Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl.[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36](O)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.[N-]=[N+]=[N-]>CN(C)C=O>[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36]([NH:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: NC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](N)C1CCCCC1
Reactant: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 82.4 %

Procedure:
Stir overnight H-(L)-Chg-(L)-Pal-NH2.2HCl (1.13 g, 3 mmol), Ac-(L)Phe(4-CN)-OH (0.84 g, 3.6 mmol), diisopropylethylamine (10 mmol). and diphenylphoshoryl azide (803 μl 3.6 mmol) dimethyl formamide (30 mL) overnight. Evaporate dimethyl formamide, precipitate by ether, filter and wash by ether to give Ac-(L)-Phe(4-CN)-(L)-Chg-(L)-Pal-NH2 (1.282 g, 82%). ##STR21##
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCNCC1
Yield: 76 %

Procedure:
A solution of the ester 2 from above (66 g, 227.27 mmol) in 1 l of ethanol is hydrogenated under normal pressure with 10 g of Pd/C (10%) for 16 hours at room temperature. The mixture is filtered over celite and evaporated under reduced pressure. Recrystallisation from ether gave 34.5 g (76%) of white crystals.
Reaction SMILES: N1([N:7]=[CH:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)CCCCC1.C1COCC1.C(O)C.[ClH:41]>C(OCC)(=O)C.[Pd]>[ClH:41].[ClH:41].[NH:12]1[CH:13]=[C:9]([CH2:8][NH2:7])[N:10]=[CH:11]1
Reactant: C(=NN1CCCCC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1c[nH]cn1
Temperature: 80 °C
Yield: 29 %

Procedure:
To a solution containing 450 mg of piperidin-1-yl-(1-trityl-1H-imidazol-4-yl-methylene)amine in 3.5 mL of 3N hydrogen chloride in ethyl acetate are added 90 mg of 10% Pd/C, 0.5 mL of THF and 0.9 mL of ethanol. The reaction medium is placed under a hydrogen pressure of 6 bar and heated at 80° C. for 3 hours. After filtering off the catalyst and evaporating off the solvents, the crude product obtained is chromatographed on silica gel (eluent: 6/4 DCM/MeOH). 50 mg of C-(1H-imidazol-4-yl)methylamine dihydrochloride in the form of a white powder are obtained in a yield of 29%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:19]=1.O1CCOCC1.O>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:7][C:8]1[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Brc1ccnc(NC2CCOCC2)c1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccnc(NC3CCOCC3)c2)ccn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
Sodium carbonate (0.989 g, 9.33 mmol) was added to 2-fluoropyridin-4-ylboronic acid (0.570 g, 4.04 mmol) and 4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (0.80 g, 3.11 mmol) in 4:1 dioxane/water (25 mL), and the suspension was purged with nitrogen. PdCl2(dppf)*DCM (0.127 g, 0.156 mmol) was added, and the mixture was heated at 80° C. under nitrogen. After agitating for 6 hours, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate (2×). The extract was washed with water, brine, dried and evaporated. Purified by chromatography on silica gel, eluted with 50-70% ethyl acetate/hexane to give 2′-fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4′-bipyridin-2-amine (0.64 g, 2.34 mmol, 75.3% yield) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:9][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CCc1cc(O)cc(CC)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
To a solution of 2′,6′-diethyl-4′-hydroxybiphenyl-3-carbaldehyde (2.44 g, 9.59 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.73 g, 12.5 mmol), and the mixture was stirred at 90° C. for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[CH:3]=1)[CH3:14]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: CCOc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1cncc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 82.5 °C
Yield: 88.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-3-ethoxypyridine (1.20 g, 5.94 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.18 g, 5.94 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol), tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.5 mL, 10.8 mmol), and anhydrous acetonitrile (3 mL) was stirred and heated under reflux at 80-85° C. for 28 h. The resulting mixture, containing beige solids, was cooled to ambient temperature, diluted with water (20 mL), and extracted with CHCl3 (3×20 mL). The combined light-yellow CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried producing a yellow oil (1.69 g). The crude product was purified by column chromatography on silica gel (100 g), eluting with ethyl acetate-hexane (1:1, v/v). Selected fractions containing the product (Rf 0.20) were combined, concentrated by rotary evaporation, and the residue was vacuum dried to give 0.67 g (35.2%) of a light-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][O:28][CH3:29].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][O:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (1.04 mL, 7.51 mmol) was added to a chilled (0°) solution of 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) in chloroform (75 mL). 4-Morpholinecarbonyl chloride (830 mg, 5.51 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and was maintained over the weekend. An equal volume of aqueous 1% sodium carbonate was added with vigorous stirring. A precipitate was isolated by filtration to provide 1.73 g of crude product as a white powder. This material was purified by column chromatography (silica gel eluting with a 0-5% methanol in chloroform gradient) and then triturated with diethyl ether to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194.0-196.0° C. Analysis: Calculated for C21H28N6O3: %C, 61.15; %H, 6.84; %N, 20.37; Found: %C, 60.82; %H, 6.94; %N, 20.34.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([C:23](=[O:28])[C:22]([F:30])([F:29])[F:21])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(Br)ccc2N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A 15] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=473 (M+H).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][NH:25][C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN[C@@H](C(N)=O)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@@H](C(N)=O)C1
Yield: 803.6 %

Procedure:
Molecular sieves (0.5 g) followed by aqueous formaldehyde (1 ml) were added to a stirred solution of (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (9) (0.102 g, 0.23 mmol) in DCM-AcOH (10:1 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (0.10 g, 0.463 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (20 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by preparative LCMS (standard basic conditions) to give the title product as a white solid (0.85 g, 80%): 1H NMR Spectrum: (DMSO d6) 1.87-1.92 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.43-2.47 (m, 1H), 2.71-2.80 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.03 (s, 1H), 7.23 (s, 1H), 7.26-7.30 (m, 2H), 7.47-7.54 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 459.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[C:13](OCC)=[O:14])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[CH2:13][OH:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(C)nc1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(F)cc2)c(CO)s1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Ethyl 4-(4-fluorophenyl)-2-methyl-5-thiazolecarboxylate (59 g) prepared by a known method (Chem. Pharm. Bull., 43(6), 947, 1995) was dissolved in tetrahydrofuran (700 ml). Lithium aluminum hydride (13 g) was added under ice-cooling and the mixture was stirred for 30 min. Water (13 ml), 15% sodium hydroxide (13 ml) and water (39 ml) were added successively to the reaction mixture, and the precipitated insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to give the title compound (37 g, yield 71%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[NH2:20][C:21]1[C:29]2[NH:28][CH:27]=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[NH:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:29]=2[N:28]=[CH:27]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2nc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2[nH]cnc12
Yield: 63.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 130 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 113 mg of 4-aminobenzimidazole hydrochloride and 127 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 80 μl of pyridine and 2.0 ml of N,N-dimethylformamide. 112 mg of N-(1H-benzimidazol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[F:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 mg, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-4-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=452.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4]>C1COCC1>[OH:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CC1
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.44 g, 29.2 mmol) in dry THF at −78° C., was added borane-methyl sulfide complex (19.0 mL, 38.0 mmol) dropwise over 20 min. The mixture was stirred for 3 h and was then allowed to slowly attain r.t. The reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc. The organic phase was washed once with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (4.80 g, 95% yield) as a mixture of two diastereomers: MS (EI) m/z 172 M.
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1.[O-]CC.[Na+].O>O1CCOCC1.CS(C)=O.C(O)(=O)C>[CH:1]1([C:7]([CH:12]2[CH2:13][CH2:14][O:15][C:11]2=[O:16])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCO1
Reactant: COC(=O)C1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C1OCCC1C(=O)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
In a similar method as for example 7, the beta keto ester of alpha-cyclohexylcarbonyl-gamma-butyrolactone is prepared (see also compound IVa in Chem. Pharm. Bull. 37(4), 958-961, 1989 by Uchida et al.): methyl cyclohexanecarboxylate (30 g) and gamma-butyrolactone (26.7 g, 1.5 moleq.) are dissolved in 120 mL of dry dioxane and 20 mL of dry dimethyl sulfoxide. Sodium ethoxide (35.4 g, 2.5 moleq.) is added and the mixture is stirred overnight under N2 at a temperature of 100° C. The mixture is then cooled to ˜50-60° C. and ca. 400 mL H2O is added. The aqueous layer is brought to pH=6 with acetic acid, and is extracted with three 100 mL portions of chloroform (careful; CO2 formation). The organic layer is washed with H2O, thereafter with a NaHCO3-solution and finally with brine (a saturated NaCl solution), and is then dried with Na2SO4. Evaporation of the volatiles gives a ca. 85% yield of an oil. This crude beta-keto-ester (34 g) and guanidinium carbonate (31.2 g; 2 moleq. of guanidine) are stirred in ethanol (200 mL). To this mixture, that is heated to 50° C. and that is kept under an argon atmosphere, a 30 (w/w) % sodium methoxide solution in methanol (18.7 g of NaOMe in 65 mL of solution; 2 moleq. of NaOMe) is added drop wise. The mixture is heated overnight at an oil bath temperature of 90° C., is then evaporated down and water is added to the residue. The pH of the mixture is adjusted to 6 by addition of an HCl solution (careful; CO2 formation), and the resulting suspension is filtered. The residue is washed with several portions of water and dried in vacuo to give a white powder in a 70% yield. 1H NMR (200 MHz, DMSO-d6): δ 10.6 (1H), 6.2 (2H), 4.6 (1H), 3.3 (2H), 2.5 (3H), 2.0-1.0 (10H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:13]([O:20][C:21]1[CH:48]=[CH:47][C:46](Br)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:48]=[CH:47][C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Piperidine (0.040 mL), cesium carbonate (0.18 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) suspension of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then piperidine (0.040 mL), cesium carbonate (0.18 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-70% hexane/ethyl acetate] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate as an orange oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].[CH3:33][N:34]([C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)[NH2:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Li+]>ClCCCl.[Cl-].[Na+].O.O.CO>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:18]([CH:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH:11]2[CH2:16][CH2:15][CH:14]([NH:35][N:34]([CH3:33])[C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[CH2:13][CH2:12]2)[CH:8]=1
Reactant: CN(N)c1cnccn1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(NN(C)c3cnccn3)CC2)CC1
Reaction time: 5 h
Yield: 9.1 %

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) and N-Methyl-N-pyrazin-2-yl-hydrazine (41 mg, 0.33 mmol) in DCE (2 mL) was treated with AcOH (100 μL, 1.5 mmol) followed by NaBH(OAc)3 (120 mg, 0.5 mmol) in two portions. After 5 h, NaHCO3 (saturated aqueous solution, 2 mL) was added to the mixture, followed by brine (20 mL), and the crude product was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated and the crude material was dissolved in a 3:2:1 mixture of THF:MeOH:water (20 mL), treated with lithium hydroxide (1.1 mmol, 46 mg) and heated to 60 deg C. for 1 hours. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 11 mg of the title compound as its trans isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 26.05 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient) and 7 mg of the title compound as its cis isomer (TFA salt): MS (m/z): 552.2 [M−H]+; HPLC retention time: 24.38 min (Phenomenex Luna C18, 2-98% acetonitrile:water with 0.1% trifluoroacetic acid, 30 min gradient).