Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]1=[O:17])[CH2:23]2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 18 h

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.053 g, 0.223 mmol; Example 216A) and 5-fluoroisoindoline hydrogen chloride (0.043 g, 0.246 mmol) in dichloromethane (0.4 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.059 mL, 0.335 mmol) and the reaction stirred for 18 hours. The reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.34-7.16 (m, 4H), 7.08-6.93 (m, 3H), 4.82 (dd, J=8.6, 16.1, 4H), 4.27 (d, J=16.2, 1H), 4.15 (d, J=16.2, 1H), 3.79-3.59 (m, 3H), 2.67-2.51 (m, 1H), 2.18 (ddd, J=8.5, 12.9, 16.1, 1H); MS (ESI+) m/z 357.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[I:18])[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>CC(O)C>[C:23]([O:27][C:28](=[O:29])[NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[I:18])[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=3[N:3]=2)[CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2I)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2I)n(C)c1=O
Reaction time: 3 h

Procedure:
8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A) (100 mg, 0.23 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (216 mg, 1.16 mmol), and triethylamine (0.32 ml, 2.32 mmol) were dissolved in 20 ml of 2-propanol and the mixture was subjected to microwaves (method F, 130° C., 300 W) for three hours. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=12.99 min.). Evaporation of the solvent afforded compound (7A) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[C:15](=[O:16])[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:17]1([CH2:20][N:11]2[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:13]([CH2:14][C:15]3=[O:16])[CH2:12]2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: COc1cccc(C23CNCC2CC3=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(CC4CC4)CC2CC3=O)c1

Procedure:
In the manner of Example 8, 5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal, can be reacted with cyclopropylmethyl bromide and sodium carbonate in toluene to give 3-cyclopropylmethyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH3:12][S-:13].[Na+]>CS(C)=O.O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:13][CH3:12])=[O:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(C#N)ccc1C=O
Reaction time: 0.75 h

Procedure:
3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol) was dissolved in DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5 mmol) was added with ice-bath cooling. The mixture was stirred for 45 min and then diluted with water (100 ml). The resulting precipitated product was filtered off with suction, washed with water and dried under reduced pressure. This gave 1.36 g (51% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:16]1[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(c3cnc4ccccc4n3)CC21
Temperature: 80 °C
Yield: 84 %

Procedure:
Intermediate 2 (0.51 mmol), 2-chloro-quinoxaline (0.51 mmol) and K2CO3 (1.53 mmol) were taken up in DMF (0.2 M). The mixture heated to 80° C. and allowed to heat at 80° C. overnight. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether (3×100 mL). The organics were combined, dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (FCC) (50-100% EtOAc/hex) to provide 3-quinoxalin-2-yl-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (84%). MS (ESI) mass calcd. for C18H22N4O2, 326.39; m/z found, 327.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.48 (s, 1H), 7.93-7.87 (m, 1H), 7.76-7.69 (m, 1H), 7.62-7.55 (m, 1H), 7.45-7.36 (m, 1H), 4.90 (br s, 1H), 4.41 (br s, 1H), 4.27-4.09 (m, 2H), 3.68-3.61 (m, 1H), 3.49-3.41 (m, 1H), 3.34-3.20 (m, 2H), 1.45 (br s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH2:1]([O:8][C:9]1[C:13]([CH:30]=[O:31])=[C:12]([CH3:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-1-phenyl-1H-pyrazole (5.1 g) in N,N-dimethylformamide (30 mL) was added phosphorus oxychloride (2.2 mL) at 80° C., and the mixture was stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into 1 mol/L aqueous sodium hydroxide solution. The mixture was extracted with diethyl ether, and the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane) to give the title compound (4.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24](O)=[O:25])[S:22][CH:23]=2)=[N:10]1.CC[N:29]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([NH2:29])=[O:25])[S:22][CH:23]=2)=[N:10]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (30.0 mg) obtained in Example 37 in DMA (2 mL) were added EDCI hydrochloride (18.5 mg) and HOBt ammonium salt (14.7 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate) to give the title compound (21.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:25])=[CH:5][CH:4]=1.[N+](=[CH2:30])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[CH2:30][CH:19]4[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: -10 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
To a stirred solution of (E)-ethyl 3-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)acrylate (1.2 g, 3.21 mmol) in diethyl ether (50 mL) was added palladium (II) acetate (0.031 g, 0.138 mmol). The reaction mixture was cooled to −10° C., and a cold solution of diazomethane (1.351 g, 32.1 mmol) in ether (generated from aqueous KOH (8 g, 143 mmol) and 1-methyl-1-nitrosourea (4 g, 38.8 mmol) at −15° C.) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through celite, diluted with diethyl ether, and washed with water and saturated NaCl solution. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel column using 15% ethyl acetate in hexane to give ethyl 2-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)cyclopropanecarboxylate as a yellow gum (510 mg, 57%). 1H NMR 400 MHz, CDCl3: δ 1.29 (t, J=4.80 Hz, 3H), 1.31 (d, J=4.80 Hz, 1H), 1.62 (d, J=4.80 Hz, 1H), 1.84-1.89 (m, 1H), 2.51-2.56 (m, 1H), 3.76 (d, J=2.80 Hz, 3H), 3.98 (q, J=174.00 Hz, 2H), 5.47 (s, 2H), 6.77-6.83 (m, 3H), 7.13-7.28 (m, 5H), 7.66 (d, J=9.60 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[SH:50].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([CH:25]=[C:3]([CH2:2][S:50][C:41]4[CH:42]=[CH:43][C:44]5[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:40]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Reactant: Sc1ccc2ccccc2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CSc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 75b (70.2 mg, 0.209 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (10 mL) and DIEA (72.7 μL, 0.417 mmol) were added. MsCl (24.3 μL, 0.313 mmol) was added, and then the reaction was stirred at rt for 3 days. Additional MsCl (24.3 μL, 0.313 mmol) and DIEA (72.7 μL, 0.417 mmol) were added and the reaction was stirred for 2 h. The solvent was removed under reduced pressure. The crude material was placed in a 50 mL round bottom flask equipped with a stir bar, followed by addition of ACN (25 mL). 2-Quinolinethiol (38.2 mg, 0.230 mmol) and K2CO3 (43.3 mg, 0.313 mmol) were added and then the reaction was stirred at rt for 1 h. The temperature was increased to 80° C. and the reaction was stirred for 18 h. The reaction was cooled to rt, diluted with DCM (20 mL), and filtered. The solvent was removed under reduced pressure. The crude produced was purified by flash column chromatography on silica gel (25-g SiO2 pre-packed column, 0-100% EtOAc/heptanes) to afford compound 75c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81-7.89 (m, 2H), 7.78 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.46-7.53 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.69 (s, 2H), 4.30-4.43 (m, 4H), 3.82-3.91 (m, J=4.5, 4.5 Hz, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H21N7OS: 480.2 (M+H). found: 480.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11](Cl)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[NH3:15]>>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11]([NH2:15])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: N
Reactant: CC1(C)COc2ccc(C(=O)Cl)cc21
Product: CC1(C)COc2ccc(C(N)=O)cc21

Procedure:
The product of stage (b) (4.2 g) was added dropwise to excess aqueous ammonia with stirring and ice cooling. After 1 hour the white precipitate was filtered off and recrystallised from ethanol to give 1.1 g of title product, mp 136°-138° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:22]I>CN(C=O)C>[CH:3]1([C:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([F:21])[CH:13]=2)[CH3:22])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C1CCCCC1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
60% Sodium hydride powder (1.1 mmol, 0.045 g) was added in portions to a cooled solution of cyclohexyl-N-(3-fluoro-4-nitrophenyl)carboxamide (1 mmol, 0.266 g) and methyl iodide (1.2 mmol, 0.16 g) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2 (50 mL) and washed with 10% NaHCO3, brine, H2O, dried over Na2SO4 and the solvent evaporated to afford 0.23 g of the title compound as a yellow oily residue (Yield: 82%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.35-2.46 (m, 2 H), 2.90 (s, 3 H), 3.06-3.20 (m, 1 H), 3.21-3.29 (m, 2 H), 3.34-3.45 (m, 2 H), 3.52-3.68 (m, 4 H), 3.72-3.83 (m, 2 H), 3.97-4.02 (m, 1 H), 4.15 (d, J=0.56 Hz, 2 H), 4.30-4.41 (m, 2 H), 7.13 (t, J=8.98 Hz, 2 H), 7.29 (s, 1 H), 7.41 (dd, J=8.84, 5.62 Hz, 2 H), 8.13 (s, 1 H), 8.56 (s, 1 H), 9.83 (br. s., 1 H), 10.32-10.41 (m, 1 H); ES+ MS: 548 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:14])([CH3:3])=[CH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25]O)[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][N:6]3[C:7]4[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:14])[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29]
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Reactant: Cc1c(C)n(C)c2c(CO)cc(Cl)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 1-Isopropenyl-6-methyl-1,3-dihydro-benzimidazol-2-one (50 mg, 0.27 mmol) and (5-Chloro-1,2,3-trimethyl-1H-indol-7-yl)-methanol (60 mg, 0.27 mmol), triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) was added dropwise DIAD (0.06 mL, 0.32 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 60 mg of the desired product as a brownish oil. LCMS (ESMS): m/z 394.28 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1.ClCCl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:19][CH2:18]2)=[O:17])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of N-benzyloxycarbonyl isonipecotic acid (123.64 g) in tetrahydrofuran (300 ml) at 0° C. was added a solution of carbonyldiimidazole (68.80 g) in tetrahydrofuran (500 ml) and dichloromethane (300 ml). The resulting solution was stirred at ambient temperature for 2 hours. This solution was cooled to 0° C. and a solution of 1-(tert-butoxycarbonyl)piperazine (87.02 g) in tetrahydrofuran (200 ml) added dropwise over 20 minutes. The suspension obtained was stirred at ambient temperature for 48 hours. Solvent was evaporated. The residue was dissolved in diethyl ether/dichloromethane (1500 ml) and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to give 1-(tert-butoxycarbonyl)-4-[1-benzyloxycarbonylpiperidin-4-ylcarbonyl]piperazine (180.00 g) as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[C:41]1([CH2:47][SH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>ClCCl>[CH2:47]([S:48][CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:8]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: SCc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CSCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (300 mg, 0.53 mmol) (preparation 25) was dissolved in stirred dichloromethane (4 ml) and phenylmethanethiol (0.13 ml, 1.05 mmol) and triethylamine (0.15 ml, 1.05 mmol) added. The reaction mixture was stirred for 48 hr at room temperature and then the solvent removed under reduced pressure. The residue was partitioned between methanol (100 ml) and hexane (100 ml) and the methanol layer washed with a further amount of hexane (100 ml). The solvent was then removed under reduced pressure from the methanol layer. The residue was purified by column chromatography on silica gel eluting with a solvent system of ethyl acetate:hexane (3:2) increasing in polarity to ethyl acetate:methanol (98:2). This gave title compound (100 mg) as a foam. MS: 599 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: N
Reactant: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2c(N)nc(C#CCCO)nc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-1-ol (650 mg, 2.74 mmol) in dioxane (4 ml) was added 30% w/w water solution of ammonia (8 ml). The reaction mixture was stirred overnight in an autoclave at 70° C.
Reaction SMILES: NC(N)=N.[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N)CC1C=CC=CC=1.[N+:22]([CH3:25])([O-:24])=[O:23]>>[N+:22]([CH2:25][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12])([O-:24])=[O:23]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: N=C(N)N
Agent: NCCc1ccccc1
Product: O=[N+]([O-])CC(O)c1ccccc1
Yield: 31 %

Procedure:
In recent years, attention has been paid to optically active guanidine compounds as base catalysts for asymmetric nucleophilic-type reactions, a representative of which is an asymmetric aldol-type reaction. However, all of the previously known optically active guanidine compounds have central chirality as a chiral element, and it cannot be said that molecular design based on only such the central chirality is sufficient to draw the potential usefulness of such optically active guanidine compounds. As one of the reactions using an optically active guanidine compound which is constructed based on central chirality as an asymmetric base catalyst, a nitroaldol reaction is reported (Non-Patent Literature 1: Tetrahedron: Asymmetry, 1994, 5, 1393; Non-Patent Literature 2: Tetrahedron Lett., 2003, 44, 8677). The Non-Patent Literature 1 disclosed that in the aldol condensation between benzaldehyde and nitromethane, optically active guanidines having a phenethylamine skeleton as an optically active site are used as an asymmetric catalyst, and 2-nitro-1-phenylethanol is obtained in a yield of 31% and an asymmetric yield of 33% ee.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([CH:18]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]2=O)=[O:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[Cl:29][C:19]1[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=1[C:16]([C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][S:10]2(=[O:13])=[O:12])=[CH:5][CH:4]=1)=[O:17]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1C(=O)CCCC1=O)c2Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (5.2 mmol) of 2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonyl-1,3-cyclohexanedione were dissolved in 30 ml of methylene chloride and 2.2 g (17.3 mmol) of oxalyl chloride and 2 drops of dimethylformamide were added. After 1 hour of stirring at 25° C., the solvent was removed. This gave 2.1 g of colored crystals.