Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[CH2:35]([NH:42][C:26](=[O:27])/[CH:25]=[CH:24]/[C:4]1[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[C:11]2[C:3]=1[C:1]#[N:2])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NCc3ccccc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.97-0 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of benzylamine (0.176 ml, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for l hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the objective product as powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Br[CH2:12][C:13]#[N:14]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][C:13]#[N:14]
Reactant: COCCOCCO
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COCCOCCOCC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-methoxy-ethoxy)-ethanol (2.35 mL) in dry THF (25 mL) was added 870 mg of NaH (60% in mineral oil) portion wise at 0° C. The mixture was stirred for 30 min at RT and cooled again to 0° C. Tetra-n-butylammonium iodide (10 mg) was added followed by dropwise addition of a solution of bromoacetonitrile (1.33 mL) in dry THF (10 mL). The mixture was stirred for 3 h at RT, concentrated, taken up in saturated aqueous NH4Cl solution and extracted with DCM. The organic phases were dried over anhydrous MgSO4 and concentrated in vacuo to give crude [2-(2-methoxy-ethoxy)-ethoxy]-acetonitrile (2.60 g) as a brown oil. The product, still containing some mineral oil, was used directly in the next step.
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=NC=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([C@@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][C@H:37]([C@H:34]2[CH2:35][CH2:36][NH:31][CH2:32][C@@H:33]2[C:47]2[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=2)[CH3:38])=[N:41][CH:42]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(S)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-chloro-pyridine as light brown foam as the respective HCl salt. MS (m/e): 351.2 [(M+H)+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])=[CH:9][CH:8]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:17][OH:18])[CH2:22][OH:23])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(CCCc1ccncc1)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCC(CO)CCCc1ccncc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
To a suspension of LiAlH4 (0.34 g) in THF (10 mL) was added a solution of diethyl 2-(3-pyridin-4-yl-propyl)-malonate (1.23 g) prepared in (2) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 3 hr and at 50° C. for 2 hr. To the reaction mixture were added water (0.34 mL), aqueous 4 N NaOH (0.34 mL) and then water (1 mL) at 0° C. The mixture was stirred at RT for 30 min. Celite and Na2SO4 were added to the mixture. The mixture was filtered using Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=9/1) to give the title compound (0.21 g, 24%).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC[O-].[Na+]>[C:5]1([S:11][CH2:2][C:3]#[N:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Sc1ccccc1
Reactant: N#CCCl
Agent: CC[O-]
Agent: [Na+]
Product: N#CCSc1ccccc1
Temperature: 20 °C

Procedure:
Chloroacetonitrile (11.4 cc) is added at a temperature in the region of 5° C., in the course of 45 minutes, to a stirred solution of thiophenol (20 g) and a 2M ethanolic solution of sodium ethylate (90 cc). Stirring is maintained for 5 hours at a temperature in the region of 20° C. The reaction mixture is filtered, and the filtrate is evaporated to dryness at 50° C. under vacuum (20 mm Hg; 2.7 kPa). The residue is dissolved in a mixture (30 cc) of cyclohexane and ethyl acetate (70:30 by volume) and the solution is poured onto silica (1,000 g) contained in a column 6.5 cm in diameter. Elution is performed with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent. Phenylthioacetonitrile (14.5 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[OH-].[K+].[C:9](#[N:12])[CH:10]=[CH2:11]>O1CCOCC1>[NH2:1][CH:2]([CH2:5][O:6][CH2:11][CH2:10][C:9]#[N:12])[CH2:3][O:4][CH2:11][CH2:10][C:9]#[N:12]
Reactant: NC(CO)CO
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCOCC(N)COCCC#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-amino-1,3-propandiol (3.0 g, 0.033 mol) in 1,4-dioxane (8 mL) was added aqueous 40% KOH (0.46 mL, 0.003 mol), and the mixture was stirred for 10 minutes. The reaction solution was cooled to 0° C., and acrylonitrile (5.20 mL, 0.079 mol) was added with a syringe. The reaction was then warmed to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was diluted with CH2Cl2 (120 mL) and washed with saturated aqueous NaHCO3 (2×70 mL) and H2O (2×70 mL). The organic phase was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography (on silica gel, MeOH:CH2Cl2=1:10 affording 1.62 g (34%) of the desired dinitrile (27) as a slightly yellow liquid. 1H NMR (CDCl3): δ 3.68 (t, J=6.4 Hz, 4H, CH2O), 3.48 (m, 4H, CH2O), 3.15 (m, 1H, CH), 2.61 (t, J=6.4 Hz, 1H, CH2CN).
Reaction SMILES: CCCCCC.C([Li])CCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[Si](C)(C)CC[Si]2(C)C)=[N:24][CH:25]=1.[F:35][C:36]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:37]=1[CH:38]=[O:39].Cl.[OH-].[Na+]>O1CCCC1>[NH2:26][C:23]1[CH:22]=[C:21]([CH:38]([C:37]2[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:36]=2[F:35])[OH:39])[C:20]([Cl:19])=[CH:25][N:24]=1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Cl)cn1
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Nc1cc(C(O)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a mixture of a hexane solution (1.58M, 8.41 ml, 13.3 mmol) of n-butyl lithium and tetrahydrofuran (40 ml) was added diisopropylamine (1.86 ml, 13.3 mmol) at −78° C. After the resulting mixture was stirred at 0° C. for 1 hour, the reaction mixture was cooled to −78° C. To the reaction mixture was added a tetrahydrofuran (10 ml) solution of 5-chloro-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (3.27 g, 12.1 mmol). At the same temperature, the resulting mixture was stirred for 1 hour. Then, a tetrahydrofuran (10 ml) solution of 2,5-difluorobenzaldehyde (1.89 g, 13.3 mmol) was added to the reaction mixture. After stirring at the same temperature for 30 minutes, 1N hydrochloric acid (50 ml) was added at 0° C. To the reaction mixture was added a 1N aqueous solution (100 ml) of sodium hydroxide. The product thus obtained was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of dichloromethane/hexane, and collected by filtration to give the title compound (1.76 g, 6.50 mmol, 54%) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:2]2[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: Cn1cc(Br)n2cnnc2c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)n2cnnc2c1=O
Yield: 48.7 %

Procedure:
The title compound of step 2 (40 mg, 0.175 mmol), the title compound of Example 90, step 1 (62 mg, 0.175 mmol), K3PO4 (93 mg, 0.438 mmol) and Pd(dppf)Cl2 (13 mg, 0.018 mmol) in dioxane (2 mL) and H2O (1 mL) was N2 purged and microwaved at 70° C. for 2 h. Silica gel chromatography (PE: EA=1:4) followed by preparative HPLC gave the title compound (31.89 mg, yield: 48.6%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.91 (s, 1H), 8.06 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.43-7.04 (m, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.52 (s, 3H), 3.23 (s, 3H), 0.99-0.96 (m, 1H), 0.41-0.36 (m, 2H), 0.23-0.20 (m, 2H). LCMS: 375.0 (M+H)+
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[O:41]=[C:39]1[C:38]2[C:37](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:36](=[O:46])[N:40]1[CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl (1S,4S,6S)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D27 (310 mg), triphenylphosphine (1073 mg, 4.09 mmol) and phthalimide (502 mg, 3.41 mmol) were collected together and dissolved in THF (7 ml). The mixture was brought to 50° C. and then DIAD (0.796 ml, 4.09 mmol) was added dropwise. The mixture was stirred for 1 hour at 50° C. then 1 ml of water were added. Volatiles were removed in vacuum and the resulting crude was purified by silica gel chromatography (column size 10 g) using Cy/EtOAc=8:2 to Cy/EtOAc=5:5 to EtOAc 100%. It was recovered the title compound D28 (488 mg). UPLC: (Acid Final_QC): rt=0.80 minutes, peaks observed: 357 (M+1). C20H24N2O4 requires 356.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:71])([CH2:68][CH2:69][OH:70])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[OH:70][CH2:69][CH2:68][C:44]1([CH3:71])[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[N:58]([CH3:67])[S:59]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CCO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
To a solution of triphenylphosphine oxide (1.28 g) in acetonitrile (25 ml) was slowly added trifluoromethanesulfonic anhydride (0.39 ml) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-4-hydroxy-2-methylbutyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.50 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.17 g, yield 42%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). melting point 149-150° C.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-])=O)=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].CC(O)=O>CCO.[Pd]>[NH2:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Temperature: 0 °C
Yield: 81 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-5-nitro-phenoxy)-pyrimidine-2,4-diamine (2.953 g, 9.2 mmol) in 250 mL EtOH and 25 AcOH was added 10% Pd/C. The mixture was placed under 50 psi of H2 via a Parr hydrogenator. After 2.5 h the mixture was filtered through a pad of celite. The pad was washed with ethyl acetate and the solution was partially concentrated in vacuo. The residue was taken up in 500 mL H2O and cooled to 0° C. The solution was adjusted to pH=12 with 50% NaOH extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.156 g, 82%) as a dark-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.[OH-].[Na+].[C:19]1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2([O:11][CH2:19]2)[CH2:9][CH2:10]1
Reactant: Cc1ccccc1
Reactant: O=C1CCN(Cc2ccc(F)cc2F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Fc1ccc(CN2CCC3(CC2)CO3)c(F)c1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
28.20 g (0.125 mol) of 1-(2,4-difluorobenzyl)-4-piperidone crude product was added to a reaction bottle, to which 200 mL of toluene was added. The reaction was heated and stirred at 80° C. in an oil bath, and to the reaction 29.60 g (0.135 mol) of trimethylsulfoxide iodide and 0.60 g (0.0018 mol) of tetrabutylammonium hydrogen sulfate were added in sequence and then 11.40 g (0.285 mol) of sodium hydroxide dissolved in 60 mL of aqueous solution was added dropwise under stirring. After the addition, the reaction was continuously stirred at bath temperature of 80° C. overnight. On the next day, the reaction was cooled, washed with water twice, extracted with a small amount of toluene, combined and dried, and the solvent was recovered to obtain light yellow liquid 22.00 g (73.6%), i.e., a crude target product, 1H-NMR (CDCl3, ppm) δ: 7.361 (1H, m), 6.76-6.89 (2H, m), 3.597 (2H, d, J=1.12 Hz), 2.651 (2H, s), 2.601 (4H, m), 1.829 (2H, m), 1.545 (2H, m).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12](Cl)[N:11]=1.Cl>>[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12]([O:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[N:11]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: OC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(OC2CCCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Temperature: 25 °C

Procedure:
Sodium hydride (60% oil dispersion, 113 mg)was added to cydopentanol (7mL). To the resulting solution, after effervescence had ceased, was added (+)-(1S-2R4R)-4-(2-amino-6-chloro-9H-purin-yl)-2-(hydroxymethyl)cyclopentanol (400 mg, 1.4 mmol). The solution was maintained at 8° for 40 minutes, cooled to room temperature, and neutralized with 1N hydrochloric acid. Volatiles were removed and the residue chromatographed on silica gel. Title compound was eluted with methanol: chloroform/15:85 as a white solid foam which solidified form acetonitrile: methanol/20:1 as a white powder (223 mg, 48%), m.p. 181°-182°; mass spectrum (Cl, CH4): 334(M+1); 1H-NMR(DMSO-d6)δ: 7.97 (s, 1, H8), 6.32 (brs, 2, NH2), 5.60 (m, 1, CHO of cydopentyl) 5.0-4.8 (m, 1, CHN), 4.78 (d. J=4.1 Hz, 1, OH), 4.66 (t,J=5.1 Hz, 1, CH2OH), 4.1 (m, 1, CHOH), 3.6-3.4 (m, 2, CH2O), 2.4-1.9 (m, 6 methylene), 1.9-1.5 (m, 7, methylene); [α]20589 +9.34°, [α]20578 +9.85°, [α]20546 +11.1°, [α]20430 +18.2°, [α]20365 +26.6° (c=0.782, methanol).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][CH2:8][CH2:9][CH2:10][SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>C1C=CC=CC=1.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>[C:2]1([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH3:7])[CH2:1][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C1=CCCC=C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reaction time: 0.25 h
Yield: 235 %

Procedure:
To a solution of 1,3-cyclohexadiene (0.96 g, 12 mmol, d=0.84, 1143 uL) and Pd(PPh3)4 (462.2 mg, 0.4 mmol) in benzene (10 mL) under nitrogen atmosphere, was added Bu3SnH (1.16 g, 4 mmol, d=1.098, 1.06 mL) dropwise at room temperature and stirred for 15 minutes. After the solvent was removed on rotavap, the product was purified on silica flash chromatography (column 1.5 cm ID×20 cm) using a solvent gradient of 10:0 (100 mL) to 19:1 (100 mL) to 9:1 (100 mL) of hexanes/EtOAc to afford cyclohexenyltributyltin (3.5 g, 9.4 mmol, 78.6% yield) as a clear liquid. Cyclohexenyltributyltin was characterized by 1H-NMR (CDCl3, 500 MHz). See FIG. 51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:28]1([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40]Br)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N.CN(C=O)C>[C:28]1([NH:34][C:35](=[O:36])[NH:37][CH2:38][CH2:39][CH2:40][N:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1ccc(CCNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(NCCCBr)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCCCN(CCc1ccc(Cl)cc1)CCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
To a mixture of bis[2-(4-chlorophenyl)ethyl]amine (48 mg, 0.16 mmol), potassium carbonate (44 mg, 0.32 mmol) and potassium iodide (26 mg, 0.16 mmol) in CH3CN (2 ml) was added N-phenylcarbamoyl-3-bromopropylamine (215 mg, 0.64 mmol) in DMF (2 ml). The mixture was stirred at 80° C. for 18 h, and then concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford [3-(phenylureido)propyl]bis[2-(4-chlorophenyl)ethyl]amine (10 mg, 13%): MS(ES+) m/e 470 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 9H), 7.03 (m, 5H), 6.59 (br, 1H), 3.24 (t, J=6.3 Hz, 2H), 2.87 (m, 1H), 2.76 (m, 1H), 2.73-2.61 (m, 8H), 1.64 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][CH2:55][C@H:54]([NH2:58])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O>[NH2:1][C:2]1[C:3]([C:9]([NH:58][C@H:54]2[CH2:55][CH2:56][CH2:57][N:52]([C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:51])[CH2:53]2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-amino-6-bromopyrazine-2-carboxylic acid (3.63 g, 16.65 mmol), HATU (9.49 g, 25.0 mg) and DIEA (4.35 mL, 25.0 mmol) was added to a solution of (s)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 19.97 mmol, commercially available from Astatech or Arch Corporation). It was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and extracted with ethyl acetate (2×150 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography to give 1,1-dimethylethyl (3S)-3-{[(3-amino-6-bromopyrazin-2-yl)carbonyl]amino}piperidine-1-carboxylate 5.00 g (75.0% yield): MS (EI) for C15H22BrN5O3: 401.12 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24].CN1CCOCC1.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[C:34](=[O:35])([O:24][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)COC(=O)OC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.30 g, 0.88 mmol) in dichloromethane (12.5 mL) was added N-methylmorpholine (0.09 g, 0.88 mmol) and iso-butyl chloroformate (0.12 g, 0.88 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 3 h. This mixture was used as a mixed anhydride for the next step amide formation.