Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][C@@H]4CCCN4CC3)=[CH:8][C:6]=2[N:7]=1.Cl.[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][C:38]2(CN[CH2:39]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][C:38]2([CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:39]2)[CH2:37][CH2:36]1)=[O:34])([CH3:30])([CH3:29])[CH3:31]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine. The title compound was obtained as a tan solid (209 mg, 84%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH3:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>O1CCCC1>[CH3:5][S:4][CH2:3][CH2:2][O:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CSCCO
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCCOc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
16.3 g of 2-hydroxyethylmethyl sulfide are added dropwise at 20°-25° C. to 8.5 g of a 55% NaH suspension in 150 ml of absolute tetrahydrofuran. The mixture is stirred for 1 hour at 20° C. and for 20 minutes at 40° C., and 25 g of 1-fluoro-2-nitrobenzene are subsequently added at 20° C. After the suspension has been stirred for 10 hours at 20° C., the tetrahydrofuran is distilled off in vacuo. Water is added to the residue, and extraction is repeatedly performed with ether. There is thus obtained an oil which can be used without further purification for the following hydrogenation stage.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:30]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31].N1C=CC=CC=1>O1CCCC1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:30]([C:32]3[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (138 mg, 0.37 mmol, 1.00 equiv) in tetrahydrofuran (6 mL) was added methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (112 mg, 0.41 mmol, 1.10 equiv) and pyridine (60 mg, 0.76 mmol, 2.00 equiv) and the resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The crude product was used directly in the next step.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([NH:39][C:40]2[C:45]([C:46]#[N:47])=[CH:44][N:43]=[CH:42][CH:41]=2)=[N:19][C:20]([C:23]2[C:24]3[CH2:38][CH2:37][CH2:36][C:25]=3[N:26]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:27]=2)=[N:21][CH:22]=1)(C(C)(C)C)(C)C.C(=O)([O-])[OH:49].[Na+]>>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:26]1[C:25]2[CH2:36][CH2:37][CH2:38][C:24]=2[C:23]([C:20]2[N:19]=[C:18]([NH:39][C:40]3[C:45]([C:46]([NH2:47])=[O:49])=[CH:44][N:43]=[CH:42][CH:41]=3)[C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:22][N:21]=2)=[N:27]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1C#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1OCCO
Temperature: 25 °C

Procedure:
0.23 mL sulfuric acid (4.18 mmol, 25.0 eq.) were added to 98 mg of 4-({5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile 2-3-10 (0.167 mmol, 1.00 eq.). The reaction mixture was stirred at rt over night. Aqueous saturated sodium hydrogen carbonate was added and the suspension was filtered and washed with water. Purification by flash chromatography provided 4.4 mg (0.01 mmol, 5%) of analytically pure target compound.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:33][C:30]1[CH:29]=[N:28][C:27]([C:11]2[CH:10]=[N:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[N:32][CH:31]=1
Reactant: CCCCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 39.6 %

Procedure:
233 mmol of 2-hexyloxypyridine-5-boronic acid, 300 ml of ethanol, a solution of 466 mmol of sodium carbonate in 150 ml of water and 2.3 mmol of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 233 mmol of 2,5-dibromopyrimidine in 600 ml of toluene. The mixture is heated at the boil until the reaction is complete. The organic phase is separated off, the aqueous phase is extracted with dichloromethane, and the combined organic extracts are dried using sodium sulfate. After the solvent has been removed in vacuo, the crude product is separated off by column chromatography on silica gel 60 using dichloromethane as eluent and is recrystallized from n-heptane, giving 31 g (40%) of a colorless solid. m.p. 103-106° C.
Reaction SMILES: C(O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])O)O.[C:13]([O-])(O)=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>C(Cl)Cl>[C:4](=[C:6]([OH:7])[CH:8]([OH:9])[CH:10]=[O:11])([CH3:2])[CH3:13]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)=C(O)C(O)C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The mannitol derivative of Example 7(a) (81 g, 0.311 mol) was suspended in CH2Cl2 (1.1 L) and saturated NaHCO3 (40 mL) and stirred at ambient temperature. Sodium periodate (100 g, 0.47 mol) was added in four portions over 20 minutes and the solution was stirred vigorously at 0° C. for 3 hours. The solvent was decanted off and the remaining solid was stirred in CH2Cl2 and then filtered to remove the excess solid. The two organic portions were combined and concentrated in vacuo. The resulting oil was distilled at reduced pressure to give the title product as a clear, viscous oil. Yield (59 g, 75%). 1H NMR (CDCl3) δ4.3 (t, 1 H), 3.9 (m, 2 H), 1.4 (d, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:39])[S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:32]=[CH:31][C:30]([S:27]([N:26]([CH3:39])[CH3:25])(=[O:28])=[O:29])=[CH:35][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(S(=O)(=O)N(C)C)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 9.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(N,N-dimethyl-sulfamoyl)phenylboronic acid (23.8 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (2.4 mg, 9%). 1H-NMR (CDCl3): 2.31 (t, 1H), 2.57 (t, 1H), 2.78 (s, 6H), 3.33 (d, 3H), 3.56 (s, 2H), 5.88 (d, 1H), 7.20 (d, 1H), 7.26 (s, 1H), 7.48 (m, 5H), 7.57 (m, 1H), 7.62 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)=[O:4].F[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:20][C:19]1[CH:21]=[CH:22][C:16]([O:12][C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])[CH:11]=[CH:10][CH:9]=2)=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(3-hydroxyphenyl)acetamide (5.0 g, 24.4 mmol) and 4-fluoro-3-nitroaniline (3.8 g, 24.4 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (8.0 g, 24.5 mmol), and the mixture was stirred at 120° C. for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the filtrate was diluted with ethyl acetate (250 mL), washed successively with water (250 mL) and saturated brine (250 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→70/30), and the obtained solution was concentrated under reduced pressure to give the title compound (3.03 g, 36%) as a yellow powder.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li][CH2:11][CH2:12]CC.C(Br)C.O>C1COCC1.CCCCCC>[CH2:11]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:12]
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC1C=Cc2ccccc21
Temperature: -70 °C
Yield: 74.7 %

Procedure:
To a solution of 30 ml (0.26 moles) of indene in 250 ml of THF, 105 ml is added (0.26 moles) of 2.5 M BuLi in hexane, with temperature being kept comprised within the range of from 30° C. to 40° C. The reaction mixture is then cooled down to -70° C. and 19 ml (0.25 moles) of ethyl bromide is added dropwise during approximately 3 hours. The temperature is allowed to rise up to approximately 20-25° C. and then the mixture is hydrolysed with water and extracted with petroleum ether. After washing until neutral, drying and evaporation of the organic phase, the obtained residue is distilled. The fraction boiling at 92-95° C./30 mm Hg is collected, and 28 g of 1-ethylindene is obtained (yield 78%)
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C=O)C>[ClH:1].[NH2:23][C:24]1[CH:29]=[C:28]([C:21]2[C:15]3[S:14][C:13]([C:11]([NH:10][C@@H:4]4[CH:5]5[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]5)[CH2:3]4)=[O:12])=[CH:17][C:16]=3[CH:18]=[CH:19][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 60 °C

Procedure:
200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 68.2 mg (0.50 mmol) of 3-aminophenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.78 ml of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 60° C. for 18 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by separation by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 201 mg (98% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) and isonicotinoyl chloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-isonicotinamide (65.5 mg, 77.9%) as a white solid: mp 225-230° C.; FAB-HRMS m/e calcd :for C23H24N4O2S (M+H)+ 421.1698, found 421.1698.
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([O:9]C)=[O:8])[CH2:2][C:3]#[CH:4].[OH-].[Na+]>O>[CH2:1]([S:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4]
Reactant: C#CCCSCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCSCC(=O)O
Reaction time: 24 h

Procedure:
Thioglycollic acid (6.0 g) was added to a stirred solution of sodium hydroxide (8.0 g) in ethanol (50 ml). But-3-ynyl methanesulphonate (7.4 g) was added and the mixture was stirred at 20° for 24 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The resulting oil was stirred in dry dimethylformamide (100 ml) and anhydrous sodium carbonate (15 g) was added. Methyl iodide (7.0 ml) was added and the reaction mixture was stirred at 20° for 3 days. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica, eluting with 1:4 diethylether:hexane. Methyl 2-(but-3-ynylthio)acetate was obtained as a colourless oil (1.2 g) (a small amount of methyl 2-(but-3-yn-1-ylthio)propionate was present). A mixture of methyl 2-(but-3-ynylthio)acetate (0.6 g) and sodium hydroxide solution (20 ml, 2N, 1:1 methanol:water) was stirred for 24 hours at 20°. Water was added and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 2-(But-3-ynylthio)acetic acid was obtained as a colourless oil (0.5 g). (A small amount of 2-(but-3-ynylthio)propionic acid was present.
Reaction SMILES: C([O:4][C:5](=[O:38])[C@@H:6]([NH:25][C:26](=[O:37])[C:27]1[C:32]([F:33])=[CH:31][C:30]([CH2:34][NH2:35])=[CH:29][C:28]=1[F:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)CC.[OH-].[Li+].C(O)(C(F)(F)F)=O>C1COCC1.O>[NH2:35][CH2:34][C:30]1[CH:29]=[C:28]([F:36])[C:27]([C:26]([NH:25][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=3[CH3:20])=[CH:12][CH:13]=2)[C:5]([OH:38])=[O:4])=[O:37])=[C:32]([F:33])[CH:31]=1
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CN)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a suspension of (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (508 mg, 0.96 mmol) in THF (10 mL) was added a solution of lithium hydroxide (240 mg, 10 mmol) in water (2 mL) at room temperature. The mixture was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the THF was removed under reduced pressure and the residue was diluted with water (100 mL) and the mixture was acidified with TFA. The crude product was purified by HPLC to afford 450 mg (78% yield) of (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid as a TFA salt as a white solid. ES-LRMS m/e calcd for C24H24F2N4O5 (M+H)+ 487, found 487.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:13])(=[O:12])[N:9]([CH3:11])[CH3:10])[N:3]=1.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:10][N:9]([CH3:11])[S:8]([C:4]1[N:3]=[C:2]([NH:15][NH2:16])[CH:7]=[CH:6][CH:5]=1)(=[O:13])=[O:12]
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)n1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CN(C)S(=O)(=O)c1cccc(NN)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To 12 g of 2-chloro-6-dimethylsulfamoylpyridine were added 30 ml of n-butanol and 4 g of hydrazine hydrate. The mixture was stirred at room temperature for 30 minutes, followed by heating under reflux for 18 hours. After cooling, crystals obtained were filtered and washed with water to obtain 6.1 g of 6-dimethylsulfamoyl-2-hydrazinopyridine. m.p.: 117° to 120° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH2:11][N:10]2[C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:33][CH2:32]2)=[O:39])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: COc1ccccc1S[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccccc3OC)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-methoxyphenylthio)pyrrolidine-2-carboxamide 12C and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-methoxyphenylthio)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (67%). MS ISP (m/e): 556.2 (100) [(M+H)]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)=[O:5])C.[OH-].[K+]>O>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1

Procedure:
4.16 g of 2-[4-(5-ethoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine are boiled with 20 ml of water and 100 ml of 2N ethanolic KOH for 30 min, the usual working up is carried out, and 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: COC1C=CC(C([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC(OC)=CC=3)[C@H:32]([OH:33])[CH2:31]2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C>[CH2:31]1[C@@H:30]([N:25]2[C:26]3[N:27]=[CH:28][N:29]=[C:21]([NH2:20])[C:22]=3[N:23]=[CH:24]2)[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]1[OH:33]
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1
Yield: 85.3 %

Procedure:
Compound 9 (0.44 g, 0.56 mmol) was treated with an aqueous solution of acetic acid 80% (17 mL) at room temperature for 5 h. The mixture was concentrated to dryness, the residue was dissolved in water (20 mL) and washed with diethyl ether (2×15 mL). The aqueous layer was concentrated and co-evaporated with toluene and methanol. The desired 2′-deoxy-β-L-adenosine (β-L-dA) (0.12 g, 83%) was obtained after purification by silica gel column chromatography (0-12% MeOH in dichloromethane) and filtration through a Millex HV-4 unit (0.45μ, Millipore): mp 193-194° C. (crystallized from water) (Lit. 184-185° C. for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J. Org. Chem. 1970, 35, 636-639] and 187-189° C. for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, pp 183-187]; 1H NMR (DMSO-d6): δ2.2-2.3 and 2.6-2.7 (2m, 2H, H-2′ and H-2″), 3.4-3.6 (2m, 2H, H-5′ and H-5″) 3.86 (pq, 1H, H-4′), 4.3-4.4 (m, 1H, H-3′), 5.24 (t, 1H, OH-5′, JH,OH=5.58 Hz), 5.30 (d, 1H, OH-3′, JH,OH=4.0 Hz), 6.32 (dd, 1H, H-1′, J1′,2′=6.2 Hz, J1′,2″=7.8 Hz), 7.3 (br s, 2H, NH2-6), 8.11 and 8.32 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 252 [M+H]+, 136 [BH2]+, (FAB−) m/z 250 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 258 nm (ε14300), λmin 226 nm (ε2100); [α]D20=+25 (c 1.03, H2O), (Lit. [α]D20=+23 (c 1.0, H2O) for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J. Org. Chem. 1970, 35, 636-639] and [α]D20=−25 (c 0.47, H2O) for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, pp 183-187]). Anal. Calcd for C10H13N5O3+1.5 H2O (M=278.28): C, 43.16; H, 5.80; N, 25.17. Found: C, 43.63; H, 5.45; N, 25.33.