Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:43])[C@H:22]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[NH:23]C(OCC2C=CC=CC=2)=O)[C@H:12]1[OH:13].[ClH:44]>O.[Pd]>[OH2:13].[ClH:44].[ClH:44].[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:43])[C@H:22]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[NH2:23])[C@H:12]1[OH:13]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1

Procedure:
A suspension of 1-(6-amino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (150 mg) prepared in Example 3 in water (200 ml) was adjusted to pH 3 with 1N hydrochloric acid. The resulting mixture was hydrogenated under medium pressure (3.0-3.5 atm.) over palladium black (30 mg) for 3 hours. The catalyst was removed by filtration and the filtrate was adjusted to pH 7 with 1N sodium hydroxide. The resulting mixture was concentrated under reduced pressure to a volume of 30 ml. The concentrate was applied to a column of non ionic adsorption resin "HP-20" (trade mark, Mitsubishi Chemical Industries, Ltd.) (50 ml) and the column was washed with water (100 ml) and then eluted with a mixture of methanol and water (3:7)(100 ml). The solvent was evaporated under reduced pressure and the residue was crystallized from 0.1N hydrochloric acid to give 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate (60 mg), mp. 215°-230° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:1]([O:5][C:6](=[O:19])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[N:15]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOS(C)(=O)=O)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (98 g) synthesized in Example 4 and triethylamine (50 mL) were dissolved in dichloromethane (800 mL), methanesulfonyl chloride (38.8 g) was added dropwise under ice-cooling, and the mixture was stirred for 2 hr at 0° C. Water was added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The title compound was quantitatively obtained as a crude brown oil and used as it was for the next step.
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]([NH:24][C:25]3[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([NH2:33])=[CH:20][CH:19]=2)[CH3:16])=[N:13][CH:14]=1>C(O)C.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]3[N:24]([C:25]4[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:1]=[N:33][C:21]3=[CH:20][CH:19]=2)[CH3:16])=[N:13][CH:14]=1
Reactant: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1N
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ncccc1-n1cnc2ccc(N[C@@H](C)c3ccc(F)cn3)nc21
Temperature: 85 °C
Yield: 84 %

Procedure:
Formamidine acetate (141 mg, 1.35 mmol) was added to a solution of N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]N2-(2-methoxypyridin-3-yl)pyridine-2,3,6-triamine in ethanol (Preparation 22c) and the resulting mixture was heated at 85° C. for 5 hours. The reaction was cooled down and diluted with ethyl acetate (50 mL), washed with brine (2×100 mL) and water (50 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (9:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (104 mg, 84%, two steps) as a green oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)[CH3:9])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[S:34])[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H](NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=S)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
A mixture the product of Step A (3 g, 8.5 mmol) and Lawesson's reagent (1.7 g, 4.25 mmol) in toluene (100 ml) was refluxed for 2 h. The mixture was cooled to room temperature and then was diluted with EtOAc (100 ml), washed with 1N NaOH (2×50 ml), dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (DCM/MeOH gradient, 0-15% MeOH) provided the desired product as a white solid (2.2 g, 71%)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:30][C:31]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=3[F:30])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Cc1cccc(N)c1F
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 2-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([I:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.0 mL (25.1 mmol) chloro-acetylchloride in 5 mL DCM are added to a solution of 5.00 g (22.83 mmol) 4-iodo-phenylamine and 7.0 mL (50.2 mmol) triethylamine in 100 mL DCM at 0° C. The ice bath is removed and the reaction is stirred for a further 1.5 h at RT. The reaction solution is diluted with 80 mL water and the organic phase is washed with saturated NaCl solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with EtOAc, suction filtered and dried in the air.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][F:36])=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CF)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (0.5 g, 0.972 mmol) is added 4.86 ml of tetrabutylammonium fluoride solution (1M in THF, 4.86 mmol). The mixture is first stirred at room temperature for 15 minutes after which it is heated for 15 minutes at 100° C. The solution is then cooled to room temperature and to it is added dichloromethane followed by water. The layers were separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](F)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])CC1.CNC(C1C2C=C(C3C([Br:52])=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[CH3:1][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([Br:52])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Br)cc12

Procedure:
Using the method of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 488 (79Br) and 490 (81Br) [M+H].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:23])[CH3:16])[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(C)(O)c2ccccc2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(O)(Cc1ccnc(N)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 122.2 %

Procedure:
To the solution of [4-(2-hydroxy-2-phenyl-propyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (140 mg, 0.43 mmol) in DCM (4 mL) is added trifluoroacetic acid (0.3 mL). The mixture is stirred for 16 hrs at room temperature. Then EtOAc (35 mL) is added followed by the addition of saturated NaHCO3 aquaous solution (15 mL) and water (15 mL). The mixture is stirred for 15 min and the aqueous layer is separated. The aqueous layer is then extracted with EtOAc (2×25 mL). All the organic layers are combined and concentrated to give 120 mg of crude product which is used in the next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)CCCCC(C)(C)P1C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C>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].O1CCCC1>[O:10]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCCC2(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with oxindole (40 mg, 0.300 mmol, 1 equivalent), 4-chlorobenzonitrile (50 mg, 0.361 mmol, 1.2 equivalents), potassium carbonate (83 mg, 0.601 mmol, 2 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (2.8 mg, 0.0030 mmol, 0.01 equivalents) and 2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane (3.0 mg, 0.0066 mmol, 0.022 equivalents). Then tetrahydrofuran (0.3 mL) was syringed into the vial. The vial was sealed with a crimp top and placed in a heating block at 80 ° C. After 24 hours, the vial was removed from the heating block, cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (2×2.5 mL), followed by washing of the filter cake with tetrahydrofuran (5 mL). A wt% analysis was performed on the filtered solution and an assay yield of 71% was measured (literature reference: Altman RA, et al. J. Am. Chem. Soc. 2008; 130: 9613-9620). 1H NMR (400 MHz, CDCl3) δ ppm 7.90-7.82 (m, 2H), 7.68-7.60 (m, 2H), 7.41-7.34 (m, 1H), 7.32-7.25 (m, 1H), 7.21-7.13 (m, 1H), 6.93 (dd, J=9.8, 2.1 Hz, 1H), 3.79 (s, 2H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([Br:12])[CH:14]=1)[CH2:4]2
Reactant: O=C(O)c1cccc(Br)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(Br)c1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-bromobenzoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent. The compound was then dissolved in tetrahydrofuran, excess hydrogen chloride (1M solution in diethyl ether) was added, and the solution was evaporated and then recrystallised from methanol/diethyl ether to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 309, 311 (MH+).
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:5][CH3:6])[CH2:3][CH3:4].[CH3:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][Cl:11]>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]([CH3:8])[CH2:10][Cl:11])=[CH:14][CH:15]=1)([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CC(CCl)Cc1ccccc1
Reactant: CCC(C)(Cl)CC
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(C)(CC)c1ccc(CC(C)CCl)cc1
Temperature: 20 °C
Reaction time: 14 h

Procedure:
365 parts by weight of 1-methyl-1-ethyl-propyl chloride are added dropwise to a mixture of 510 parts by weight of 2-methyl-3-phenyl-propyl chloride and 49 parts by weight of anhydrous iron (III) chloride at 30° C. The resulting mixture is stirred for 8 hours at 50° C. and for 14 hours at room temperature (20° C.). The crude product is poured into ice water and dissolved in CHCl3, the solution is repeatedly washed with water and dried over Na2CO3, the solvent is evaporated and the residue is distilled.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:11]=[C:12]([C:31]4[O:32][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[N:34][N:35]=4)[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:11]=[C:12]([C:31]4[O:32][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[N:34][N:35]=4)[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(=O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl N-[5-[(3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (104 mg, 0.18 mmol) in DCM (1 mL) at 0° C. was treated with a solution of Dess-Martin periodinane (921 μL 0.3 M, 0.28 mmol) in DCM. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the crude material was purified by silica gel column chromatography using 5-60% EtOAc in DCM to yield tert-butyl N-[5-[(3aR,6aS)-6-oxo-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (57 mg, 55%) as a yellow solid. LC/MS m/z 463.5 [M+H-Boc]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([S:41](Cl)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:41]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:43])=[O:42])=[C:3]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:4]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12)c1ccccc1

Procedure:
N-{4-(1-Piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 40 mg of a purple solid. MS (posES-FIA) m/z=Found: 523.2; Calcd 523.14; 1H NMR δ 8.83-8.59 (m, 1H), 8.10 (d, 1H), 8.02-7.97 (m, 1H), 7.90 (d, 1H), 7.74-7.38 (m, 8H), 6.69-6.65 (m, 1H), 6.39-6.34 (m, 2H), 3.35-3.14 (m, 8H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:21][CH:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][CH:4]2[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>ClCCl>[F:18][C:16]([F:17])([F:19])[O:15][C:12]1[CH:11]=[CH:10][C:9]([N:7]2[CH2:8][CH:4]3[CH2:3][C:2]4([CH2:21][CH:5]3[C:6]2=[O:20])[CH2:1][O:30]4)=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-Methylene-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one (0.78 g, 2.6 mmol) in dichloromethane (20 mL) was added mCPBA (0.9 g, 5.2 mmol) at 0° C., and the mixture was stirred for 6 h at room temperature. Saturated solution of NaHCO3 (30 mL) was added and stirred for another 0.5 h. The mixture was extracted with dichloromethane (2×30 mL), washed with brine (60 mL) and dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC with petroleum ether/ethyl acetate (1:1) to yield rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH:5]=O.Cl.Cl.[CH:22]([C@@H:35]1[N:40]2[CH2:41][CH2:42][N:43]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:44][C@@H:39]2[CH2:38][NH:37][CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na].C(=O)([O-])O.[Na+]>ClCCl>[CH:22]([C@@H:35]1[N:40]2[CH2:41][CH2:42][N:43]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:44][C@@H:39]2[CH2:38][N:37]([CH2:5][C:4]2[CH:7]=[C:8]([N:11]3[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]3)[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:36]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Reactant: O=C(OCc1ccccc1)N1CCN2[C@@H](CNC[C@@H]2C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@H]2CN(C(=O)OCc3ccccc3)CCN2[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
To a solution of 2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzaldehyde (582 mg) and (4S,9aS)-4-benzhydryl-8-(benzyloxycarbonyl)octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (1.0 g) in dichloromethane (10 ml) was added portionwise sodium tritacetoxyborohydride (824 mg) under ice-cooling, and then it was stirred at room temperature for 90 minutes. The mixture was poured into aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (23 g) using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (4S,9aS)-4-benzhydryl-8-benzyloxycarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine (0.98 g) as a colorless foam.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(CN)c1
Reactant: CCCC=O
Product: CCCCNCc1cccc(OC(C)C)c1
Yield: 16.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (3-isopropoxyphenyl)methanamine (Matrix, 200 mg, 1.21 mmol) and butyraldehyde (110 μL, 1.21 mmol) were converted to the title compound (43 mg, 16%). 1H NMR (CDCl3) δ 7.29-7.17 (m, 1H), 6.99-6.74 (m, 3H), 4.57 (td, J=6.1, 12.1 Hz, 1H), 3.80 (s, 2H), 2.65 (t, J=7.3 Hz, 2H), 1.63-1.50 (m, 2H), 1.40-1.24 (m, 8H), 0.90 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 222.2 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].ClCCl.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][C:8]([C:7]1[CH:6]=[C:5]([S:2]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)(=[O:4])=[O:3])[CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(N)nc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
To a mixture of 2.0 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 40 mL of dichloromethane were added 5.0 mL of pyridine, 1.0 g of methyl 6-aminonicotinate, and 761 mg of N,N-dimethylpyridin-4-amine, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 1.8 g of methyl 6-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate as a colorless powder.