Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].P([CH2:11][C:12]#[N:13])(OCC)(OCC)=O.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][C:22](=O)[C:18]=2[CH:17]=1>C1COCC1>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH:21]=[C:22]([CH2:11][C:12]#[N:13])[C:18]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)CO2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2occ(CC#N)c2c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Under inert atmosphere, 83 mmol of sodium hydride are suspended in 100 ml of anhydrous THF. The temperature is cooled at -15° C. and 83 mmol (14.7 g) of (EtO)2POCH2CN in 50 ml of 1BF are dropply added. Then 55 mmol (9 g) of compound obtained in stage A in 100 ml of THF are dropwised at -15° C. The solution is stirred during 2 hours at that temperature before being hydrolysed. The mixture is extracted with ethyl acetate and the organic layers are washed with brine, dried over magnesium sulfate and concentrated. The title product is obtained after purification by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:24]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[NH:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(ccn2-c2ccc(N)nc2)c1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2-c2ccc(N)nc2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of compound 76 (120 mg, 0.53 mmol) in EtOH (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (183 mg, 0.64 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then the suspension was diluted with CH2Cl2 (50 mL) and treated with saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional CH2Cl2 (50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel (MeOH:CH2Cl2, 5:95 to 2M NH3 in MeOH:CH2Cl2, 5:95) to give compound 77 (86 mg, 48.9%) as a yellow solid. HPLC analysis indicated that the product is >99% pure. 1H NMR (DMSO-d6) δ 8.06 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.42 (d, J=3.0 Hz, 1H), 7.11-7.06 (m, 2H), 6.71 (d, J=8.9 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=3.0, 1H), 6.30 (brs, 2H), 6.16 (brs, 2H); ESI-MS (m/z, %): 334 (M+1, 100%); ESI-HRMS calculated for C18H16N5S (MH+): 334.1120, observed: 334.1135.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[CH3:20][C:19]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:12][C:11]=2[N:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(=O)CC(c2ccncc2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
To a mixture of 5-(4-pyridyl)cyclohexane-1,3-dione (0.90 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 15 hours and cooled, insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 3.5 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) to give oil of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[O:21]1[CH2:20][CH:19]1[CH2:17][O:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1O
Reactant: BrCC1CO1
Product: COC(=O)CCC(=O)c1ccc(C)cc1OCC1CO1

Procedure:
Methyl 3-(2-hydroxy-4-methylbenzoyl)propionate was reacted wtih epibromohydrin in a similar manner to the procedure described in Example 1 (ii) to give methyl 3-[2-(2,3-epoxypropoxy)-4-methylbenzoyl]propionate, m.p. 61.5°-63°.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1>CO>[C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccccc2)c1

Procedure:
0.90 g of methyl 3-phenylbenzoate was fed into 20 ml of a solvent mixture of aqueous solution of 2 M of sodium hydroxide, tetrahydrofuran and methanol (4/2/1) to conduct the reaction at 70° C. for 2 hours. The solvent was evaporated, and the residue was fed into 3 M of hydrochloric acid. The precipitate thus formed was taken by the filtration and dried to obtain the title compound in the form of white crystals.
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][CH2:10][NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([N:11]1[C@H:12]2[C@H:8]([CH2:7][C:4]3([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=42)[CH2:5][CH2:6][N:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3]3)[CH2:9][CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CCN[C@@H]1c1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@H]2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3[C@H]21

Procedure:
The product of Step 2 (52 mg) was dissolved in dichloromethane (10 ml), treated with triethylamine (0.07 ml) and acetyl chloride (0.014 ml) for 1 h. The reaction mixture was diluted with dichloromethane, washed with water. The organic phase was concentrated to give (3aR,9bS)-tert-butyl 1-acetyl-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 14 (47 mg). LC-MS: m/e=329.6 (M+-tBu, 100%). Rt=3.21 min.
Reaction SMILES: Cl.Cl.Cl.[Br:4][C:5]1[C:6]([C:22]2[S:26][C:25]3[C:27](OC)=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[N:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:9][CH:10]=1.[Cl:33]C1C2SC=CC=2C=CC=1>>[Br:4][C:5]1[C:6]([C:22]2[S:26][C:25]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[N:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)sc12
Reactant: Clc1cccc2ccsc12
Agent: Cl
Product: CN1CCN(CCCNc2ncc(Br)c(-c3cc4cccc(Cl)c4s3)n2)CC1

Procedure:
Using the methods of [5-bromo-4-(7-methoxybenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is synthesized from 7-chloro-benzo[b]thiophene and isolated as a solid. ES+(m/z) 480 (35Cl, 79Br), 482 (37Cl, 79Br or 35Cl, 81Br) and 484 (37Cl, 81Br) [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:28]=2)[N:14]=1>CCOC(C)=O.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[CH:28]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A134) (392 mg, 0.671 mmol) in EtOAc (40 mL) and DMF (2 mL) was stirred with 10% Pd/C (wetted with ca. 53% water, 100 mg) under a hydrogen atmosphere at room temperature overnight. The mixture was filtered through Celite and the filter cake was washed with EtOAc (50 mL). The volatiles were removed in vacuo and the resulting yellow oil was adsorbed onto silica gel and purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the title compound (A135) as a yellow solid (300 mg, 76%), 1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 7.85 (s, 1H), 7.64-7.46 (m, 1H), 7.22-7.06 (m, 4H), 4.32-4.04 (m, 3H), 3.67 (s, 2H), 3.60 (s, 3H), 3.14-2.94 (m, 4H), 2.87-2.75 (m, 2H), 2.14-1.99 (m, 2H), 1.97-1.79 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=O)[CH2:30][CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:34]([CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C3CCN(C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-1-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 1-methyl-4-piperidinecarboxylic acid, the title compound was obtained in 85% yield (96.9% purity by HPLC).
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH:7]([C:9](=[O:11])[CH3:10])[CH:6]([CH3:12])[CH2:5]1)([CH3:3])[CH3:2].O1CCC(=O)[CH2:15][CH2:14]1>>[CH:1]([CH:4]1[CH2:8][CH:7]([C:9]([OH:11])([C:14]#[CH:15])[CH3:10])[CH:6]([CH3:12])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)C1CC(C(C)C)CC1C
Reactant: O=C1CCOCC1
Product: C#CC(C)(O)C1CC(C(C)C)CC1C

Procedure:
The title compound was prepared according to the procedures described in Example 6A, substituting 1-(4-isopropyl-2-methylcyclopentyl)ethanone (prepared as described in Roger, A. et al. Bull. Soc. Chim. Fr. 1967, 3030-3037) for tetrahydro-4H-pyran-4-one used in Example 6A.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:23])[CH:20](O)[CH3:21])[CH3:17].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])(=[O:5])=[O:4]
Reactant: CCOC(=O)C(C)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of trifluoromethanesulfonic anhydride (30 mL, 170 mmol) in anhydrous dichloromethane (50 mL) was added drop-wise a solution of 2-hydroxypropanoic acid ethyl ester (20 g, 170 mmol) and pyridine (14 mL) in dichloromethane (50 mL) at 0° C. (Ice bath) over a period of 1 h under nitrogen. The ice bath was then removed and the reaction mixture was stirred for additional 2 h. The inorganic salt was then filtered off and the organic solution was washed with water, dried over sodium sulfate, and evaporated to give desired product as pink colored oil (37.4 g, 88%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.38 (t, J=4.8 Hz, 3H), 1.77 (d, J=4.8 Hz, 3H), 4.32-4.37 (m, 2H) and 5.28 (q, J=6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([O:11][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Cn1cncn1)(C(=O)OCc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL flask stirring under nitrogen was charged 4.19 g (0.015 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]-butanoic acid in 75 mL of methyl ethyl ketone. To the slurry was added 2.83 g (0.0157 mole) of potassium carbonate and the mixture was heated to reflux. After 30 minutes, 2.56 g (0.01575 mole) of benzyl bromide was added and the mixture was stirred at reflux for 2 hours then at 50° C. for 12 hours. After monitoring by GLC showed the consumption of starting material, the reaction was quenched by adding 20 mL of saturated sodium bicarbonate and 100 mL of ether. The phases were separated and the ether phase was washed with saturated sodium bicarbonate (2×50 mL) then with 50 mL of brine, dried and concentrated, giving 4.26 g (77% yield) of a thick oil, Example 177 of Table 1.
Reaction SMILES: [N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@@H:36]([C:47](O)=[O:48])[CH2:37][C:38]3[CH:43]=[C:42]([Br:44])[C:41]([OH:45])=[C:40]([Br:46])[CH:39]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:50]=[CH:51][CH:52]=[CH:53][C:22]=2[NH:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@H:36]([CH2:37][C:38]3[CH:39]=[C:40]([Br:46])[C:41]([OH:45])=[C:42]([Br:44])[CH:43]=3)[C:47]([N:10]3[CH2:11][CH2:12][CH:7]([CH:4]4[CH2:5][CH2:6][N:1]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:48])=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:50]=[CH:51][CH:52]=[CH:53][C:22]=2[NH:21]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
208 mg (0.82 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added to a solution of 500 mg (0.82 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 315 mg (0.98 mmol) TBTU and 150 μL (1.06 mmol) triethylamine in 5 mL DMF and the reaction mixture was stirred overnight at RT. To complete the reaction a further 315 mg (0.98 mmol) TBTU, 150 μL (1.06 mmol) triethylamine and 208 mg (0.82 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added and the mixture was again stirred overnight at RT. The reaction mixture was purified directly by HPLC without any further working up. The fractions containing the product were combined, evaporated down i.vac., neutralised with saturated NaHCO3 solution, the aqueous phase was extracted twice with 100 mL DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried in the air.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[C:12]1[CH:32]1[CH2:34][CH2:33]1)C.[Li+].[OH-]>C1COCC1.O>[CH:32]1([C:12]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])[C:15]3=[N:16][C:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=[C:14]3[CH:13]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCn1c(C2CC2)cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C

Procedure:
7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (step 1)(250 mg, 0.535 mmol) in THF (6 ml) and water (2 ml) was treated with LiOH.monohydrate (45 mg, 1.069 mmol) and stirred at room temperature for 12 hours followed by heating at 60° C. for 10 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether (×1). The aqueous was acidfied using citric acid, and extracted with EtOAc. The organic solvent was dried (Na2SO4) and the solvent was removed under reduced pressure. Purification of the product by chromatography on silica eluting with 1% MeOH in DCM, followed by further purification using preparative HPLC according to the following conditions to afforded the titled compound;
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+]>[C:14]1([NH:20][C:21](=[O:22])[NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[O:6][CH2:5][C:2]([OH:4])=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Reactant: O=C=Nc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CO[C@@H]1CCCC[C@H]1NC(=O)Nc1ccccc1
Yield: 39.3 %

Procedure:
To a solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (0.419 g, 2 mmoles) in 2N NaOH (10 ml), phenylisocyanate (0.476 g, 4 mmoles) was added under stirring. After 1 hour the solution was extracted with diethyl ether (10 ml) and the aqueous phase was acidified with HCl 18% to pH 3. The title compound separated in the form of white crystals, which were filtered off and dried over P2O5. Thus, there were obtained 0.23 g (40%) of the title compound, melting point 166°-168° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:18]1[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=1)=[O:12]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in toluene (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure to give 2.76 g of 6-bromo-1-(4-methylphenyl)-1-hexanone.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:10]1([C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:9])[CH2:23][CH2:22]3)=[O:20])=[CH:28][CH:29]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Reactant: O=C(O)c1cccnc1
Product: O=C(NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1)c1cccnc1

Procedure:
In a manner similar to that described in Example 4, nicotinic acid and 1-[4-(1H-imidazol-1-yl)benzoyl]-4-piperidinamine are converted to the title compound.
Reaction SMILES: CO.C[C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[CH:8]=[N:7][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:5][CH:4]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(F)ccc2[nH]c(-c3cnc(NCCCC4CCN(C)CC4)nc3)nc12
Reaction time: 0.5 h

Procedure:
A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:13]([NH:15][C@H:16]([C:32](O)=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:47][CH:48]([CH2:57][CH:58]([CH3:60])[CH3:59])[CH:49]([OH:56])[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:56][CH:49]([CH:48]([NH:47][C:32](=[O:33])[CH:16]([NH:15][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:57][CH:58]([CH3:60])[CH3:59])[C:50]([O:52][CH:53]([CH3:54])[CH3:55])=[O:51]
Reactant: O=C(NCCCC[C@H](NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CC(C)CC(N)C(O)C(=O)OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Temperature: -10 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
N-[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, 4 g (6.6 mmol), 1.58 g (6.6 mmol) of [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride, and 1.79 g (13.2 mmol) of 1-hydroxybenzotriazole are combined in 80 ml of dimethylformamide. The [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride is neutralized with 1.4 ml (10.1 mmol) of triethylamine. The solution is cooled to -10° C. and 1.36 g (6.6 mmol) of dicyclohexylcarbodiimide is added with stirring. The reaction mixture is kept cold for 8 hours while stirring under nitrogen, allowed to warm to room temperature overnight, filtered, the filtrate concentrated and the residue partitioned between ethyl acetate and water. The organic layer is separated and extracted with saturated solution of sodium bicarbonate, dried (sodium sulfate), filtered and concentrated. The residue is flash chromatographed over silica gel 60 (230-400 mesh), eluted with hexane-ethyl acetate (2:3), the eluates collected, dissolved in diethyl ether, filtered and the filtrate concentrated to afford 4.01 g (77%) of the title compound as a white amorphous solid.