Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[NH2:4])[CH3:2].O[CH:13]=[C:14]1[C:23]2([CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)[O:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=O.C(O)(C(F)(F)F)=O.NN>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([N:3]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3([CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:25][CH2:24]3)[C:14]=2[CH:13]=[N:4]1)[CH3:2]
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCn1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol) and benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (770 mg, 2.0 mmol) in dichloroethane (5 mL) was allowed to stir at 25° C. with TFA (78 μL, 1.0 mmol) for 2 h. Once LC/MS analysis showed complete imine formation, more TFA was added to deprotect the hydrazine and cyclize the product. The reaction was diluted with dichloromethane, and aqueous sodium bicarbonate was added with stirring. The layers were separated and the organics were further washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes) to afford benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 65%). ESI-MS m/z calc. 403.2, found 404.7 (M+1)+; Retention time: 1.94 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=7.6 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.10-6.99 (m, 2H), 5.16 (s, 2H), 4.47 (q, J=7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3.45-3.26 (m, 2H), 2.15-2.03 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J=7.3 Hz, 4H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][CH:12]1[NH:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1.C(O)(C)C.C(OC(C)C)(C)C>C(O)C>[OH:10][CH2:11][CH:12]1[N:17]([C:2](=[S:3])[NH:1][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1
Reactant: S=C=Nc1cccnc1
Reactant: OCC1Cc2ccsc2CN1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: OCC1Cc2ccsc2CN1C(=S)Nc1cccnc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A solution of 3-isothiocyanatopyridine (1.36 g) in absolute ethanol (40 cc) is added dropwise, at a temperature of about 0° C., to a solution of (RS)-5-hydroxymethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.69 g) in absolute ethanol (60 cc). The resulting solution is stirred for 20 hours at a temperature of about 20° C. and the solid formed is then filtered off. The filtrate is evaporated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. and a white solid is obtained which is combined with the solid isolated by filtration. These solids are dissolved in a mixture, heated under reflux, of isopropanol and diisopropyl ether (1:2 by volume; 150 cc) and the solution, after cooling, is kept at +5° C. for 20 hours. The resulting crystals are filtered off, washed with diisopropyl ether (50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-5-Hydroxymethyl-6-[(pyrid-3-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.3 g) is thus obtained in the form of white crystals melting at 165° C.
Reaction SMILES: O1[C:11]2([CH3:12])[CH:2]1[C:3](=[O:14])[C:4]1[C:9]([C:10]2=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC12OC1C(=O)c1ccccc1C2=O
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(C)C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 30.5 %

Procedure:
A mixture of 1.88 g of 2,3-epoxy-3-methyl-1, 4-naphthoquinone, 3.16 g of piperazinecarboxylic acid, ethyl ester and 100 ml of absolute ethanol was stirred for 12 hours at 50° C. The solvent was then removed and the remainder filtered through a one inch plug of silica gel and eluted with chloroform. The eluate was evpaorated, giving 1 g of the desired product as a viscous red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([OH:22])=[O:21])=[C:7]([C:11]([C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH3:23][Si](C=[N+]=[N-])(C)C>CO>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1ccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)O
Solvent: CO
Product: COC(=O)Cc1c(C(=O)c2nccn2C)[nH]c2cc(Cl)ccc12
Reaction time: 19 h
Yield: 28.7 %

Procedure:
To a stirred solution of [6-chloro-2-(1-methylimidazole-2-carbonyl)indol-3-yl]acetic acid (Example 241, 65 mg, 0.21 mmol) in methanol (10 ml) was added (trimethylsilyl)diazomethane (1.0 M solution in hexanes, 1.05 ml, 2.1 mmol) at room temperature. After stirring for 19 h, the mixture was concentrated. The residue was purified by TLC developing with ethyl acetate-hexane (1:2) to afford 20 mg (23%) of the title compound as yellow solids.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Cl[C:10]1[C:14]2[CH:15]=[C:16]([CH:28]=[O:29])[C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)=[C:18]([F:19])[C:13]=2[O:12][N:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>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]>[CH3:27][C@H:22]1[O:23][C@@H:24]([CH3:26])[CH2:25][N:20]([C:17]2[C:16]([CH:28]=[O:29])=[CH:15][C:14]3[C:10]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)=[N:11][O:12][C:13]=3[C:18]=2[F:19])[CH2:21]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Reactant: OB(O)c1cn[nH]c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1CN(c2c(C=O)cc3c(-c4cn[nH]c4)noc3c2F)C[C@H](C)O1

Procedure:
1H-pyrazole-4-boronic acid pinacolate ester, 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos), and tris(dibenzylideneacetone)dipalladium(0) were reacted using a method similar to the one described for the synthesis of Intermediate 554.
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)(C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH2:9])[CH3:25])[C:20]=2[CH:19]=1
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Reactant: COCCOCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCCCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
25 mg sodium hydride 55-65% in oil was added to a solution of 165 mg (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 1.5 mL N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min, then 120 mg 3-(methoxyethoxy)propyl bromide was added added and the reaction mixture was stirred at room temperature for an additional 22 h. The reaction mixture was distributed between water and ethyl acetate. The phases were separated, the organic phase washed with water, 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1. The product fractions were evaporated and the residue taken up in 4.0 mL of a 2.16 M solution of hydrochloric acid in ethyl acetate. The mixture was stirred at room temperature for 1 h, the solid collected by filtration, neutralised with aqueous ammonium hydroxide and purified by chromatography on silica gel with dichloromethane:methanol:aqueous ammonium hydroxide=90:9:1. The product fractions were dried over magnesium sulfate and evaporated to yield 80 mg (S)-2-{6-[3-(2-methoxy-ethoxy)-propoxy]-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl}-1-methyl-ethylamine as light brown oil. MS: M+H=347.5; M+H−NH3=330.4.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[C:22]([C:23](Cl)=[N:24]O)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:24]=2)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1
Reactant: ON=C(Cl)c1c(Cl)ccnc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2c(Cl)ccnc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A solution of methyl isobutyrylacetate (1.37 mL, 10.2 mmol) in THF (2.1 mL) was stirred at 0° C. as a 0.5 N solution of sodium methoxide in methanol (20.3 mL, 10.2 mmol) was added. A solution of 2,4-dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (1.94 g, 8.64 mmol) in THF (19 mL) was added and the resulting solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexanes to 3:7 ethyl acetate:hexanes gradient elution) and fractions containing the product concentrated. The residue was azetroped with methanol then dichloromethane to provide methyl 3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.64 g, 66% as 0.15 dichloromethane). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J=5 Hz, 1H), 7.82 (d, J=5 Hz, 1H), 3.79 (septet, J=7 Hz, 1H), 3.63 (s, 3H), 1.34 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([O:11][CH3:12])[N:7](C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]([NH:17][C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][CH2:29][C:30]2[N:31]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]OS(C)(=O)=O)[C:36]=3[Cl:48])[CH:32]=[CH:33][CH:34]=2)=[O:27])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].[C:49](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:14]([NH:17][C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][CH2:29][C:30]2[N:31]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH:42]([O:1][C:2]4[C:10]5[N:9]=[C:8]([O:11][CH3:12])[NH:7][C:6]=5[CH:5]=[CH:4][CH:3]=4)[CH3:49])[C:36]=3[Cl:48])[CH:32]=[CH:33][CH:34]=2)=[O:27])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: COc1nc2c(O)cccc2n1C
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COS(C)(=O)=O)c2Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc2c(OC(C)c3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 84 h
Yield: 23.7 %

Procedure:
A mixture of 4-hydroxy-2-methoxy-1-methyl-1H-benzimidazole (47.4 mg), 2-[(E)-3-(6-acetamidopyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(methanesulfonyloxymethyl)phenyl]pyrrole (143 mg) and potassium carbonate (110 mg) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 3.5 days. The mixture was partitioned between chloroform and water. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=9:1, V/V) to give 2-[(E)-3-(6-acetamidopyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methoxy-1-methyl-1H-benzimidazol-4-yloxymethyl)phenyl]pyrrole (39 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)C(=O)[C:15]1=O.F[C:26]1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:26][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:14]=[C:15]1[C:7](=[O:9])[C:6]3[C:5]([N:11]1[C:10]2=[O:12])=[CH:4][CH:3]=[CH:2][CH:13]=3
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Product: Cc1ccc2nc3n(c(=O)c2c1)-c1ccccc1C3=O
Yield: 34 %

Procedure:
Using the procedure in Example 12 and substituting 5-methylisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave the title compound in 34% yield: mp 266°-267° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 8.22 (s, 1H), 7.94 (d, 1H), 7.93 (d, 1H), 7.79 (dt, 1H), 7.66 ppm (1H), 7.45 (dt, 1H), 2.55 (s, 3H); MS (M+H)+ 263, (M+CH4CN)+ 304.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1>[Pd].CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CC#Cc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Yield: 88.1 %

Procedure:
A warm solution of 2-(4′-fluorophenyl)-4-[4′-(1-dimethylamino-2-propyn-3-yl)phenyl]thiazole (0.2 g, 0.6 mmol) in abs. EtOH (20 mL) containing a catalytic amount of palladium on activated carbon (5%, 20 mg) is shaked under hydrogen atomsphere (30 psi) for 2 h. After removal of the catalyst by filtration, the filtrate is concentrated to give 2-(4′-fluorophenyl)-4-[4′-(3-N,N-dimethylaminopropyl)phenyl]thiazole as desired product (0.18 g, 89%) 1H NMR (CDCl3): δ 1.65 (m, 2H), 2.24 (s, 6H), 2.32 (t, 2H), 2.69 (t, 2H), 7.14 (t, 2H), 7.27 (d, 2H), 7.40 (s, 1H), 7.89 (d, 2H), 8.02 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O-].[Na+].[C:13](OCC)(=[O:15])C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCOC(C)=O
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)nc(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyridine (4.5 g) in methanol was added sodium methoxide (25% in methanol, 6.8 mL) at room temperature. The mixture was stirred for 12 h then poured into ethyl acetate/water and separated. The organic layer was washed with water, brine and dried over magnesium sulfate. Upon evaporating, the residue was purified by crystallization (100% hexanes) to give title compound as solid (3.1 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([C:18](=[O:21])[NH:19][CH3:20])[CH:13]=[C:12]([O:22][CH3:23])[C:11]=1[C:24](=[O:27])[NH:25][CH3:26])=[O:8]>>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([C:18](=[O:21])[NH:19][CH3:20])[C:13]([N+:1]([O-:4])=[O:2])=[C:12]([O:22][CH3:23])[C:11]=1[C:24](=[O:27])[NH:25][CH3:26])=[O:8]
Reactant: CNC(=O)c1cc(OC)c(C(=O)NC)c(NC(=O)CCl)c1OC
Reactant: O=[N+]([O-])O
Product: CNC(=O)c1c(NC(=O)CCl)c(OC)c(C(=O)NC)c([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 50 mL of red fuming nitric acid, chilled to 0° C., was added 2.3 g (6.69 mmol) of 30. After stirring at 0° C. for 45 minutes, 100 mL of ice water was added and the mixture quickly extracted with ethyl acetate. The ethyl acetate extract was dried over Na2SO4, evaporated down to a small volume, and placed on a silica gel column. Gradient chromatography (ethyl acetate to 5% methanolic ethyl acetate) afforded the desired product as a pure white solid: 1.5 g (58%) yield; TLC (ethyl acetate-methanol [9:1]), Rf =0,40; mp 259°-260° C.; IR (KBr pellet) 3370, 1676, 1651, 1568, 1534, 1472, 1404, 1373, 1315, 1054 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ9.99 (1H, s, acetamido proton), 8.64 and 8.28[2H, 2 s, J=2.3 Hz, 1- and 4-carbamyl protons, no assignments made), 4.25 (2H, s, methylene), 3.79 and 3.68 (6H, 2 s, 3- and 6-methoxys, no assignments made), 2.73 (6H, 2 overlapping d, J=4.4 Hz, 1- and 4-carbamyl methyls, no assignments made); mass spectrum (EI mode), m/z 388 (P+, 390 (P+, 37Cl).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:12]1[N:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[N:16][CH:17]=1.[N:28]1C=CC=CC=1>>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:15]1([NH:28][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:14]=[N:13][CH:12]=[CH:17][NH:16]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(N)cn2)s1
Reactant: c1ccncc1
Product: CC(=O)Nc1nc(C)c(C2(NS(=O)(=O)c3ccccc3)C=NC=CN2)s1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (0.115 mL) was added to a stirred mixture of N-[5-(5-aminopyrazin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (75 mg) and pyridine (5 mL) and the reaction mixture was heated to 85° C. for 2 hours. Additional benzenesulfonyl chloride (0.115 mL) was added and the mixture was heated to reflux for 10 minutes. The reaction mixture was evaporated. A 7M methanolic ammonia solution (10 mL) was added to the residue and the mixture was stirred at room temperature for 1 hour. The resultant mixture was evaporated and the residue was purified by preparative HPLC. There was thus obtained the title compound (22 mg); 1H NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 2.46 (s, 3H), 7.58 (m, 3H), 7.92 (m, 2H), 8.31 (s, 1H), 8.41 (s, 1H), 11.56, (br s, 1H), 12.11 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][NH2:21]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:21][CH2:20][C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Reactant: NCc1ccco1
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccco1
Temperature: 130 °C

Procedure:
5 g of 2-amino-3-cyano-4-chloroquinolin and 1 ml of furylmethylamine (furfurylamine) are heated under stirring at 130° C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from 20 ml ethanol to obtain 4.8 g of the title compound. Mp.: 208° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[C:5]([CH:16]([CH3:19])[C:17]#N)[N:4]=[C:3]1[CH3:20].C[OH:22].O.[C:24](=O)([O-])[OH:25].[Na+]>CO.C(OCC)C.Cl>[CH3:1][N:2]1[C:6]([S:7][C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[C:5]([CH:16]([CH3:19])[C:17]([O:25][CH3:24])=[O:22])[N:4]=[C:3]1[CH3:20]
Reactant: CO
Reactant: O=C([O-])O
Reactant: Cc1cc(C)cc(Sc2c(C(C)C#N)nc(C)n2C)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(C)c1nc(C)n(C)c1Sc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In 5 ml of methanol/diethyl ether (1/3 v/v %) saturated with hydrogen chloride was dissolved 60 mg (0.21 mmol) of 2-[1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]propiononitrile (43a), and the mixture was left at 4° C. for 23 hours. To the reaction mixture, 2 ml of methanol and 0.3 ml of water were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain 57 mg of Compound I-96 as oil (yield 85%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28]C)=[O:27])[CH2:15]1.CCN(C(C)C)C(C)C.[OH-].[K+].Cl>CO.C1COCC1>[CH2:5]([O:4][C:2]([NH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([OH:28])=[O:27])[CH2:15]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
Step (a) Benzyl chloroformate (1.40 mL, 9.79 mmol) was added to a flask charged with (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate hydrochloride salt (2.5 g, 8.9 mmol), DIEA (5.0 mL, 29 mmol), and THF (20 mL). The mixture was stirred for 5 minutes at ambient temperature and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with methylene chloride (40 mL) and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was diluted with methanol (30 mL) and 2N potassium hydroxide (10 mL, 20 mmol) and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture then was concentrated to approximately one-half the volume and quenched with cold 1N hydrochloric acid (30 mL, 30 mmol). The mixture was extracted with methylene chloride (30 mL) and the extract dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.51 g, 6.86 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(Cl)Cl>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4CCCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
Add to a solution of {4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopentyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8, 40.2 g, 68 mmol) in 400 mL of methanol, a suspension of Pd black (2 g) in a small amount of water. Then add a solution of ammonium formate (13.3 g, 215 mmol) in 100 mL of water, and heat at a gentle reflux overnight. TLC shows the presence of starting material (TLC, silica plates, 4:1 DCM:methanol; Rf: starting material 0.75, product 0.15). Add an additional 5 g of ammonium formate and reflux 24 hours. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (500 g) using DCM:methanol (4:1) to give 33.4 g of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a) as a white solid.