (ε10900).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:18]1([C:16]([C:14]2[S:15][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])[N:10]=3)=[CH:12][CH:13]=2)=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: NCCN1CCNC1=O
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NCCN1CCNc1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5-(2-(methylsulfonyl)pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone (100 mg, 0.26 mmol), 1-(2-aminoethyl)imidazolidin-2-one (36 mg, 0.28 mmol) and triethylamine (56 mg, 0.52 mmol) in toluene (3 mL) was refluxed for 6 h. After cooling to rt, the solvent was evaporated in vacuo and then methanol (5 mL) was added. After stirring for 15 min the solid was filtered and dried to give title compound as a light yellow solid. MS (M+H)+ 403.