Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11]O.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:27]([CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(F)c(F)c(CO)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1cc(F)c(F)c(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2,3-difluoro-5-methoxy-phenyl)-methanol (715 mg, 4.11 mmol) in toluene (10 mL) was added DPPA (1.04 mL, 4.93 mmol) and DBU (0.805 mL, 5.34 mmol), followed by stirring at RT for 1 h. The reaction mixture was diluted with EtOAc, the organics were washed with diluted brine (20 mL), dried (Phase separator) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) to afford the title compound as a colorless oil. TLC Rf (c-hexane/EtOAc 3:1)=0.55; MS (LC/MS): 208.0 [M+NH4]+; tR (HPLC conditions c): 5.46 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13](=[O:17])[C:14]([OH:16])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:18]([NH2:21])[C:19]#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O>[O:17]=[C:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:14]([NH:21][CH2:18][C:19]#[CH:20])=[O:16]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: C#CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (6.1 g, 48 mmol) was added to a solution of phenylglyoxylic acid (6.0 g, 40 mmol) and 3 drops of DMF in dry DCM (50 mL). The reaction mixture was stirred at RT for 3 h then the solvent was removed. The residue was taken up in dry DCM (50 mL) and the solution was cooled to 0° C. A mixture of propargyl amine (2.2 g, 40 mmol) and triethylamine (4.05 g, 40 mmol) was added cautiously over a period of 10 min then the mixture was allowed to warm to RT. Stirring was continued for 2.5 h then water (10 mL) was added. The mixture was washed with 1 M HCl, sat. sodium hydrogencarbonate (aq.), then brine. The organic phase was then dried (Na2SO4) and the solvent was removed. The residue was crystallized from cyclohexane to afford the product as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[CH3:12][C:8]1[NH:22][N:21]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=2[OH:9])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1[nH]nc(-c2ccc(O)cc2O)c1-c1ccccc1

Procedure:
This compounds was synthesised in the same manner as described above. 7-Hydroxy-2-methyl-3-phenyl-chromen-4-one (0.5 g, 1.70 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as an off white solid (0.37 g, 88%); Rf 0.7 Cf SM 0.8 ethyl acetate/hexane (80/20).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl.Br[C:14]1[CH:15]=[C:16]([CH2:21][NH2:22])[CH:17]=[CH:18][C:19]=1[F:20].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:22][CH2:21][C:16]1[CH:15]=[CH:14][C:19]([F:20])=[C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:17]=1
Reactant: NCc1ccc(F)c(Br)c1
Reactant: OCc1cccc(B(O)O)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Temperature: 150 °C
Yield: 13.2 %

Procedure:
To a solution of [3-(hydroxymethyl)phenyl]boronic acid (2 g, 13.2 mmol) in 1,4-dioxan (40 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (3.18 g, 13.2 mmol), potassium carbonate (9.1 g, 66 mmol) and tetrakis(triphenylphosphine) palladium(0) (456 mg, 0.4 mmol). The mixture was split into 4×20 mL capacity microwave vials and each was treated with water (3 mL). The mixtures were each heated at 150° C. for 20 mins. One sixth of the total reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was dried (magnesium sulphate) and evaporated to dryness and the product purified by flash chomatography on silica using 0-50% ethyl acetate/cyclohexane followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. Product-containing fractions were combined and evaporated to dryness to afford 402 mg of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The remaining five-sixths of the reaction mixture was worked up in the same manner and purified by flash chomatography using ethyl acetate/cyclohexane @1:1 followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. This yielded 1.97 g of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(O[CH:18](OCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:19]1([CH:18]2[O:12][CH2:11][CH:10]([C:4]3([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:13][O:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(OCC)c1ccccc1
Reactant: OCCC1(C(CO)CO)CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCC1(C2COC(c3ccccc3)OC2)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]propane-1,3-diol (200 mg) in N,N-dimethylformamide (8 mL) were added benzaldehyde diethyl acetal (752 mg) and p-toluenesulfonic acid pyridinium salt (48 mg) at room temperature. After stirring the solution at room temperature for 16 hours, saturated aqueous sodium bicarbonate solution was added thereto, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution (0.2 mL) and dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=4:6) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][C:2]1(C)C(C)(C)OB(C=C)O1.I[C:13]1[C:14]([NH2:20])=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>CO.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].C(Cl)(Cl)Cl>[CH:1]([C:13]1[C:14]([NH2:20])=[N:15][C:16](=[O:19])[NH:17][CH:18]=1)=[CH2:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc(=O)[nH]cc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: C=Cc1c[nH]c(=O)nc1N
Yield: 67.4 %

Procedure:
7.24 g of 4,4,5,5-tetramethyl-2-vinyl-1,3,2dioxaborolan (46.4 mmol), 10.00 g of 5-iodocytosine (42.2 mmol), 1.11 g of triphenylphosphine (14.2 mmol), 1.05 g of Pd2dba3.CHCl3 (1.1 mmol) and 15.1 ml tributylamine (63.3 mmol) in 200 ml of methanol were heated to reflux for 28 hours. After cooling the suspension to room temperature the crude product was filtered off and washed with methylene chloride. Crystallisation from boiling methanol gave 3.9 g (61%) of 5-vinylcytosine as white crystals, m.p. >290° C., MS (EI-MS): (m/z) 137 [M+H]+. 1H-NMR (250 MHz, D6-DMSO): 5.03 (1H, d, J=11.0), 5.45 (1H, d, J=17.3), 6.52 (1H, dd, J=17.3, 11.0), 6.8-7.2 (3H, br), 7.56 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.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]>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Br:1])[CH:3]=[N:4][C:5]=1[CH:13]=[CH2:14]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ncc(Br)cc1C(=O)OC
Temperature: 80 °C

Procedure:
Methyl 5-bromo-2-chloronicotinate (500 mg, 2.0 mmol) was dissolved in EtOH (20 mL) with potassium vinyltrifluoroborate (269 mg, 2.0 mmol), TEA (0.28 mL, 2.0 mmol), and [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) (29 mg, 0.04 mmol). The reaction was heated at 80° C. for 1 h, filtered through a Celite pad. The filtrate was concentrated, partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was separated, dried over MgSO4 and concentrated. Purification over silica gel using automated flash chromatography (EtOAc/hexanes 0-20%) affords the compound, methyl-5-bromo-2-vinylnicotinate, as a white solid (484 mg, 76%). LC-MS (M+H)=242.1.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[CH:32]=3)[CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:4].CO.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[ClH:35].[O:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:8]4[N:7]=[C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[NH:10][C:9]=4[CH:11]=3)=[CH:32][C:19]=2[CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1,1-Dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (517 mg, 1.18 mmol) was taken into methanol (2 mL) and 4M hydrogen chloride in dioxane (2 mL) and the mixture was allowed to stand at room temperature for 30 minutes. The suspension obtained was diluted with excess ethyl ether and the solid collected by filtration to give methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate dihydrochloride salt (462 mg, 95% yield) as a white solid. MS (EI) for C18H18N4O3: 339 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[CH2:24]([S:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Product: CCS(=O)(=O)Nc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from Intermediate 4 and ethane sulfonyl chloride using the method of Example 4; mass spectrum (API): Found 421 (MH−), C20H26N2O4S2 requires 422; 1H-NMR (400 MHz, CDCl3): 1.42 (9H, m), 2.98 (2H, m), 3.18 (3H, m), 3.37 (2H, m), 4.36 (2H, m), 7.21 (2H, m), 7.29 (1H, m), 7.39 (4H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1.O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65](=O)([O-:67])[O-:66].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30](/[C:29](=[C:19]1/[C:20]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=2[O:22][CH2:23][C:17]2[CH:16]=[C:15]([CH2:14][C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:65]([OH:67])=[O:66])=[CH:3][C:4]4=[N:10][C:9]=3[CH:11]3[CH2:13][CH2:12]3)[CH:34]=[CH:33][C:18]/1=2)/[CH3:32])#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4cc(Br)ccn34)cc2COc2cc(F)ccc21
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4cc(C(=O)O)ccn34)cc2COc2cc(F)ccc21
Temperature: 80 °C
Yield: 104.3 %

Procedure:
[step 5] (E)-2-{8-[(7-bromo-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (2.5 g, 4.8 mmol) obtained in step 4 was dissolved in DMF (26 mL), water (6.8 mL), 1,3-bis(diphenylphosphino)propane (0.60 g, 1.5 mmol), potassium carbonate (0.80 g, 5.8 mmol) and palladium acetate (0.33 g, 1.5 mmol) were added. After purging 3 times with carbon monoxide under reduced pressure, the mixture was stirred with heating at 80° C. for 7 hr. The reaction mixture was filtered through celite, activated carbon (0.75 g) was added to the obtained filtrate, and the mixture was stirred with heating at 60° C. for 1.5 hr. The mixture was filtered again through celite, 2 mol/L hydrochloric acid was added to the filtrate, and the mixture was extracted 3 times with a mixed solvent of chloroform-methanol. The combined organic layers were washed 3 times with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained residue were added isopropylalcohol (25 mL) and ethanol (20 mL), and the mixture was stirred at 80° C. for 1 hr and further at room temperature for 1 hr. The precipitated crystals were collected by suction filtration to give (E)-3-{[11(6H)-(1-cyanoethylidene)-3-fluorodibenzo[b,e]oxepin-8-yl]methyl}-2-cyclopropylimidazo[1,2-a]pyridine-7-carboxylic acid (2.4 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][CH:13]=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>ClC1C=CC=CC=1Cl>[CH3:17][N:16]1[C:12]2[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[NH:1][C:18](=[O:19])[C:13]=2[N:14]=[CH:15]1
Reactant: Cn1cncc1-c1cc2ccccc2cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: Cn1cnc2c(=O)[nH]c3cc4ccccc4cc3c21
Temperature: 180 °C
Yield: 41.2 %

Procedure:
A mixture of 5-(3-amino-2-naphthyl)-1-methylimidazole (Preparation 17) (0.48 g, 2.14 mmol) and 1,1′-carbonyidiimidazole (0.42 g, 2.57 mmol) in o-dichlorobenzene (22 mL) was heated at 180° C. for 5 hours. The suspension was cooled to RT, filtered, and dried under vacuum, affording the title compound as a light yellow solid (0.22 g, 42%). 1H NMR(DMSO): 11.57(s, 1H), 8.71(s, 1H), 8.15(s, 1H), 8.10(d, J=8.4, 1H), 7.89(d, J=8.4, 1H), 7.84(s, 1H), 7.53(m, 1H), 7.46(m, 1H), 4.30(s, 3H). (ESI) m/z (M+H)+=250.08.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[CH2:35][CH2:36][O:37][CH3:38]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:35][CH2:36][O:37][CH3:38])[CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: COCCBr
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(CCOC)CC3)c2)nc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (350 mg), diisopropylethylamine (685 μL), and N,N-dimethylformamide (3.5 mL) was added 2-bromoethylmethyl ether (282 μL), followed by reacting at 60° C. for 2 hours. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=99:1-90:10) to obtain 5-chloro-6-ethyl-3-({1-[1-(2-methoxyethyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide (225 mg) as a yellow solid.
Reaction SMILES: B.O1CCCC1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH3:42])([CH3:41])[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH:30]=3)=[O:27])[CH2:19]2)=O)=[CH:10][CH:9]=1.Cl>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH3:42])([CH3:41])[CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH:30]=3)=[O:27])[CH2:19]2)=[CH:10][CH:9]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(C(=O)C(C)(C)Cc3ccc(F)cc3)C2)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CC(C)(C)Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A solution of borane in tetrahydrofuran (1.0 M, 5.3 mL, 5.3 mmol) was added to 1-{1-[3-(4-fluorophenyl)-2,2-dimethylpropionyl]-piperidin-3-ylmethyl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (66 mg, 134 μmol) and the resulting solution was stirred at room temperature for 18 hours. A mixture of 1.0 N hydrochloric acid (5 mL) and methanol (5 mL) was added very slowly until the resulting vigorous reaction subsided, then the remainder was added quickly and the resulting solution was stirred at room temperature for 5 hours. The solution was concentrated under vacuum. The residue was dissolved in 1.0 N aqueous sodium hydroxide and dichloromethane, and the phases were separated. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified twice by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide a white amorphous solid (24 mg, 38%). 1H NMR (300 MHz, CDCl3) δ7.81 (s, 1H), 7.68 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.84 (t, J=9 Hz, 2H), 4.09 (s, 3H), 3.09 (m, 2H), 2.95 (m, 1H), 2.55 (s, 2H), 2.40 (m, 3H), 2.10 (m, 1H), 1.9-1.5 (m, 5H), 1.0 (m, 1H), 0.85 (s, 6H). Mass spec (ES+) m/z 480.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:18]#[N:19].CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1.O>C(O)(=O)C>[C:18]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:2]=1[N:1]1[CH:22]=[CH:26][CH:25]=[CH:24]1)#[N:19]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccnc(-c2ccc(N)c(C#N)c2)c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccc3)c(C#N)c2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
131 mg of methyl 2-(4-amino-3-cyanophenyl)isonicotinate and 67 μl of 2,5-dimethoxytetrahydrofuran were dissolved in 1.3 ml of acetic acid solution, followed by heating and stirring at 100° C. for 4 hours. The solution was poured into water, followed by extraction with ethyl acetate. The solvent of the organic layer was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 to 1:1) to obtain 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].ClCCl>C(O)C.O1CCOCC1.[Pd]>[CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@H](C3CCCCC3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCO
Product: C1CCC([C@H]2CC[C@H](N3CCNCC3)CC2)CC1

Procedure:
To a solution of benzyl 4-(trans-4-cyclohexylcyclohexyl)-1-piperazinecarboxylate (4 g) in ethanol (40 ml) and dioxane (40 ml) was added 10% palladium on carbon (0.8 g), and hydrogen gas at atmosphere pressure for 7 hours. To the reaction mixture was added dichloromethane (40 ml). The reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to give 1-(trans-4-cyclohexylcyclohexyl)piperazine (1.56 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>>[NH2:15][CH2:11][C:10]1([OH:12])[CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: N
Product: NCC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane (U.S. Pat. No. 4,508,724) are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH:13]=2)=[N:6][C:5]2[N:18]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:20][C:4]=2[C:3]=1[C:24]([OH:26])=O.[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CS(C)=O.CO.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:14])([CH3:15])[CH:13]=2)=[N:6][C:5]2[N:18]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:20][C:4]=2[C:3]=1[C:24]([NH:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35])=[O:26]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)c(Cl)c(C3=CC(C)(C)NC(C)(C)C3)nc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2c(Cl)c(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 12 h
Yield: 26 %

Procedure:
A solution of 5-chloro-1-isopropyl-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.07 g, 0.18 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.056 g, 0.372 mmol) in DMSO (1 mL) and was stirred at room temperature for 15 min. Then PyBOP (0.145 g, 0.279 mmol) was added to it and stirring was continued for 12 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound (26% yield). LCMS: 511.20 (M+1)+; HPLC: 91.79% (@ 254 nm) (Rt; 4.914); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.74 (d, 3H, J=4 Hz), 8.05 (s, 1H), 6.06 (s, 1H), 5.89 (s, 1H), 5.15-5.08 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 2.59 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H), 1.54 (s, 6H), 1.49 (s, 6H), 1.48 (d, 6H, J=7.6 Hz).