Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:12])=[CH2:11].[H][H].[I:15]I>CO.[Pd].S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:15])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: II
Reactant: [H][H]
Reactant: C=C(C)c1ccc(OC)cc1F
Agent: [Ag+2]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the 2-fluoro-1-isopropenyl-4-methoxybenzene (Intermediate 4, 1.96 g, 11.81 mmol) in MeOH (30 mL) was charged with hydrogen at 1 atm and a catalytic amount of Pd/C. The mixture was stirred at room temperature for 1 h. The mixture was filtered through Celite. The filtrate was then added to a mixture of silver sulfate (3.68 g, 11.81 mmol) and iodine (3.00 g, 11.81 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 3 h until the color of solution became light yellow. The mixture was filtered and the filtrate was concentrated. The title compound was obtained after flash column on silica gel using EtOAc:hexane 5:95 as the elute. 1H NMR (CDCl3, 500 MHz) δ 7.61 (d, J=8.0 Hz, 1H), 6.56 (d, J=12.5 Hz, 1H), 3.90 (s, 3H), 3.18 (m, 1H), 1.28 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1([CH2:43]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCC4CCCCC4)cc3C)c2cc1OC
Yield: 92.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-cyclohexyl-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH3:26])[C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[CH:14][C:13]1=2>C(#N)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH3:26])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]1=2
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(NC(=O)OC(C)(C)C)ccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2cc(N)ccc21
Product: Cl
Reaction time: 0.33 h
Yield: 165.1 %

Procedure:
To a solution of 11 mg (0.025 mmol) of tert-butyl (E)-[5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-yl]carbamate in 0.5 ml of acetonitrile and 1 drop of anisole was added 1 drop of trifluoroacetic acid. The solution was stirred for 20 minutes, concentrated under reduced pressure and the residue partitioned between brine and dichloromethane. The organic phase was dried over magnesium sulphate, filtered and evaporated, redissolved in a solution of hydrogen chloride in ethyl acetate and the solvent removed to afford 7.9 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-7-amine hydrochloride as a red solid MS: m/e 346.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}methanesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [BH4-].[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]1[SH:14].I[C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=2)=[C:18]([O:36][CH2:37][CH2:38][CH3:39])[CH:17]=1>O1CCCC1.C(O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:19]2[CH:34]=[CH:35][C:16]([S:14][C:4]3[N:3]([CH3:2])[C:7]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[N:6][N:5]=3)=[CH:17][C:18]=2[O:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:24]=1)[CH3:33]
Reactant: Cn1c(S)nnc1-c1ccncc1
Reactant: CCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1cc(Sc2nnc(-c3ccncc3)n2C)ccc1CNc1ccc(CC(=O)OCC)cc1
Reaction time: 8 h

Procedure:
265 mg (0.66 mmol, 3 eq) of resin-supported borohydride and 3 mg (0.01 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 64 mg (0.33 mmol, 1.5 eq) of 4-methyl-5-pyridin-4-yl-4H-[1,2,4]-triazole-3-thiol in 1.5 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 100 mg (0.22 mmol, 1 eq) of ethyl [4-(4-iodo-2-propoxybenzylamino)phenyl]acetate in 1.5 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered and then concentrated. 0.111 g (97%) of the expected compound is recovered.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=2)[N:9]=1.[Cl-:26].[NH4+:27]>>[ClH:26].[C:16]1([N:15]2[C:11]([CH2:10][CH:8]3[NH:9][C:3](=[NH:27])[CH2:4][CH2:5][CH2:6][CH2:7]3)=[N:12][C:13]([C:22]([F:25])([F:24])[F:23])=[N:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: COC1=NC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)CCCC1
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)N1

Procedure:
The product of Example 153 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15](=O)[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CO.CCOCC>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15](=[N:21][OH:22])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1cccc(Oc2ccc(Cl)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(/C=C/c1cccc(Oc2ccc(Cl)cc2)c1)=NO
Reaction time: 1 h
Yield: 101.3 %

Procedure:
The product from step (a) (19 g) and hydroxylamine hydrochloride (6.9 g) were taken up in methanol (100 ml), pyridine (20 ml) was added and the mixture stirred for 1 hour. The mixture was then stripped, redissolved in ether (200 ml), washed with 2 N aqu. HCl and satd. aqu. NaCl, dried over MgSO4, and stripped to give the desired product (20.3 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[CH3:26][N:27]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:26]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:24][CH2:25]3)([C:17]([F:18])([F:20])[F:19])[C:4]=2[CH:3]=1)#[N:27]
Reactant: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: N#Cc1ccc2c(c1)C(CCC1CC1)(C(F)(F)F)c1nc[nH]c(=O)c1N2
Temperature: 170 °C
Yield: 46 %

Procedure:
A mixture of 17 (110 mg, 0.297 mmol), Zn(CN)2 (71 mg, 0.594 mmol, 2 equiv), [(t-Bu)3P]2 Pd (0.78 g, 0.149 mmol, 0.5 equiv) and Zn powder (29 mg, 0.446 mmol, 1.5 eq) were suspended in anhydrous NMP and degassed. The reaction mixture was heated to 170° C. for 30 h. After cooling to 25° C., the reaction was quenched with 2 N NH4OH (20 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Chromatography (SiO2, 50 to 60% EtOAc-hexane) afforded the desired product as an off-white solid (49 mg, 46%). mp>280° C. ESI HRMS m/z 361.1293 (M++H, C18H16F3N4O requires 361.1276).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[C:8]([OH:12])=[O:18]
Reactant: O
Reactant: Cc1cc(C)cc([N+](=O)[O-])c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reaction time: 1.75 h
Yield: 40 %

Procedure:
3,5-Dimethylnitrobenzene (30 g, 0.198 M) was heated with stirring to 80° in a mixture of pyridine (400 ml) and water (250 ml). KMnO4 (62.7 g, 0.396 M) was added in portions over 0.75 hours, and heating continued at 85-90° for 1.75 hours. The hot solution was filtered through celite, washing with hot water (150 ml). The pink filtrates were decolourised with a few drops of sodium metabisulfite, and evaporated to dryness. The residue was dissolved in water (250 ml), and extracted with diethyl ether (2×90 ml). The aqueous layer was acidified (concentrated hydrochloric acid), and extracted with ethyl acetate (3×120 ml). Combined organic extracts were washed with NaH2PO4 solution, brine, and dried over MgSO4. Crude product was eluted through a pad of silica, using a mixture of ethyl acetate/dichloromethane/acetic acid (25:25:1), to give 3-methyl-5-nitrobenzoic acid (14.5 g, 40%), mp 171-172°. Nmr (DMSO-d6): δ 2.51 (s, 3H); 8.17 (s, 1H); 8.30 (t, 1H); 8.42 (t, 1H); 13.58 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[C:12]([F:15])([F:14])[F:13].C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:9][C:4]1[C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)ccc(Cl)c1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(O)ccc(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1.57 g of 4-chloro-2-nitro-3-trifluoromethylphenol and 5 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 1.8 g of electrolytic iron, 7 ml of acetic acid and 7 ml of water, which was stirred for 30 minutes. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.1 g of 2-amino-4-chloro-3-trifluoromethylphenol.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[NH2:17][OH:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.O>[OH:18][N:17]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCCN1CC(=NO)c1cccnc1
Yield: 65.2 %

Procedure:
To 0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20, 0.15 g (2.21 mmol) of hydroxylamine hydrochloride salt and 0.12 g of sodium sulfate were added in methanol/water (1.5:1). The mixture was reacted at 30˜40° C. for 12˜36 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate for three times, washed with brine for two times, and dried over sodium sulfate. After concentrating under reduced pressure, it was purified by separation with silica gel column chromatography (chloroform/methanol (30:1˜10:1)) to obtain 0.21 g (66% yield) of 1-(2-hydroxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (1.56:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].Cl>CCOC(C)=O>[OH2:18].[ClH:1].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3[C:3]=2[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=3)[CH2:29][CH2:30]1)=[O:24]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(C(=O)c3ccco3)CC2)c2nc(-c3ccccc3)cc-2[nH]1
Product: O
Temperature: 180 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1 (e)) (500 mg, 2.05 mmol) and the 1-(2-furoyl)piperazine (Avocado Chemical Company) (810 mg, 4.10 mmol). The flask was purged with N2 and the mixture was heated to 180° C. for 30 min. The reaction was allowed to cool to room temperature and the crude material was purified by flash chromatography on silica gel with 50% EtOAc/CHCl3 as eluant to give 500 mg (63% yield) of an off white solid. The free base (200 mg, 0.52 mmol) was dissolved in hot EtOAc (10 mL) and anhydrous ethereal HCl (0.52 mL, of a 1.0 m soln, 0.52 mmol) was added dropwise. The mixture was stirred for 2 h and allowed to cool to room temperature. The resulting solid was filtered and dried under high vacuum to give 205 mg (96% yield) of the title compound as a light yellow solid. Mp: 192-193° C. 1H NMR (DMSO-d6; 400 MHz): d 2.54 (s, 3), 3.89 (br s, 4), 4.17 (t, 4, J=4.3), 6.62 (q, 1, J=1.7), 6.9 (s, 1), 7.05 (d, 1, J=3.4), 7.4 (m, 3), 7.85 (s, 1), 7.93 (d, 2, J=6.92). MS m/z: 388 (M+1). Anal. Calcd for C22H21N5O2.HCl.H2O: C, 59.79; H, 5.47; N, 15.85; O, 10.86; Cl, 8.02. Found: C, 59.99; H, 5.33; N, 15.79; Cl, 8.06.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30].O>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:29]([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
500 mg of the compound [1-1] was dissolved in 10 mL of tetrahydrofuran and cooled to −78° C. Thereafter, 2.33 mL of n-butyllithium (1.57M hexane solution) was added thereto. After the 1 hour stirring at the same temperature, 193 μL of picolinaldehyde was added to the resulting white suspension, and the suspension was stirred overnight while heating back to room temperature. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL of ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70) to obtain 212 mg of tert-butyl((1S)-1-{4-[hydroxy (pyridin-2-yl)methyl]phenyl}ethyl)carbamate [12-1] (hereinafter, referred to as the compound [12-1]) as a light brown oily product.
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](Cl)[N:3]=1.[CH2:19]1[CH:23]([CH2:24][OH:25])[CH2:22][CH:21]([NH2:26])[CH2:20]1.[OH-].[Na+]>C(N(CC)CC)C.C(O)C>[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:26][C@H:21]2[CH2:20][CH2:19][C@@H:23]([CH2:24][OH:25])[CH2:22]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCC(CO)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(N[C@H]2CC[C@@H](CO)C2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (530 mg, 2.00 mmol) from Example 4, 3-aminocyclopentyl-1-methanol (276 mg, 24 mmol), triethylamine (1.12 g, 10.98 mmol), and ethanol (20 mL) was stirred at reflux for 5 hours. An additional amount of triethylamine (1.17 g) was then added and the solution was refluxed for 8 additional hours. The solution was allowed to cool to room temperature and 2 mL of 1 N NaOH was added. The solution was concentrated and the residues were placed on silica gel column which was eluted with 10% methanol-chloroform (0.36 g, 52%). Recrystallization of such a sample from ethanolacetonitrile gave title compound as white powder, m.p. 177-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([Cl:46])=[CH:41][N:40]=1.O>CN(C=O)C>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41]2[C:42]([Cl:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (8.15 g, 19.1 mmol) in DMF (19 mL) was treated with potassium carbonate (3.42 g, 24.8 mol) and stirred at 25° C. for 5 minutes. The reaction mixture was treated with 2,4,5-trichloropyrimidine (2.40 mL, 21.0 mmol) dropwise and stirred at 20° C. overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give a crude orange oil. The residue was purified with silica gel chromatography to give the desired product (10.9 g, 99.5%). LCMS calculated for C28H33Cl2N5O4Na (M+Na)+: m/z=596.0, 598.0.
Reaction SMILES: [C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[Br-].Cl.[CH2:14](OCC)C>>[C:1]1([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOCC
Reactant: CC(=O)CCCC1=CCCC1
Agent: Cl
Agent: [Br-]
Product: CC(C)(O)CCCC1=CCCC1
Temperature: 25 °C
Yield: 11 %

Procedure:
5-(Cyclopent-1-enyl)-2-pentanone (5.95 g; 39 mmol) in ethyl ether (6 ml) was added dropwise to a 3M solution of methylnagnesium bromide in the same solvent (17 ml; 51 mmol) during 15 minutes. After 2 hours at reflux, the mixture was cooled down to room temperature, poured into ice (20 g), acidified with 5N HCl (20 ml) and extracted with MTBE (60 ml). The aqueous phase was separated and extracted again with MTBE (2×100 ml). The combined organic phases were washed with saturated NaHCO3 (80 ml), H2O (80 ml), brine (80 ml), dried over MgSO4 and concentrated in vacuo. Bulb-to-bulb distillation (80° C./0.06 torr) yielded quantitatively 5.84 g of 5-(cyclopent-1-enyl)-2-methylpentan-2-ol containing 11% of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: C[N:2]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:6](=[O:16])[NH:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3]1.[H][H].[CH2:26](O)C>[Pd]>[NH:2]=[C:17]([C:5]1[C:6](=[O:16])[N:7]([CH3:26])[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:4]=1[OH:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1Oc2cc(-c3ccccc3)[nH]c(=O)c2C1c1ccccc1
Reactant: CCO
Reactant: [H][H]
Agent: [Pd]
Product: Cn1c(-c2ccccc2)cc(O)c(C(=N)c2ccccc2)c1=O

Procedure:
A mixture of 16.5 g. (0.0545 mole) of N-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridin-4(5H)-one, 330 ml. ethanol and 1.65 g. 10% palladium on carbon is hydrogenated at 50 psi and room temperature. The hydrogenation is ceased after 1 equivalent of hydrogen is absorbed (ca 2.5 hours). The mixture is treated with methylene chloride and the catalyst is removed by filtration. The solvents are removed in vacuo to a volume of ca 50 ml. and then ether is added, to precipitate solids which are removed by filtration to give 3-(α-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2-(1H)-pyridone, m.p. 238°-240° C. The above compound is dissolved in methanol and treated with sodium hydroxide solution to yield after evaporation the sodium salt of 3-(α-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone.