Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[Cl:1][C:2]1[S:6][C:5]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc(Cl)s1
Product: Clc1ccc(-c2ccc(Cn3ccnc3)cn2)s1

Procedure:
Synthesized using 5-chloro-2-thiophenylboronic acid (205 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 83 mg, 0.30 mmol, 47%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.17 (s, 2H), 6.91-6.92 (m, 2H), 7.13 (s, 1H), 7.33 (d, J=4.0 Hz, 1H), 7.46 (dd, J=8.2, 2.1 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.80 (s, 1H), 8.42 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 118.16, 119.1, 124.2, 127.3, 129.5, 129.8, 133.1, 135.9, 137.2, 142.5, 148.5, 152.1; MS (ESI): m/z=275.98 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:12])([CH3:11])[CH2:6][C:5]2([CH3:14])[CH3:13].C([Li])(C)(C)C.[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[CH3:11][C:7]1([CH3:12])[C:8]2[C:4](=[CH:3][C:2]([N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:10][CH:9]=2)[C:5]([CH3:14])([CH3:13])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 59.3 %

Procedure:
5-Bromo-1,1,3,3-tetramethyl-indan 19b (1.4 g, 5.53 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to −78° C. in a dry ice-acetone bath. t-Butyllithium (4.4 mL, 11.1 mmol) was added dropwise at the same temperature and the mixture was stirred for 40 minutes. A solution of di-tert-butyl azodicarboxylate (1.59 g, 6.92 mmol) in 10 mL of tetrahydrofuran was added dropwise by a constant-pressure addition funnel. The reaction mixture was stirred at −78° C. for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was quenched with 5 mL of methanol and was warmed up to room temperature. The mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 19c (1.326 g, yield 59.3%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:16]([CH3:18])[CH3:17].CN1CCC[C:21]1=[O:25].C[O-].[Na+].Cl>O.[Cu]I.CCOC(C)=O>[CH3:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:25][CH3:21])=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])[C:5]([CH:16]([CH3:18])[CH3:17])=[CH:6]1
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Agent: [Cu]I
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)c2c(c1)c(C(C)C)cn2C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To methyl 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylate (620 mg, 2 mmol) and Copper(I)iodide (476 mg, 2.500 mmol) was added N-Methyl-2-pyrrolidone (NMP) (4 mL). To the mixture was added dropwise a solution of sodium methoxide (in methanol) (1802 mg, 8.34 mmol) with stirring over a 5 min period, during which time contents turned dark green. The reaction was heated to 120° C., upon which the contents were nearly black colored. The black colored mixture was stirred at 120° C. After 1 h 45 min, the dark reddish brown colored contents were removed from heating and allowed to cool. Upon reaching 80° C., water (150 uL) was added and the reaction mixture was allowed to cool to room temperature with stirring overnight. The reaction contents were then acidified with 1N HCl (8 mL), upon which the contents became a brown suspension. The mixture was diluted with water (8 mL), and lightened a bit. Next added EtOAc (10 mL), and the contents become a biphasic mixture. The contents were filtered through Celite, and the filter cake was washed with EtOAc. The filtrate was poured into a separatory funnel, and the organic phase was separated and set aside. The aq. phase was extracted with EtOAc (2×10 mL), and combined with the previously saved organic layer. The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 10 to 50% EtOAc in hexanes) gave the title compound as a cream colored solid (80 mg, 16%). Note: Some material loss occurred during purification due to a collection malfunction. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.82 Hz, 6H), 3.08-3.16 (m, 1H), 3.74 (s, 3H), 3.80 (s, 3H), 7.09 (s, 2H), 7.21 (s, 1H), 12.9-13.1 (br s, 1H). MS(ES) [M+H]+ 248.2.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:60][C:61]([F:80])([F:79])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][C:69]2[C:70]3[CH2:78][CH2:77][NH:76][CH2:75][C:71]=3[N:72]=[CH:73][N:74]=2)=[CH:64][CH:63]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:48]1([N:76]2[CH2:77][CH2:78][C:70]3[C:69]([NH:68][C:65]4[CH:64]=[CH:63][C:62]([C:61]([F:80])([F:60])[F:79])=[CH:67][CH:66]=4)=[N:74][CH:73]=[N:72][C:71]=3[CH2:75]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ccccc2)C3)cc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
To 2 mL of Dioxane was added 10 mol % of palladium(II)acetate (12 mg) and 20 mol % rac-BINAP (58 mg). After stirring for 3 hours, bromobenzene was added (0.054 ml, 0.53 mmol), cesium carbonate (682 mg, 2.12 mmol), N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.51 mmol) and activated molecular sieves (340 mg). The mixture was sonicated for 10 minutes and heated in a sealed tube via microwave at 160° C. for 3 hours in a Personal Chemistry Microwave (Smith Creator). After completion, the mixture was filtered through celite, evaporated and purified by flash chromatography over silica gel using a 0-100% gradient of ethyl acetate/hexanes to give the desired product as a white solid (36 mg).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[S:17][CH2:16]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH:37]=O.C([BH3-])#N.[Na+].[Cl-].[Na+]>C(O)C.O>[ClH:1].[ClH:1].[CH2:12]([O:11][C:9]([CH:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[S:17][CH2:16]1)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:10])[CH3:13]
Reactant: O=CCCCC=O
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCN)C(=O)OCC)CSc2ccccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCN2CCCCC2)C(=O)OCC)CSc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 147 %

Procedure:
In 5 ml of ethanol is dissolved 60 mg of ethyl 3(R)-(5-amino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate dihydrochloride, and 0.5 g of 25% aqueous glutaraldehyde solution and 0.3 g of sodium cyanoborohydride are added to the solution, followed by stirring at room temperature for 2 hours. Water (50 ml) is added to the reaction solution, followed by adding sodium chloride to saturate the solution. The solution is extracted twice with 30 ml of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is dissolved in a small amount of ethyl ether, and 0.2 ml of 5N hydrogen chloride-ethyl acetate solution is added to the solution to give 50 mg of ethyl 3(R)-(1-ethoxycarbonyl-5-piperidinopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.dihydrochloride as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[O:4][C:5](=[O:7])[CH:6]=1.[CH3:9][NH:10][NH2:11]>CC(O)=O>[Br:1][C:2]1[C:3](=[O:4])[NH:11][N:10]([CH3:9])[C:5](=[O:7])[CH:6]=1
Reactant: CNN
Reactant: O=C1C=C(Br)C(=O)O1
Solvent: CC(=O)O
Product: Cn1[nH]c(=O)c(Br)cc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromofuran-2,5-dione (100 g, 0.565 mol) in HOAc (1.0 L) cooled in an ice-water bath, 40% aq. methylhydrazine solution (65 g, 0.565 mol) was added dropwise while the internal temperature was held below 20° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried in vacuo to give desired product as a white solid: LC/MS m/z=206.9 (M+H)+; 1H NMR (400 MHz, CD3OD) δ: 7.35 (s, 1 H), 3.60 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH:3]=1.Cl.C(C1C=CC=CN=1)(=N)N.Cl.C(C1C=C([Cl:41])C=CN=1)(=N)N>>[Cl:41][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[N:11]=[C:10]([OH:20])[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[N:13]=2)[CH:19]=1
Reactant: N=C(N)c1cc(Cl)ccn1
Reactant: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Agent: Cl
Agent: N=C(N)c1ccccn1
Product: Oc1cc(-c2cc(Cl)ccn2)nc(-c2cc(Cl)ccn2)n1

Procedure:
The procedure is as described in the case of 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol (ligand PM1) in Example 3 except that, instead of 2-amidinopyridine hydrochloride, the 2-amidino-4-chloropyridine hydrochloride from Example 8 is used. After recrystallisation from DMSO, 2,6-bis(4-chloropyrid-2-yl)-pyrimidin-4-ol (ligand PM5) is obtained in the form of a colourless solid. 1H-NMR (360 MHz, DMSO-d6): 12.53 (br s, 1H); 8.74 (d, J=5.0 Hz, 1H); 8.74 (s, 1H); 8.71 (d, J=5.0 Hz, 1H); 8.64 (d, J=2.3 Hz, 1H); 7.83 (dd, J=5.0, 2.3 Hz, 1H); 7.71 (dd, J=5.0, 2.3 Hz, 1H); 7.30 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[F:10][C:9]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 4-bromo-3-(trifluoromethy)aniline (360 mg, 1.50 mmol, 1 eq.) in DMF (5 mL) is added phenyl boronic acid (274 mg, 2.25 mmol, 1.5 eq.), K2CO3 (621 mg, 4.5 mmol, 3 eq.), and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol, 0.1 eq.). The mixture is purged with N2 (g) for 5 minutes and heated at 120° C. for 20 h. After cooling to room temperature, the reaction is diluted with EtOAc and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by gradient silica gel chromatography (hexanes to 3:1 hexanes/EtOAc) to give 2-trifluoromethyl-biphenyl-4-ylamine. [MS: (ES+) 238.1 (M+1)+].
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1([C:34]2[CH:39]=[CH:38][C:37]([P:40](Cl)(Cl)=[O:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCC.C(OCC)C.C1CCCCC1>[C:28]1([C:34]2[CH:39]=[CH:38][C:37]([P:40]3(=[O:41])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccc(-c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: O=P1(c2ccc(-c3ccccc3)cc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.94 g, 0.0615 mol) in hexane was added to a solution of tetramethylethylenediamine (1.86 g, 0.016 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound which was stirred for an additional 2 hours at 26° C. 4-Phenylphenylphosphonic dichloride (8.7 g, 0.032 mol) was directly added to this suspension followed by 60 ml. of cyclohexane. The resulting mixture was stirred for 16 hours at 26° C. The reaction was quenched with the rapid addition of a solution of acetic acid (6 g, mol) in 30 ml. of anhydrous cyclohexane. After stirring for 30 minutes, the cyclohexane layer was removed under vacuum and the resulting residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with water, dried over sodium sulfate and concentrated in vacuo to yield an oily residue. The oily residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in anhydrous diethyl ether to yield 1-(4-phenylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.55 g, 5% yield) as a white solid having a melting point of 259°-261° C. and the following analysis:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22]([C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=O)C>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=NC(=O)c1cnccn1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Clc1ccc(-n2ncnc2-c2cnccn2)cc1

Procedure:
To a solution of 12.1 g. of 4-chlorophenylhydrazine hydrochloride in a mixture of 13.5 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene pyrazinecarboxamide. The procedure of Example 2 is then followed giving 3.8 g. of the desired product as tan crystals, mp. 129°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][N:10]=1.[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CO>[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[CH:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[N:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:23])[CH2:33][CH2:32]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (338 mg, 0.79 mmol) and O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (300 mg, 0.79 mmol) were dissolved in a mixture of 20 ml of acetonitrile and 10 ml of methanol. 131 mg (0.83 mmol) of 1-(2-dimethylaminoethyl)-piperazine was added and the mixture stirred at ambient temperature for 6 h. The resulting mixture was distributed between dichloromethane and a 2 M aqueous solution of sodium carbonate. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic layers were combined, washed with a saturated aqueous solution of sodium bromide, dried over sodium sulfate, and evaporated. The crude material was purified by flash chromatography on silica gel using a stepped gradient of ethyl acetate and a 4:4:1 solvent mixture of ethyl acetate, dichloromethane and methanol containing 2% v/v of 35% wt ammonia in water to afford [4-(2-dimethylamino-ethyl)-piperazin-1-yl]-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone (160 mg, 42%) as an oil. 1H-NMR (d6-CDCl3) δ: 8.87 (d) [1H], 8.36 (d) [1H], 7.75 (dd) [1H], 7.68 (t) [1H], 7.67 (m) [1H], 7.53 (m) [1H], 7.46 (mt) [1H], 7.42 (md) [1H], 7.13 (dt) [1H], 7.10 (d) [1H], 3.89 (s) [3H], 3.81-3.86 (m) [2H], 3.48-3.55 (m) [2H], 2.58-2.64 (m) [2H], 2.56 (m) [2H], 2.50 (m) [2H], 2.44-2.52 (m) [2H]. MS: m/z 485 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C#N)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([O:19]CC)=O.[O-]CC.[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)c1ccccn1
Yield: 41.9 %

Procedure:
Combine a solution of 4-fluorophenylacetonitrile (1.00 g, 7.4 mmol) and ethyl picolinate (1.12 g, 7.4 mmol) in absolute ethyl alcohol (15 mL) under N2 with 21 wt % sodium ethoxide solution in denatured ethyl alcohol (4.2 mL, 11.1 mmol) and heat to reflux for 2 hours, then pour onto ice. Adjust the pH to 4 with concentrated hydrochloric acid and collect the precipitate by vacuum filtration. Dissolve the residue in 48% aqueous hydrobromic acid (25 mL) and heat to reflux for 2 hours. Pour the solution onto ice and adjust the pH to 7 with 5N aqueous sodium hydroxide solution. Extract the aqueous solution three times with CH2Cl2. Combine the organic extracts, dry (Na2SO4), filter, and concentrate in vacuo to afford the title compound 668 mg (42%) as a brown amorphous solid. MS FAB+ m/z=216.1
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:42][NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(OC)c(OC)c4)nc32)[C@H](O)[C@@H]1O
Yield: 35.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (200 mg, 0.4 mmol) was dissolved in stirred tetrahydrofuran (5 ml) and 3,4-dimethoxybenzaldehyde (130 mg, 0.8 mmol) added. The reagents were stirred together until everything had dissolved and then sodium triacetoxyborohydride (130 mg, 0.6 mmol) added. The reaction mixture was stirred for 24 hr and then quenched by the addition of methanol (1 ml). The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0.5) increasing to (92:7:1). This gave the title compound (90 mg) as a foam. MS: 641 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH3:13]I.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A mixture of sodium hydride (3.24 g, 12.84 mmol) in tetrahydrofuran (35 mL) cooled to 0° C. was treated with a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 10.7 mmol) in tetrahydrofuran (10 mL). The reaction was warmed to 25° C. and was stirred at 25° C. for 1 h. At this time, the reaction was treated with methyl iodide (1.0 mL, 16.05 mmol) and then was stirred at 25° C. for 18 h. The reaction was then cooled to 0° C. and was treated with a saturated aqueous ammonium chloride solution. The resulting mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.48 g, 89.7%) as a yellow oil: 1H NMR (DMSO-d6, 300 MHz) δ8.27 (s, 1H), 7.80 (s, 1H), 4.18 (q, J=7.32 Hz, 2H), 3.84 (s, 3H), 1.24 (t, J=6.96 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:17]([C@H:14]1[CH2:13][CH2:12][C@H:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:16][CH2:15]1)=[O:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid (M) (20 mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg, 0.14 mmol), HOBt (18 mg, 0.14 mmol), triethylamine (0.019 mL, 0.14 mmol) and benzyl amine (0.007 mL, 0.7 mmol). The reaction mixture was stirred at room temperature for 1 h followed by quenching with aqueous NaHCO3 and EtOAc. The layers were separated and the organic was washed twice with water, dried over Na2SO4, filtered and concentrated. Purification of the crude oil by preparative reverse-phase HPLC gave trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid benzylamide (Example 9) (14 mg): 1H NMR (300 MHz, CD3OD) δ 7.40-7.20 (m, 9 H), 4.39 (s, 2 H), 3.55 (m, 1 H), 2.31 (m, 1 H), 2.20 (br d, 2 H), 1.98 (br d, 2 H), 1.77 (m, 2 H), 1.50 (m, 2 H); mass spectrum m/z 349 [(M+H)+; calcd for C21H25N4O: 349].