Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(=O)(O)[O-].[Na+].[CH3:22][C:23]1[NH:24][C:25]2[CH:31]=[C:30]([C:32](=[O:41])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1>O.C(Cl)(Cl)Cl>[CH3:22][C:23]1[N:27]([CH2:13][C:12]2[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[C:26]2[CH:28]=[CH:29][C:30]([C:32](=[O:41])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:31][C:25]=2[N:24]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
N,N-dimethylformamide (10 ml), 4-nitrobenzyl bromide (3.24 g), and sodium bicarbonate (2.52 g) are added to 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (3.56 g), and the solution is heated for two hours at 80° C. Chloroform and water are added to the reaction solution and layers are separated. After the organic layer is concentrated under reduced pressure, it is purified through silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and a mixture of 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole is obtained. Further, the position isomers in this mixture are separated through medium pressure silica gel column chromatography (eluate: ethyl acetate/methanol=85/15). Each is recrystallized in a mixed solvent of chloroform and diethylether, and thus, 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.37 g) (191) and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.19 g) (192) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[NH:20][CH3:21].[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:26]=1[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:20]([C:3]2[C:4]([CH3:19])=[CH:5][C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])=[CH:7][C:2]=2[F:1])[CH3:21])=[CH:27][C:26]=1[CH3:33]
Reactant: CNc1c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1F
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2F)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A mixture of (2-fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl)-methyl-amine (326 mg, 1.05 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (320 mg, 1.80 mmol) in 4 mL acetic acid is stirred for 2.5 hours at room temperature. Sodium triacetoxyborohydride (773 mg, 3.65 mmol) is added and stirred. Upon completion of the reaction, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 40 g silica with ethyl acetate in heptane gradient (10% to 20%) to provide 457 mg (92%) of the titled compound as an oil. MS (ES) m/z 475.3 (M+1).
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[C-:18]#[N:19].[Na+]>CN(C=O)C>[C:18]([C@H:6]1[CH2:9][C@H:8]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)#[N:19]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C#N)C1
Temperature: 140 °C

Procedure:
cis-3-[(tert-Butoxycarbonyl)amino]cyclobutyl methanesulfonate (0.200 g, 0.754 mmol) in DMF (3 mL) was treated with NaCN (55 mg, 1.13 mmol, Aldrich) and the reaction was heated in the microwave to 140° C. for 10 minutes, followed by stirring overnight at 125° C. with an additional 55 mg (1.13 mmol) of NaCN having been added. The reaction mixture was partitioned between saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted three additional times with EtOAc. The combined extracts were dried over sodium sulfate, decanted, and the solvent was removed in vacuo. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes, afforded tert-butyl (trans-3-cyanocyclobutyl)carbamate. Yield: (61 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([NH2:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C@@:27]([OH:31])([C:24]4[CH:23]=[C:22]([CH3:21])[O:26][N:25]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([NH2:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(C(N)=O)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure as described in Example 62-c by reacting 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxamide and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 6.41 (1H, s), 6.59 (1H, s), 7.16 (2H, br. s.), 7.34 (1H, d, J=5.52 Hz), 7.44 (1H, dd, J=8.43, 1.18 Hz), 7.75 (1H, s), 8.21 (1H, s), 8.26 (1H, d, J=8.35 Hz), 8.38 (1H, d, J=5.52 Hz), 8.93 (1H, s); LC-MS: m/z=+404 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH:61]=[CH:62][C:63]=1[F:64])[CH2:38][N:39]1[C:44](=[O:45])[C:43]([CH2:46]OS(C)(=O)=O)=[CH:42][C:41]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([F:60])[CH:53]=2)=[N:40]1.CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([CH:61]=[CH:62][C:63]=1[F:64])[CH2:38][N:39]1[C:44](=[O:45])[C:43]([CH2:46][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[CH:42][C:41]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([F:60])[CH:53]=2)=[N:40]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 55 %

Procedure:
Following the procedure of Example 1 (10), 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as slightly-yellow neeldes (yield: 55.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[OH:10].[Br:21][CH2:22][C:23](Cl)=[O:24]>>[Br:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:10])([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1
Product: O=C(CBr)Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1

Procedure:
Prepared from (2-amino-5-bromophenyl)(dithien-2-yl)methanol and bromoacetyl chloride using the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 8.42 (s, 1H), 8.05 (d, J=9.0 Hz, 1H) 7.59 (m, 3H), 7.05 (m, 2H), 6.87 (m, 2H), 6.78 (d, J=3 Hz, 1H), 3.92 (s, 2H); MS (ES) m/z 484 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:23][C:22]1[CH:21]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1ccc(Nc2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80.4 %

Procedure:
An oven-dried resealable schlenk tube containing a stir bar was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-ditbutylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04 mmol), ethyl 4-aminobenzoate (125 mg, 0.75 mmol) and K2CO3 (173 mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and backfilled with argon. 3-Bromoaniline (56 μL, 0.5 mmol) and tbutanol (1 mL) were added through the septum via syringe. The septum was replaced with a Teflon screw cap. The schlenk tube was sealed and put into a pre-heated oil bath at 80° C. The reaction mixture was stirred for 11 h, allowed to cool down to room temperature and filtered through celite with ethyl acetate. The filtrate was concentrated under reduced pressure. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 103 mg (80%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14](O)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:31][CH:28]4[CH2:30][CH2:29]4)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NC2CC2)C3)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid of Example 8 (80 mg), cyclopropylamine (0.029 mL), 1-hydroxybenzotriazole monohydrate (32 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg) and dehydrated N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (30 mg, 34%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][NH:12][C:11](=[O:14])[C:10]=1[C:15]([O:17]CC)=O>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[NH:13][NH:12][C:11](=[O:14])[C:10]=3[C:15]([OH:17])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2N)[nH][nH]c1=O
Solvent: CN(C)C=O
Product: O=c1[nH][nH]c2c1c(O)nc1cc(Cl)ccc12

Procedure:
3.1 g (0.011 mol) of ethyl 5-(2-amino-4-chloro-phenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate were dissolved in 30 ml of dimethylformamide and boiled under reflux for 2 hrs. The mixture was concentrated, the residue was suspended in 150 ml of methanol at reflux, cooled, suction filtered and dried in a vacuum. Yield: 1.1 g (42%) of 7-chloro-4-hydroxy-2,3-dihydro-1H-pyrazolo[4,3-c]quinolin-3-one as brownish crystals; m.p. >350° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13]>ClCCl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
mCPBA (1.7 g of 75% pure material) was added to a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridine (1.74 g, 4.31 mmol) in dichloromethane (50 mL). The reaction was stirred at room temperature for 30 minutes; an analysis by TLC then indicated the presence of starting material. Additional mCPBA (0.25 g of 75%) was added, and the reaction was stirred for another 30 minutes and found to be complete. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether and isolated by filtration to provide 1.64 g of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a pale yellow solid.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12].[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([CH3:16])[CH3:15]>CC(O)C.C[O-].[Na+]>[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:3](=[O:13])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:11]1[SH:12])([CH3:16])[CH3:15]
Reactant: CC(C)c1ccccc1N
Reactant: COC(=O)c1ccccc1N=C=S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)c1ccccc1-n1c(S)nc2ccccc2c1=O
Yield: 54.9 %

Procedure:
2-Isothiocyanato-benzoic acid methyl ester (0.58 mL, 3.69 mmol) was added to a solution of 2-isopropyl aniline (500 mg, 3.69 mmol) and sodium methoxide (10 mg) in 2-propanol (10 mL) at room temperature and heated at reflux for 16 hr. The reaction mixture was concentrated to dryness under vacuum. The crude material was washed with dichloromethane (2×10 mL), 10% methanol in chloroform (2×10 mL) and dried under reduced pressure to afford 3-(2-isopropyl-phenyl)-2-mercapto-3H-quinazolin-4-one (600 mg, 55%) as white solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].[ClH:8].[CH:9]([O-])([O-])OC>CO>[ClH:8].[CH3:9][O:6][C:5](=[O:7])[C@H:3]([CH3:4])[NH:2][CH3:1]
Reactant: CN[C@@H](C)C(=O)O
Reactant: COC([O-])[O-]
Agent: Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)OC
Reaction time: 24 h

Procedure:
In 600 ml of methanol was suspended 53.5 g (0.52 mol) of N-methyl-L-alanine and under ice-cooling and stirring, 75 g of dry hydrogen chloride gas was dissolved. The suspension of the starting material cleared gradually with reaction time and, on stirring overnight, yielded a homogeneous solution. To the reaction mixture was added 85 g (0.8 mol) of methyl orthoformate and the mixture was allowed to stand at room temperature for 24 hours. The small quantities of insolubles were filtered off and the filtrate was concentrated under reduced pressure. By the above procedure was obtained a solid product of N-methyl-L-alanine methyl ester hydrochloride.
Reaction SMILES: Cl[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.[CH3:18][NH:19][CH2:20][C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][N:19]([CH3:18])[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CNCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N(C)Cc2ccco2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 59 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), N-methylfurfurylamine (The Sigma-Aldrich Library of Rare Chemicals) (0.16 g, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 53.6 mg (59%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 168-169° C. 1H NMR (CDCl3; 500 MHz): δ 2.62 (s, 3), 3.35 (s, 3), 4.83 (s, 2), 6.42-6.44 (m, 2), 6.79 (s, 1), 7.36-7.48 (m, 4), 7.64 (d, 2, J=7.2), 8.91 (br s, 1). MS m/z: 319.5 (M+1), 317.0 (M−1). HRMS: Calcd for M+H: 319.1559. Found: 319.1566.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].CCN(CC)CC>C(Cl)Cl>[Cl:12][CH2:13][C:14]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8][CH2:9]1)=[O:15]
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1N(C(=O)CCl)CCC2
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 8-methyl-1,2,3,4-tetrahydroquinoline (1) (2.77 g, 18.8 mmol) in dry CH2Cl2 (50 mL) at 0° C. was added chloroacetyl chloride (1.80 mL, 22.6 mmol) followed by dropwise addition of Et3N (6.30 mL, 45.2 mmol). The reaction was stirred overnight under N2. The reaction mixture was then diluted with CH2Cl2 (50 mL), washed with water (2×15 mL), and saturated NaCl (15 mL). Dried over MgSO4, filtered, and concentrated to give compound 2 (3.7 g). This crude material was used in subsequent reactions without further purification.
Reaction SMILES: FC1N=C2C(NC=N2)=C(Cl)N=1.C1(N)CCCCC1.C(N(C(C)C)CC)(C)C.F[C:29]1[N:37]=[C:36]2[C:32]([NH:33][CH:34]=[N:35]2)=[C:31]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[N:30]=1.[O:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1>C(O)CCC.C(O)C>[O:45]1[CH2:46][CH2:47][N:48]([C:51]2[CH:57]=[CH:56][C:54]([NH:55][C:29]3[N:37]=[C:36]4[C:32]([NH:33][CH:34]=[N:35]4)=[C:31]([NH:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[N:30]=3)=[CH:53][CH:52]=2)[CH2:49][CH2:50]1
Reactant: Fc1nc(NC2CCCCC2)c2[nH]cnc2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1nc2nc(Nc3ccc(N4CCOCC4)cc3)nc(NC3CCCCC3)c2[nH]1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2-(4-Morpholinoanilino)-6-cyclohexylamino-purine (i.e., reversine or Compound A) was synthesized using the methods similar to those previously described in Ding et al., J. Am. Chem. Soc. 124:1594 (2002). To a solution of 2-fluoro-6-chloropurine (87 mg, 0.5 mmol) in n-butanol (5 mL) was added cyclohexylamine (58 μL, 0.5 mmol) and diisopropylethylamine (100 μL, 0.6 mmol). The mixture was heated to 80° C. with vigorous stirring for 12 hours. The solvent was then removed under reduced pressure and the crude was used directly in the next step reaction without further purification. The crude 2-fluoro-6-cyclohexylamino-purine (0.5 mmol) was dissolved in ethanol (1 mL), followed by addition of 4-morpholinoaniline (178 mg, 1.0 mmol). The mixture was heated to 75° C. in a sealed tube with vigorous stirring for 24 hours. The solvent was then removed under reduced pressure and the crude material was directly purified by flash chromatography to afford 2-(4-morpholinoanilino)-6-cyclohexylamino-purine as a pale white solid (130 mg, overall 67% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.14-1.24 (m, 1H), 1.26-1.39 (m, 4H), 1.59-1.67 (m, 1H), 1.73-1.81 (m, 2H), 1.94-1.99 (m, 2H), 3.07 (dd, J=4.8, 4.7 Hz, 4H), 3.74 (dd, J=4.8, 4.7 Hz, 4H), 3.90-4.06 (m, 2H), 6.93 (d, J=9.1 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 8.31 (s, 1H), 8.38 (br. s, 1H), 9.68 (br. s, 1H); 13C NMR (125 MHz, CD3OD) δ 26.1, 26.5, 33.4, 40.4, 52.1, 67.4, 116.5, 118.6, 124.9, 133.2, 141.8, 147.9, 148.6, 152.9, 153.31; MALDI-FTMS for C21H28N7O (MH+): calcd 394.2350; found 394.2341.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:31])[CH2:24][N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][OH:28])[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:14]([OH:13])[CH:23]([OH:31])[CH2:24][N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][OH:28]
Reactant: CCN(CCO)CC(O)C1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCN(CCO)CC(O)C(O)[C@@H](N)CC1CCCCC1
Yield: 94.7 %

Procedure:
83 mg of the compound obtained in step (1) was dissolved in 0.8 ml of ethanol, and palladium black was added thereto. The hydrogenation was conducted at room temperature under atmospheric pressure. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 49 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-[ethyl(2-hydroxyethyl)amino]-2,3-pentanediol as colorless oily substance.
Reaction SMILES: [CH2:1]([C:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:9]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
2.5 g of 4-octylcarbonyloxybenzoic acid was dispersed in 50 ml carbon tetrachloride, after dropping 10 ml of thionyl chloride to this solution, refluxed for three hours. After reducing the solvent, 4-octylcarbonyloxybenzoic chloride (CK) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CC(C)=O.CCOC(C)=O>[Cl:26][C:20]1[CH:19]=[C:18]2[C:23]([N:24]=[CH:25][C:16]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](C)Oc1ccc(O)cc1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2cnc3ccc(Cl)cc3n2)cc1

Procedure:
A solution of the product of Part B (27.0 g, 0.095 moles), ethyl acetate (215 mL), conc HCl (12 drops) and Pd/C (1.7 g) was shaken on a Parr hydrogenator for 3.5 hours, after which TLC (60:40 hexane/EtOAc; Rf 0.36) indicated the reaction was complete. The mixture was filtered through celite, washed with EtOAc, and evaporated to an amber oil. The oil was dissolved in EtOAc, dried over MgSO4, filtered through celite and MgSO4, and evaporated to a clear filtrate and dried under high vacuum to afford methyl (R)-(+) 2-(4-hydroxyphenoxy)propanoate (18.5 g, 100% yield). A mixture of methyl (R)-(+) 2-(4-hydroxyphenoxy)propanoate (18.5 g, 0.094 moles), 2,7-dichloroquinoxaline (14.5 g, 0.073 mole), and powdered potassium carbonate (13.3 g, 0.964 mole) in dry acetone (170 mL) was refluxed overnight. When a TLC showed the reaction was complete (Rf 0.30, 1:1 hexane:EtOAc), the mixture was filtered and washed with acetone, dried with MgSO4, and evaporated to dryness to a beige solid. This was purified by several silica gel columns (80:20 hexane:EtOAc, then 75:25 hexane:EtOAc) to obtain a fluffy white solid which was recrystallized repeatedly from hexane to afford methyl (R)-(+) 2-[4-(7-chloroquinoxalinyloxy)phenoxy]propionate as a solid: mp 80° C. 1H NMR (CDCl3) δ8.65 (s), 7.97 (d, J=9 Hz, 1H), 7.75 (d, J=2 Hz, 1H), 7.54 (dd, J=2 Hz, 9 Hz, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 4.80 (q, J=7 Hz, 1H), 3.80 (s, 3H), 1.66 (d, J=7 Hz, 3H). [α]D25 =+40.43. MS calc 358.78, found 358.78. Anal Calcd for C18H15N2O4Cl: C, 60.26; H, 4.21; N, 7.81. Found: C, 60.16; H, 4.10; N, 7.68.