Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:24]1([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I98) (34 mg, 0.057 mmol) was dissolved in DCM (4 mL) and TFA (0.4 mL) was added. The resulting mixture was stirred for 16 hours at room temperature then concentrated under reduced pressure. The residue was suspended in 10% aqueous NaOH (2 mL) and brine (3 mL) then extracted with ethyl acetate (4×5 mL). The combined organic phases were washed with brine, dried (sodium sulphate) and evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (25) (27.5 mg, 98%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.72-7.66 (m, 2H), 726-7.20 (m, 3H), 7.20-7.13 (m, 3H), 6.90 (s, 1H), 3.49 (s, 2H), 3.37 (s, 2H), 3.14-2.98 (m, 4H), 2.67 (t, J=4.7 Hz, 4H), 2.26 (s, 4H). LCMS Method C: rt 4.52 min; m/z 499.1 [M+H]+; m/z 497.1 [M−H]−.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>C(O)(=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][C:17]2[NH:2][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][C:12]=3[C:16]=2[CH2:15]1
Reactant: CC1CCC(=O)CC1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2[nH]c3c(C(=O)O)cccc3c2C1
Yield: 87.2 %

Procedure:
A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (20 ml) was slowly boiled under stirring and 1.2 ml (9.8 mmol) of 4-methylcyclohexanone was dropped thereinto. The obtained mixture was heated under reflux for 8 hours and then allowed to cool. After adding water, the precipitate thus formed was recovered by filtration, washed with water and dried to thereby give 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylic acid. This product was dissolved in acetone (50 ml) and 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added thereto. The reaction mixture was heated under reflux under stirring for 2 hours, then allowed to cool and extracted with water and ethyl acetate. The organic layer was taken up, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus 1.49 g of methyl 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate was obtained. This product was suspended in diphenyl ether (10 ml) and 890 mg of 10% palladium-carbon was added thereto. The obtained mixture was heated under reflux under stirring in a nitrogen atmosphere for 1 hour. After allowing to cool, It was dissolved by adding tetrahydrofuran. Then the catalyst was filtered off and the filtrate was concentrated. After adding n-hexane, the crystals thus formed were recovered by filtration to thereby give 1.26 g of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=4)[C:25]4[C:30]([CH:31]=3)=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)=[O:22])[CH:17]=[CH:16][N:15]2[CH:44]=1)=O)C.O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:10][C:12]1[N:13]=[C:14]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=4)[C:25]4[C:30]([CH:31]=3)=[CH:29][C:28]([C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=4)=[O:22])[CH:17]=[CH:16][N:15]2[CH:44]=1
Reactant: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)ccc4n3Cc3cccc(F)c3)cc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccn2cc(CO)nc2c1)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Temperature: -5 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To 0.47 mL (0.47 mmol) of a molar solution of LiAlH4 diluted in 1 mL of anhydrous THF, cooled to −5° C., is added dropwise by syringe a suspension of 190 mg (0.36 mmol) of N-[2-(ethyloxycarbonyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.3, in 4 mL of anhydrous THF. After stirring for 3 hours at room temperature, the reaction medium is poured slowly into a mixture (v/v) of water and concentrated sodium hydroxide, and is then extracted with 3×100 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. The crude reaction product obtained is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 30 mg of the expected product are thus obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]12CC(CC1)C[CH:24]2N>>[CH:5]12[CH2:4][CH:3]([CH2:23][CH2:24]1)[CH2:2][CH:1]2[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: NC1CC2CCC1C2
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CC3CCC2C3)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using bicyclo[2.2.1]hept-2-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.80-0.94 (m, 1H), 0.98-1.06 (m, 1H), 1.10-1.19 (m, 1H), 1.26-1.36 (m, 2H), 1.48-1.56 (m, 1H), 1.65-1.77 (m, 1H), 1.93 (s, 3H), 2.07 (s, 3H), 2.12-2.20 (m, 1H), 2.22-2.30 (m, 1H), 2.50-2.58 (m, 1H), 3.70-3.80 (m, 1H) 4.42-4.51 (m, 2H), 7.20-7.27 (m, 1H) 7.50-7.58 (m, 1H), 7.68-7.80 (m, 1H), 8.65 (d, J=4.92 Hz, 1H); MS (ESI) m/z 324.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>>[CH3:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:5]2[N:4]=[C:3]([O:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[C:2]([Br:1])=[CH:7][N:6]=2)[CH2:26][CH2:25]1
Reactant: C[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(Cl)ncc2Br)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1

Procedure:
Using the procedure of Example 1 Step 2, (R)-tert-butyl 3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate was reacted with cis-4-methylcyclohexanamine to provide the title compound at 55% yield. 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 5.13 (sb, 1H), 4.28 (m, 2H), 3.96 (m, 1H), 3.60-3.15 (m, 4H), 2.66 (m, 1H), 2.02 (m, 1H), 1.77-1.58 (m, 7H), 1.44 (s, 9H), 1.28-1.16 (m, 3H), 0.91 (d, 3H); MS (ESI) m/z: Calc: 544.2 (M+). Found. 545.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2C=CC=CC=2)=[CH:6][CH:5]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>>[NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Yield: 100 %

Procedure:
As a comparative example, Tyr(Bzl) was treated with a deprotecting reagent of 1M trimethylsilyltrifluoromethanesulfonate and thioanisle/trifluoroacetic acid from which anisole is removed to get Tyr. The yield of Tyr after 10 minutes was 64% and the formation of 3-Bzl-Tyr due to rearrangement was observed. The same reaction was repeated except that hydrogen fluoride was used in place of trimethylsilyltrifluoromethanesulfonate, then Tyr was recovered in an yield of approximately 100% within 10 minutes. However, the product contained 35% of 3-Bzl-Tyr as a by-product.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[O:20])[CH2:13][CH2:12]1>C1COCC1>[OH:20][CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]1)[CH:5]1[S:6][CH2:7][CH2:8][NH:3][C:4]1=[O:9]
Reactant: O=C1CSCCN1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C(O)C2SCCNC2=O)CC1
Temperature: 25 °C

Procedure:
Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) was washed with hexanes under a nitrogen atmosphere and suspended in 100 mL of anhydrous THF. Thiomorpholin-3-one (1.0 g, 8.55 mmol) was added, followed immediately by 2-(4-methylpiperazin-1-yl)-benzaldehyde (1.58 g, 7.75 mmol). The reaction was then heated to reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous ammonium chloride (NH4Cl) and saturated brine and then dried with MgSO4. Purification using flash chromatography gave 2-{hydroxy-[2-(4-methylpiperazin-1-yl)phenyl]-methyl}-thiomorpholin-3-one as a white solid, m.p. 137-139° C. Mass spectrum 322 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([OH:21])=O.[N:22]1([CH2:28][CH2:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C@H:36]([NH2:40])[CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[C@@H:3]1[CH2:18][C:19]([NH:40][C@H:36]1[C:37]2[C:32](=[CH:31][C:30]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:39][CH:38]=2)[CH2:33][CH2:34][CH2:35]1)=[O:21]
Reactant: N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(CCN4CCCCC4)ccc32)cc1

Procedure:
A solution of (R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (310 mg, 1.0 mmol), crude (R)-6-(2-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (310 mg, 1.2 mmol), HOBt (135 mg, 1.0 mmol) and EDCI (191 mg, 1.0 mmol) in 1 mL of DMF was stirred overnight at room temperature. After quenching with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, EtOAc/MeOH=100:15 to 100:20 to EtOAc/2.0M NH3 in MeOH=100:10 to 100:15 to 100:20 ) gave the desired product as a white solid. MS: 551.2 (M+1).
Reaction SMILES: [SiH3][O:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1>>[S:11]1[CH:10]2[C:5]([CH2:6][NH:7][CH2:8][CH2:9]2)=[CH:4][C:3]1=[O:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: [SiH3]Oc1cc2c(s1)CCNC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1C=C2CNCCC2S1

Procedure:
In the following, Reaction 2 and Reaction 3 are explained by Examples 5 to 17. In this case, yield means yield of 5-alkyl-2-silyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (mole) or 2-silyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (mole) based on 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2one.p-toluenesulfonate (mole).
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([CH2:10][CH2:11][O:12][CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:8]=[N:9][C:4]2=[C:3]([NH2:18])[N:2]=1.[CH2:19]([O:35][CH2:36][CH2:37][CH2:38]O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH3:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:35][CH2:36][CH2:37][CH2:38][O:15][P:14]([OH:17])([CH2:13][O:12][CH2:11][CH2:10][N:7]1[C:5]2[N:6]=[CH:1][N:2]=[C:3]([NH2:18])[C:4]=2[N:9]=[CH:8]1)=[O:16]
Reactant: CCCCCCCCCCCCCCCCOCCCO
Reactant: Nc1ncnc2c1ncn2CCOCP(=O)(O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCCCOP(=O)(O)COCCn1cnc2c(N)ncnc21
Reaction time: 18 h

Procedure:
To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder.
Reaction SMILES: [C:1]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][OH:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[K+].[Br-].C1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(O)C=1>C(Cl)Cl.CO>[C:1]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH:18]=[O:19])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1C(=O)N1CCC[C@H]1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: O=CC1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.03 g (3.3 mmol) of the title compound of Example 28 was dissolved in 50 ml of methylene chloride at room temperature under a nitrogen atmosphere. 3.76 g (10.0 mmol) of pyridinium dichromate and 4 g powdered 4A molecular sieves were added, and the reaction was allowed to stir at ambient temperature for 3 hours. The sieves and precipitated salts were then removed by filtration and the filtrate washed with water, 5% sodium bicarbonate solution and 1N HCl solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a dark brown oil which crystallized on standing. The crude product was heated in 1:1/ethyl acetate:methylene chloride with enough methanol added for the crude product to go into solution and decolorized with activated charcoal. The title compound was recrystallized from 1:1/ethyl acetate:ether to yield 0.24 g (24%). TLC: (90:10/CH2Cl2 :MeOH): Rf =0.80. mp=158-160. 1H NMR (CDCl3) δ: 9.42(s); 9.32 (s,1H); 7.32-7.85(m,9H); 4.20-4.50(m,1H); 3.32-3.70(m,2H) 1.70-2.30(m,4H). IR (KBr): 1578, 1590, 1613, 1725 cm-1. Standard Combustion Analysis Calculated: C,74.25; H,5.58; N,4.56. Found: C,73.66; H,5.64; N,4.65. High Resolution Mass Spectrum: m/e=308.1291±0.4 ppm (calculated for C19H18NO3). 2,4-DNP test: positive.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34].C(N(C(C)C)CC)(C)C>ClCCl.O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:33]([C:32]2[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:40])=[O:34])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (19.0 mmol, 8.37 g) and 2,6-dichlorobenzoyl chloride (21 mmol, 4.4 g) in dichloromethane (90 mL) was added diisopropylethylamine (32.3 mmol, 5.6 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water (100 mL) and the two layers were separated. The aqueous phase was extracted with dichloromethane (100 mL) and the combined extracts were washed with brine (200 mL). The dried (MgSO4) solution was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with (hexane:ethyl acetate:dichloromethane, 1:1:1) to obtain 11.54 g (99%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as a colorless solid, mp 200-202° C. HRMS: Obs. mass, 613.1367. Calcd. mass, 613.1363 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Clc1cc(N2CCNCC2)nc(Cl)n1
Reactant: C1CCNC1
Product: Clc1nc(N2CCCC2)cc(N2CCNCC2)n1

Procedure:
After adding 2.00 g (3.81 mmoles) of 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(2,4-dichloro-6-pyrimidinyl)piperazine in small portions to 20 ml of pyrrolidine at a temperature below 10° C., the reaction mixture is stirred at room temperature for 1 hour, then evaporated. After distributing the evaporation residue between 40 ml of chloroform and 10 ml of 1% sodium hydroxide solution the organic phase is separated, dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column. By using a 99:1 mixture of chloroform and methanol the less polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(4-chloro-2-pyrrolidino-6-pyrimidinyl)piperazine is first eluted from the column, which is recrystallized from a mixture of ether and hexane to give a yield of 2.01 g (88.2%), m.p.: 210°-220° C. By further elution the more polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(2-chloro-4-pyrrolidino-6-pyrimidinyl)piperazine is obtained which is similarly recrystallized from a mixture of ether and hexane to give a yield of 0.13 g (5.7%), m.p.: 169°-200° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[CH:26][C:25](Br)=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[CH:26][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: OB(O)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(-c3ccccc3)ccc2s1
Temperature: 80 °C

Procedure:
0.15 ml of 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) of PdCl2(dppf) are added to a mixture of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 14A) and 12.1 mg (0.10 mmol) of phenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 14 h, filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 7.3 mg (18% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:48]C1C=CC=CC=1C(O)=O>>[Br:48][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)c1ccccc1Br
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-benzoic acid (CAS Reg. No. 88-65-3). Colorless powder (75%). MS (Turbo Spray): m/z=309.2 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH2:25]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C)cc21
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.68 g) and 10% palladium on carbon (0.30 g) in MeOH (15 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.50 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2](Cl)([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:9])[C:3]([O:5]CC)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([CH3:1])[C:3]1=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=C(c1ccccc1)C(C)(Cl)C(=O)OCC
Reactant: NCc1ccccc1
Product: CC1=C(c2ccccc2)CN(Cc2ccccc2)C1=O

Procedure:
Generally following the procedures of the preceding examples, ethyl 2-methyl-2-chloro-3-phenyl-3-butenoate (R=phenyl, R1 =methyl) was reacted with benzylamine to yield N-benzyl-3-methyl-4-phenyl-3-azoline-2-one (R=phenyl, R1 =methyl).