Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In one aspect, substrates A and B were prepared as follows. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid (1w) in THF was added methyl 2-aminoacetate hydrochloride (2w), Et3N and HATU. The mixture was stirred at room temperature for 16 h. The reaction was filtered through Celite. The reaction filtrate was diluted with 100 mL of water and stirred for 15 min. The suspension was filtered off, rinsed with water and dried to afford (S)-methyl 2-(2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)acetate (3w).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[Cl-].[Cd+2:14].[Cl-]>CCOCC>[CH3:3][CH:2]([Cd:14][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:2][CH3:3])[CH3:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(C)Br
Reactant: [Cd+2]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCC(C)[Cd]C(C)CCCCCCCCC

Procedure:
A Grignard reagent is made from 2-bromoundecane and magnesium (II, step (f)) which is treated (II, step (g)) with cadmium chloride to form the corresponding dialkylcadmium, di(2-undecyl)cadmium, (5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([NH:9][CH2:10][C:11]#[N:12])=[O:8].[CH:20]([Si:23]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].ClCCl>C1(C)C=CC=CC=1.C(OC(=O)C)C.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]>[C:11]([CH2:10][NH:9][C:7]([CH:6]([O:5][C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][Si:23]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:20]([CH3:21])[CH3:22])=[O:26])[CH2:28][CH2:29]3)=[CH:38][CH:37]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8])#[N:12]
Reactant: CC(C)CC(Oc1cccc(Br)c1)C(=O)NCC#N
Reactant: CC(C)[Si](OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)CC(Oc1cccc(-c2ccc(N3CCN(C(=O)O[Si](C(C)C)(C(C)C)C(C)C)CC3)cc2)c1)C(=O)NCC#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 2-(3-bromophenoxy)-N-(cyanomethyl)-4-methylpentanamide (1 g, 3.07 mmoles) in toluene (20 mL) was added 4-(4-{[(triisopropylsilyl)oxy]carbonyl}-1-piperazinyl)phenylboronic acid (1.25g, 3.07 mmoles) followed by solid potassium carbonate (0.85 g, 6.14 mmoles) and finally [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (250 mg, 0.31 mmoles). The reaction was stirred overnight at 80° C. and cooled to room temperature prior to taking it up in ethylacetate. The organic phase was washed three times with 1.2 N hydrochloric acid, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (10% EtOAc, 90% Hexanes) to give triisopropylsilyl 4-[3′-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.C(Cl)(=O)OCC.[C@@H:49]1([N:58]2[CH:65]=[CH:64][C:62]([NH2:63])=[N:61][C:59]2=[O:60])[O:55][C@H:54]([CH2:56][OH:57])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]>O1CCCC1.CN(C)C=O>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:63][C:62]4[CH:64]=[CH:65][N:58]([C@@H:49]5[O:55][C@H:54]([CH2:56][OH:57])[C@@H:52]([OH:53])[C@@H:50]5[OH:51])[C:59](=[O:60])[N:61]=4)=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)Nc5ccn([C@@H]6O[C@H](CO)[C@@H](O)[C@@H]6O)c(=O)n5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (2.74 g) and triethylamine (0.78 ml) in tetrahydrofuran (40 ml) was added dropwise ethyl chlorocarbonate (0.61 g) at -15° C., and the reaction mixture was stirred for 20 minutes at -15° C. To the reaction mixture a solution of 1-β-D-arabinofuranosylcytosine (1.37 g) in dimethylformamide (30 ml) was added dropwise at -15° C. to -10° C. After the addition, the mixture was stirred for one hour at 5° C. and then for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was washed with methanol and dried to afford a crude reaction product, which was purified by silica gel column chromatography to yield N4 -[N-(cholest-5-en-3β-oxycarbonyl)glycyl]-1-β-D- arabinofuranosylcytosine (1.8 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6]Br)=[C:4]([F:11])[CH:3]=1.[C-:12]#[N:13].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][C:12]#[N:13])=[C:4]([F:11])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Cl)cc(F)c1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(F)cc(Cl)cc1F
Temperature: 100 °C
Yield: 58.6 %

Procedure:
Step A To the solution of 4-chloro-2,6-difluorobenzyl bromide (Alfa) (2.5 g, 10 mmol) in ethanol (13 mL) and H2O (10 mL) was added KCN (1.75 g, 27 mmol). The reaction mixture was heated at 100° C. for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give (4-chloro-2,6-difluoro-phenyl)-acetonitrile as a yellow oil (1.1 g, 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]=2)[O:3]1.O1CCOCC1.Cl.[CH2:32](OC(ON1C(=O)CCC1=O)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O.CCCCCCC>[CH3:24][C:2]1([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC1(C)OB(C2=CC3CCC(C2)N3C(=O)OCc2ccccc2)OC1(C)C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (Intermediate G21.2, 1.93 g, 5.76 mmol) in dry Dioxane (20 ml), 4 M hydrogen chloride 1,4 dioxane (5.76 ml, 23.03 mmol) was added and the solution was stirred for 1 h. Then, solvent was removed. Crude was dissolved in dry DCM (20.00 ml), N-(benzyloxycarbonyloxy)succinimide (1.964 ml, 6.91 mmol) and triethylamine (3.14 ml, 23.03 mmol) were added and the suspension was stirred for 1 h. Then, solvent was removed and the product was purified by Biotage Si 25 g with a gradient of heptane and EtOAc affording the title compound (810 mg, 2.194 mmol, 38.1% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([CH3:18])[C:11]=3[N:10]=[C:9]2[O:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].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.[Fe+2]>[CH3:18][N:12]1[CH:13]=[N:14][C:15]2[C:16](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([C:29]#[N:30])=[N:7][CH:6]=3)[C:9]([O:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=3)=[N:10][C:11]1=2
Reactant: CN(C)C=O
Reactant: Cn1cnc2c(=O)n(-c3ccc(Cl)nc3)c(Oc3cc(F)c(F)c(F)c3)nc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1cnc2c(=O)n(-c3ccc(C#N)nc3)c(Oc3cc(F)c(F)c(F)c3)nc21
Temperature: 120 °C

Procedure:
1-(6-chloropyridin-3-yl)-9-methyl-2-(3,4,5-trifluorophenoxy)-1,9-dihydro-6H-purin-6-one (0.3 g, 0.73 mmol), Zn(CN)2 (0.43 mg, 3.65 mmol), Pd2(dba)3 (0.07 g, 0.073 mmol) and DPPF (0.04 g, 0.073 mmol) are added to DMF (3 mL). The mixture is purged with N2 for 3 min and then heated at 120° C. for 18 h. Water (20 mL) is added and the resulting mixture is extracted with DCM (2×20 mL). The organic layer is passed through celite and Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (MeOH:CH2Cl2=2:98) to afford the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 7.90 (s, 2H), 7.68 (s, 1H), 7.25 (s, 2H), 6.85-6.89 (m, 2H), 3.65 (s, 3H, s). MS (M+1): 399.07; RT=1.41 min. The IC50 determined as described in Example 6 is 100 nanomolar or less.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(O)=[O:2].[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:19][S:16]([NH:15][C:13]1[C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:8]2[C:9](=[O:10])[C:4]([C:1]([NH:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[O:2])=[CH:5][O:6][C:7]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cc2occ(C(=O)O)c(=O)c2cc1Oc1ccccc1
Reactant: Nc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CS(=O)(=O)Nc1cc2occ(C(=O)Nc3nnn[nH]3)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with 5-aminotetrazole in the presence of dicyclohexylcarbodiimide to obtain 7-methylsulfonylamino-6-phenoxy-3-(1,2,3,4-tetrazol-5-yl-aminocarbonyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.F[C:39](F)(F)C([O-])=O.CCN(C(C)C)C(C)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:39])=[O:31])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CCCCN2)CC1
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCCC1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-2-piperidylcarboxamide, trifluoroacetate (Step 2) (0.16 mmol), ClCH2CH2Cl (1 mL) and DIEA (Aldrich) (0.06 mL, 0.32 mmol). Formaldehyde (Aldrich, 37% aqueous soln) (0.03 mL, 0.33 mmol) was added to the reaction mixture, followed by NaBH(OAc)3 (Aldrich Chemical Company) (52 mg, 0.25 mmol), and the reaction mixture was stirred at RT 18 h. The mixture was diluted with CH2Cl2, and the organic solution was washed with satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 5:95 MeOH-CH2Cl2) to give N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-(1-methyl(2-piperidyl))carboxamide as a white solid, (71 mg) (two diastereomers). MS (ESI, pos. ion) m/z: 562 (M+H); (ESI, neg. ion) m/z: 560 (M−H). Calc'd for C27H36ClN5O4S: 561.22.
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].[CH2:7]([NH:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14]N1)=[O:11])[CH3:8].[OH-].[Na+].[Cl-].[Na+]>C(#N)C>[CH2:7]([NH:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][N:4]1[CH3:3])=[O:11])[CH3:8]
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.1 %

Procedure:
3.43 ml of 35% formalin and 804 mg of sodium cyanoborohydride were added to a solution of 2.36 g of (2S, 4S)-2-ethylcarbamoyl-4-(4-methoxybenzylthio)-pyrrolidine dissolved in 42 ml of acetonitrile, and the mixture was stirred at room temperature for 40 minutes. At the end of this time, a 1N aqueous solution of sodium hydroxide was added, and the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with ethyl acetate) to afford 1.93 g of the title compound as colorless crystals. Infrared Absorption Spectrum (KBr) δmax cm-1 : 1655, 1513, 1252.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]2[N:11]([CH3:22])[N:12]=[C:13]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12.ClC1N=C[N:27]=C2N(C)N=C(C3OC([N+]([O-])=O)=CC=3)C=12>>[NH2:27][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]2[N:11]([CH3:22])[N:12]=[C:13]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: CC(C)c1nc(Cl)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1
Product: CC(C)c1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-6-isopropyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was recrystallized from dimethylformamide to give 4-amino-6-isopropyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point 230°C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][O:14][CH2:15][C@@H:16]([C:18]([NH:20]C(OC(C)(C)C)=O)=[O:19])[NH2:17])[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].Cl>CCOC(C)=O>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][O:14][CH2:15][C@@H:16]([C:18]([NH2:20])=[O:19])[NH2:17])[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](N)C(=O)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(COC[C@H](N)C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of O-[[3-(allyloxycarbonyl)phenyl]methyl]-N-(t-butoxycarbonyl)-L-serinamide (69 g, 182.5 mmol) in EtOAc (1000 mL) at 0° C. is slowly bubbled HCl gas for 1 hour, during which time a white precipitate is observed. The mixture is warmed to room temperature over 30 minutes, after which time EtOAc is removed by evaporation. The resulting residue is triturated with ether (500 mL) with vigorous stirring for 30 minutes. The precipitate is collected by vacuum filtration, washed with ether (2×100 mL) and then air dried to yield O-[[3-(allyloxycarbonyl)phenyl]-methyl]-L-serinamide.HCl as a free-flowing white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 93.6 %

Procedure:
A solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid ethyl ester (8.8 g) in methanol (30 mL) was treated with 2N sodium hydroxide solution (20 mL) and the mixture was heated at reflux for 15 minutes. The crude solid obtained from the usual work up, was crystallized from dichloromethane-hexane to yield 7.5 g of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid mp 186°-188° C. A portion was recrystallized from ether-hexane to furnish the analytical specimen, mp 187°-188° C. Anal. Calculated for C17H12F2O2 : C, 71.32: H, 4.22; F, 13.27 Found: C, 71.48; H, 4.22; F, 13.53.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH2:15][CH:14]=[CH2:13])([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Product: C=CCC1(O)CCC(C(=O)OCC)CC1

Procedure:
The title compound is prepared from 4-oxo-cyclohexanecarboxylic acid ethyl ester and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=213 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:23](#[N:25])[CH3:24]>>[NH2:25][CH:23]([C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:24]
Reactant: O=C1CCCc2ccccc21
Reactant: CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(N)C1(O)CCCc2ccccc21

Procedure:
As set forth in the foregoing reaction scheme, the 1-aminoalkyl-3,4-dihydronaphthalene compounds of the invention wherein n is 1 are obtained by reacting a 1,2,3,4-tetrahydro-1-naphthalenone with, for example, trimethylsilylcyanide in the presence of a catalytic amount of, for example, aluminum trichloride followed by reduction with lithium aluminum hydride to obtain the corresponding 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene. Similarly, the compounds of the invention wherein n is 2 may be obtained by reacting a 1,2,3,4-tetrahydro-1-naphthalenone with, for example, acetonitrile and n-butyl lithium, followed by reduction with lithium aluminum hydride to obtain the corresponding 1-aminoethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene. The 1-aminoalkyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene intermediate is then subjected to acid dehydration to obtain the corresponding 1-aminoalkyl-3,4-dihydronaphthalene compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:6]([OH:8])=O.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][N:21]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:6]([NH:28][C@@H:26]([C:23]1[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=1)[CH3:27])=[O:8]
Reactant: COc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N[C@H](C)c2cnc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-methoxy-5-(5-methylpyridin-2-yl)benzoic acid (26 mg, 0.11 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (29 mg, 0.21 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol), 1-hydroxybenzotriazole hydrate (33 mg, 0.21 mmol), triethylamine (22 mg, 0.21 mmol) and methylene chloride (3 mL). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified via preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the desired product as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:9]=1[CH2:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:27][C@@H:26]1[C@@H:28]([O:29][C:28](=[O:29])[CH3:30])[C@H:30]([O:31][C:32](=[O:33])[CH3:34])[C@@H:32]([CH2:34][O:35][C:5](=[O:7])[CH3:6])[O:33][C@H:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][C:9]2[CH:10]=[C:11]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:8]=2)[CH:20]=1)(=[O:27])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 15 h

Procedure:
Acetic anhydride (0.3 ml) was added to a solution of (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) in pyridine (5.0 ml) at room temperature and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.34 g).
Reaction SMILES: Cl.C1(NC2C(C)=C(C)N=C(NCC3C=CC=CN=3)N=2)CCCCC1.[CH2:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1)[CH3:26].Cl[C:36]1[N:41]=[C:40]([NH:42][CH:43]2[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]2)[C:39]([CH3:51])=[C:38]([CH3:52])[N:37]=1>>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([NH:42][C:40]2[C:39]([CH3:51])=[C:38]([CH3:52])[N:37]=[C:36]([NH:34][CH2:33][C:29]3[CH:28]=[C:27]([CH2:25][CH3:26])[CH:32]=[CH:31][N:30]=3)[N:41]=2)[CH2:44][CH2:45]1
Reactant: CCc1ccnc(CN)c1
Reactant: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Agent: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: CCc1ccnc(CNc2nc(C)c(C)c(NC3CCC(F)(F)CC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-ethylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine and 2-chloro-N-(4,4-difluorocyclohexyl)-5,6-dimethylpyrimidin-4-amine (Step A) instead of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine. The product was purified by crystallization from ethanol to afford the titled compound as the hydrochloride salt as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.59 Hz, 3H), 1.57-1.1.89 (m, 11H) 2.25 (s, 3H) 2.62 (m, 2H) 3.95 (s, 1H) 4.64 (d, J=5.12 Hz, 2H) 7.17 (d, J=5.12 Hz, 1H) 7.24 (s, 1H) 7.64 (d, J=6.40 Hz, 1H) 8.31 (s, 1H) 8.40 (d, J=4.94 Hz, 1H) 12.58 (bs, 1H); MS (ESI) m/z 375.9 (M+1)+.