Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77(m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][NH:64][CH:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][NH:64][CH:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=507, obsd.=507).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:14])[N:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:14][CH2:8][CH:9]([OH:14])[CH2:10][N:27]2[CH2:26][CH2:25][N:24]([CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28]2)[N:4]=1
Reactant: Cc1cc(C(F)(F)F)nc2cccc(O)c12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: Cc1cc(C(F)(F)F)nc2cccc(OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c12

Procedure:
Following the same procedures as in Example 1-(a) and (b), reaction and treatment were carried out using 2-trifluoromethyl-4-methyl-5-hydroxyquinoline prepared in Example 54 and N-diphenylmethylpiperazine in order to obtain the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:31]2[CH:32]=[C:27]([CH2:26][C:24]#[N:25])[CH:28]=[CH:29][CH:30]=2)[CH:3]=1
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CC#N)c2)n1
Reaction time: 1 h

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [800 mg, 2.29 mmol, see Example 52, step 1], (3-cyanomethyl-phenyl)-boronic acid, pinacol ester (563 mg, 3.43 mmol), and Cs2CO3 (1.86 g, 5.72 mmol) in ethylene glycol dimethyl ether (15 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.11 mmol) at room temperature. After 1 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford (3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-acetonitrile (1.2 g). LCMS: RT=2.47 minutes, 92% purity. MS: 431 (M+H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1>CO>[OH:7][CH2:8][C:9]1[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(COC2CCCCO2)o1
Solvent: CO
Product: CC(=O)c1ccc(CO)o1
Temperature: 35 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Crude 1-[5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-yl]-ethanone (89 g, 0.40 mol) was dissolved in MeOH (500 mL) and treated with Amberlyst 15 (15 g) at rt. The reaction mixture was stirred at 35° C. for 1 h, cooled to rt and filtered over celite. Et3N (1 mL) was added and the mixture was evaporated to dryness. The residue was stripped with methylcyclohexane and 1-(5-hydroxymethyl-furan-2-yl)-ethanone (55 g, 99%) was obtained as a yellow oil that solidified on standing.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1)[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:11][CH3:12])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl) benzo[b]-thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-(4-ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.42 g) and THF (6 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.21 g (43%) of a tan solid, m.p. 128-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][CH:7]=1)=[O:5])[CH3:2].C(O[CH:18](OC(C)C)[N:19]([CH3:21])[CH3:20])(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])/[CH:12]=[CH:18]/[N:19]([CH3:21])[CH3:20])[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(C(C)=O)c1
Reactant: CC(C)OC(OC(C)C)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a solution of 5-Acetyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.560 g, 3.1 mmol) in 5 mL of dimethylformamide, N,N-dimethylformamide diisopropyl acetal (1.9 mL, 9.3 mmol) was added. The mixture was stirred for at 65° C. for 6 hrs. After cooling to room temperature an aqueous solution of NaHCO3 2% (30 mL) was added and extracted with ethyl acetate (50 mL×2). Organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 0.531 g (72%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:15][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][NH:2][C:3]([C:5]1[C:10]([N:12]2[CH2:15][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH2:13]2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: CNC(=O)c1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1nccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A mixture of 3-chloro-pyrazine-2-carboxylic acid methylamide (100 mg, 0.41 mmol) and 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 5) (71 mg, 0.41 mmol) and K2CO3 (113 mg, 0.82 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give the pure product (70 mg, yield 44%). [M+1] 343. IC50 (uM) 3.882.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:18]([S:25][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 2-bromothiazole-4-carboxylate (2.0 g, 8.40 mmol) in DMF (15 mL) was added K2CO3 (1.16 g, 8.40 mmol) followed by benzyl mercaptan (1.07 g, 8.40 mmol) in DMF (5 mL) over 20 min. Upon completion of addition, the reaction mixture was stirred at RT for 16 h. After this time, the reaction mixture was diluted with water and extracted in EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel chromatography (10% EtOAc in hexane) to provide ethyl 2-(benzylthio)thiazole-4-carboxylate (2.0 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42 (s, 1H); 7.47-45 (m, 2H); 7.36-7.28 (m, 3H); 4.52 (s, 2H); 4.31 (q, 2H, J=7.2 Hz); 1.31 (t, 3H, J=7.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1>C1COCC1.[Li+].[OH-].O>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:10]=[CH:9][CH:8]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{3-[4-(3-Bromo-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl)-acetic acid methyl ester (142 mg, 0.3425 mmol) was dissolved in THF (34.5 ml) and 1N LiOH/water (6.85 ml). The reaction was stirred vigorously at RT for 2 h. The organic solvent was evaporated off. The aqueous solution was acidified to pH 3 with 1N HCl, whereupon a white precipitate formed. The precipitate was filtered and dried under vacuum, giving {3-[4-(3-bromo-phenylamino)-[1,3, 5]triazin-2-ylamino]-phenyl}-acetic acid. MS m/z 401=[M+H]+. Calc'd for C17H14BrN5O2: 399.03.
Reaction SMILES: [CH2:1]([C:4]1[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6][N:5]=1)[CH2:2][CH3:3].C[O-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:19]([N:5]1[CH:4]([CH2:1][CH2:2][CH3:3])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CCCc1n[nH]c(=O)c2cncn12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C=CCN1NC(=O)c2cncn2C1CCC
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 4-n-propyl-imidazo[1,5-d]-as-triazin-1(2H)-one (0.01 mol) in dimethylformamide (50 ml) is added sodium methoxide (0.01 mol) followed by the addition of allyl bromide (0.012 mol). The reaction mixture is stirred at 20° C. for 16 hours, then heated at 40° C. for 45 minutes, cooled and poured on a mixture of ice and dilute hydrochloric acid. The product is isolated by extraction with chloroform and evaporation. It is purified by recrystallization from cyclohexane or a cyclohexane-benzene mixture; or by silica gel dry column chromatography in chloroform.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:37])[C:24]=2[CH:23]=1>>[CH:23]1[C:24]2[C:25](=[O:37])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32](=[O:36])[C:33]=2[CH:34]=[CH:35][C:22]=1[CH2:21][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c(=O)[nH]c1=O
Yield: 35.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 35.1%).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)=[O:28])=[C:14]([NH:13][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:6][CH2:7]3)=[O:12])[C:18]=2[CH:19]=1)([OH:25])=[O:24]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](NC(C)C)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (690 mg) obtained in Example 311 is suspended in tetrahydrofuran/methanol (1:1, 10 ml), and under ice-cooling, thereto is added 4N aqueous sodium hydroxide solution (3 ml). The mixture is warmed to room temperature, and stirred for 18 hours. The reaction solution is concentrated under reduced pressure, and poured into ice-water. The mixture is neutralized with 10% hydrochloric acid, and the precipitates are collected by filtration, washed successively with water, tetrahydrofuran, and diethyl ether, and dried to give the title compound (702 mg).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25]/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Product: O=C1/C(=C(\NC2CCCCC2)c2ccccc2)Sc2ccccc21
Yield: 56 %

Procedure:
Prepared as in Example 31 with a yield of 56% of theory from 2-benzoyl-benzo[b]thiophen-3-ol and cyclohexylamine. Lemon-yellow crystals were obtained, m.p. 122°-123° C. (petroleum ether/ethyl acetate 85:15).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O>C1COCC1.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: c1ccc(Cn2cnc3cncnc32)cc1
Temperature: 62.5 °C

Procedure:
To a stirred suspension of 9-benzyladenine (6) (22.0 g, 97.6 mmol) in anhydrous THF (500 mL) was added t-butyl nitrite (9.34 g, 478.5 mmol) and the reaction mixture heated under an atmosphere of nitrogen at 60-65° C. for 4 h. THF and the excess reagent were distilled off and the residue obtained redissolved in chloroform (100 mL) and washed with brine solution (2×50 mL). The chloroform layer was dried over anhydrous sodium sulfate and distilled off to give a reddish oil, which was purified by flash chromatography on silica gel using EtOAc/hexane (8:2) for elution. Yield 10.68 g (42.3%). Mp 99-100° C. 1H NMR (CDCl3): δ 5.49 (s, 2H, CH2), 7.34-7.40 (m, 5H, Ar—H), 8.10 (s, 1H, purine C6—H), 9.06 (s, 1H, purine C8H), 9.20 (s, 1H, purine C2H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@@H:9](O)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([OH:62])(=[S:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:61][C:54](=[O:62])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(Cl)ncc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reaction time: 0.38 h

Procedure:
A solution of 438 mg of (3R,5S)-1-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methyl-3-hydroxypyrrolidine and 672 mg of triphenylphosphine in 6.5 ml of anhydrous THF is cooled to −10° C. in an argon atmosphere. Diethyl azodicarboxylate (0.40 ml) is added dropwise to the mixture over a period of 7 min while maintaining the solution at −5° C. or below, and the mixture is stirred in this state for 23 min. Thiobenzoic acid (90%) (0.34 ml) is added dropwise to the mixed solution at −10° C. over a period of 5 min, and the mixture is stirred in this state for additional 25 min. The solvent is removed by evaporation under reduced pressure to give an oil which is then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 505 mg of the title compound as a bright yellow viscous material.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[N:29]=[CH:30][CH:31]=[C:32]2[C:33]=1[CH:34]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:18]3)=[CH:14][CH:15]=1)=[N:36]2
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 33-2 (0.64 g, 2.5 mmol), 3-1 (0.88 g, 2.5 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (14 mL) was heated to 120° C. for 4.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→70% ethyl acetate/hexane) gave the title compound as a foam. MS (M+H+): calculated=471.98, observed=472.1.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=O)[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(Cl)(=O)C([Cl:16])=O>ClCCl>[CH2:1]1[CH:8]2[C:4]3([C:10]([Cl:16])=[O:12])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of commercially available hexahydro-2,5-methano-pentalene-3a-carboxylic acid (10 g, 0.06 mol) in dichloromethane (200 mL) was added oxalyl chloride (8.7 g, 0.066 mol). The mixture was stirred overnight and then concentrated under reduced pressure to afford the title compound as a colorless oil (11 g, 99%). MS (DCI/NH3) m/z 184 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@:5]1([CH2:19][CH3:20])[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C:6]1=O.C([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30]N)C>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@:5]1([CH2:19][CH3:20])[C:6]2[NH:30][C:25]3[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:7]=2[CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CCc1ccccc1NN
Reactant: CC[C@@]1(CC(=O)OC)CCC(Cc2ccccc2)CC1=O
Product: CC[C@@]1(CC(=O)OC)CCC(Cc2ccccc2)c2c1[nH]c1ccccc21

Procedure:
This material can be prepared from (1S)-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester as described in Example 2, Step (b), for racemic material by substituting phenylhydrazine for 2-ethylphenylhydrazine.
Reaction SMILES: [N:1]([C@@:4]1([OH:23])[C@@H:8]([CH2:9][O:10]C(=O)C)[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]>O1CCOCC1.[NH4+].[OH-].CCOCC>[N:1]([C@@:4]1([OH:23])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=S)[nH]c2=O)C[C@@]1(O)N=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@@](O)(N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Reaction time: 18 h

Procedure:
3'-Azido-5'-O-acetyl-4-thiothymidine (0.25 g; 0.76 mMol, Example 11) was dissolved in a mixture of 5 mL of dioxane and 5 mL of conc. NH4OH and stirred for 18 hrs. The solvent was removed in vacuo and the residue applied to a silica gel column followed by elution with CHCl3 /EtOAc (3:1 v/v). The appropriate fractions were combined and the solvent removed in vacuo to yield a yellow oil which was dissolved in Et2O, forming crystals upon concentration: 0.16 g (0.56 mMol; 74%).