Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][NH:11][C:12]2[N:13]=[C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:15][C:16]=2[C:17]([NH2:19])=[O:18])[CH:7]=[CH:8][CH:9]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].IC.[C:41](=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][N:11]2[C:12]3[N:13]=[C:14]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:15][C:16]=3[C:17](=[O:18])[N:19]=[C:41]2[S:28][CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: O=C([O-])[O-]
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.6 %

Procedure:
Sodium hydride (2.62 g, 65.4 mmol) was added portionwise to a suspension of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (3 g, 8.18 mmol) and 1,1′-thiocarbonyldiimidazole (4.37 g, 24.53 mmol) in Tetrahydrofuran (THF) (80 mL). The mixture was stirred at rt for 21 h, then quenched by the dropwise addition of water. The solvent was evaporated and the residue was suspended in water. The pH was adjusted to about 7 by the addition of 6 N HCl, while cooling in an ice bath. The yellow solid was collected by filtration, washed with water, then hexanes and dried. The solid obtained was suspended in Tetrahydrofuran (THF) (80 mL) and treated with iodomethane (0.562 mL, 9.00 mmol). After few hours minimal conversion was observed by LC/MS. Sodium carbonate (1.300 g, 12.27 mmol) and additional iodomethane (0.562 mL, 9.00 mmol) were added and stirring was continued overnight. LC/MS analysis showed that the reaction was still not complete. Additional sodium carbonate (1.300 g, 12.27 mmol) and iodomethane (0.562 mL, 9.00 mmol) were added and the mix was warmed at 45° C. for 4 h (an additional aliquot of sodium carbonate and iodomethane were added during this time). The reaction has stalled and only reached about 40% conversion. It was then cooled to rt, the solvent was evaporated and the residue was suspended in water. The pH was neutralized by the addition of 6 N HCl. The solid was collected, washed with water and dried. The dry solid obtained was suspended in N,N-Dimethylformamide (DMF) (35 mL). Potassium carbonate (3.96 g, 28.6 mmol) and iodomethane (1.534 mL, 24.53 mmol) were added and the mixture was stirred at 50° C. for 1.5 h. After cooling, it was poured into ice/water and the precipitate formed was collected, washed with water and dried to afford 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (2.27 g, 5.37 mmol, 65.6% yield) which was used in the next step without further purification. LC/MS (ES+): [M+H]+=422.9 (80% pure). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=7.83 Hz, 1H), 7.15 (t, J=7.83 Hz, 1H), 6.60 (d, J=7.33 Hz, 1H), 5.49 (s, 2H), 3.63-3.72 (m, 4H), 3.52 (d, J=4.55 Hz, 4H), 2.46 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)(=[O:21])[CH3:20].[CH:37](/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:38].[NH4+].[Cl-]>C1COCC1>[OH:38][CH:37]([CH2:20][C:19](=[O:21])[C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)/C=C(\C)C=O
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)/C=C(\C)C(O)CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 0.42 h
Yield: 79.2 %

Procedure:
To a solution of diisopropylamine (0.5 mL, 3.52 mmol) in 7 mL of THF at -78° C. under argon was added a 1.6M solution of n-butyllithium in hexane (2.2 mL, 3.52 mmol). The mixture was stirred for 25 min, and a solution of ketone 39 (0.78 g, 3.2 mmol) in 4 mL of THF was added slowly. The mixture was stirred for 20 min, and a solution of ethyl (E)-3-formyl-2-butenoate 40 (0.45 g, 3.2 mmol) (ethyl (E)-3-formyl-2-butenoate 40 is readily available from Fluka) in 3 mL of THF was added slowly. The mixture was stirred for 35 min at -78° C., poured into saturated aqueous NH4Cl, and extracted with 40% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a light-yellow solid. Flash chromatography yielded the desired alcohol 41 as a white crystalline solid (0.98 g, 80%): m.p. 126°-128° C.; Rf 0.13 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:8][C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
tert-Butyl 4-[6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-propylpyridin-3-yl]piperazine-1-carboxylate (60 mg, 0.126 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.5 mL). Sodium hydride (7.3 mg, 0.152 mmol) and benzyl bromide (17 μL, 0.139 mmol) were added sequentially under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (54 mg (yield 76%)) was obtained as a yellow oil.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[C:7]([CH3:15])=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1>C1COCC1>[Br:5][C:6]1[C:7]([CH3:15])=[N:8][CH:9]=[C:10]2[NH:12][CH:1]=[CH:2][C:11]=12
Reactant: Cc1ncc([N+](=O)[O-])cc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ncc2[nH]ccc2c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.9 %

Procedure:
To a stirred suspension of vinylmagnesium bromide (1 M in THF, 37.5 mL, 37.50 mmol) was added dropwise a solution of 3-bromo-2-methyl-5-nitropyridine (2.50 g, 11.52 mmol) in THF, under an atmosphere of nitrogen, at 0° C. The resulting solution was allowed to warm to RT and stirred for 1 day then quenched with saturated NH4Cl(aq). The resulting mixture was partitioned between EtOAc and water, the organic layer separated, dried (MgSO4) and evaporated to give a red crude oil, which was purified by column chromatography (Si—PCC, 50-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 0.1% formic acid in water on a gradient of methanol 5-75%). The relevant HPLC fractions were loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH and the desired product eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (22 mg, 1%). LCMS (Method H): RT 2.23 min, [M+H]+ 211.1 (79Br), 213.1 (81Br)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]([OH:17])=[CH:4][CH:3]=1.[CH3:18][O-:19].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:5]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:18]=1[OH:19])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:17]
Reactant: C[O-]
Reactant: Cc1ccc(O)c(-c2cccc3[nH]nnc23)c1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cc(Cc2cc(C)cc(-c3cccc4[nH]nnc34)c2O)c(O)c(-c2cccc3[nH]nnc23)c1
Yield: 95 %

Procedure:
6.2 g of the Mannich base obtained in Example 1 and 4-methyl-6benzotriazolyl-phenol 4.5 g were dissolved in 200 ml of xylene, and sodium methylate (28% methanol solution) 0.2 g was added. The solution was heated with stirring under reflux at 140°-150° C. for 10 hours with a stream of nitrogen. After distilling of the solvent, and recrystallizing the residue from xylene, the desired product 2,2'-methylene-bis-(4methyl-6-benzotriazolyl-phenol) was obtained in 95% yield.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.O[CH2:25][C:26]1[CH:30]=[C:29]2[C:31]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=3[NH:95][C:96](=[O:101])[C:97]([CH3:100])([CH3:99])[CH3:98])=[C:32]3[N:36]=[C:35]([C:37]([C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=4[NH:82][C:83](=[O:88])[C:84]([CH3:87])([CH3:86])[CH3:85])=[C:38]4[NH:42][C:41](=[C:43]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=5[NH:69][C:70](=[O:75])[C:71]([CH3:74])([CH3:73])[CH3:72])[C:44]5[CH:45]=[CH:46][C:47](=[C:49]([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=6[NH:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C:27]=1[NH:28]2)[N:48]=5)[CH:40]=[CH:39]4)[CH:34]=[CH:33]3.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:25][C:26]2[CH:30]=[C:29]3[C:31]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=4[NH:95][C:96](=[O:101])[C:97]([CH3:100])([CH3:99])[CH3:98])=[C:32]4[N:36]=[C:35]([C:37]([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=5[NH:82][C:83](=[O:88])[C:84]([CH3:87])([CH3:85])[CH3:86])=[C:38]5[NH:42][C:41](=[C:43]([C:63]6[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=6[NH:69][C:70](=[O:75])[C:71]([CH3:72])([CH3:73])[CH3:74])[C:44]6[CH:45]=[CH:46][C:47](=[C:49]([C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=7[NH:56][C:57](=[O:62])[C:58]([CH3:59])([CH3:60])[CH3:61])[C:27]=2[NH:28]3)[N:48]=6)[CH:40]=[CH:39]5)[CH:34]=[CH:33]4)=[O:15])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(CO)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Reactant: O=C(O)CCCCCCCn1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccccc1-c1c2nc(c(-c3ccccc3NC(=O)C(C)(C)C)c3cc(COC(=O)CCCCCCCn4ccnc4)c([nH]3)c(-c3ccccc3NC(=O)C(C)(C)C)c3nc(c(-c4ccccc4NC(=O)C(C)(C)C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 0.17 h
Yield: 89 %

Procedure:
8-Imidazol-1-yloctanoic acid hydrochloride (90.1 mg, 0.37 mmol) and triethylamine (TEA, 0.1 ml, 0.74 mmol) were dissolved in dry DMF (4 ml) and stirred for 10 min. After removing TEA under reduced pressure, 2-hydroxymethyl-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin, 76 mg, 73 μmol), 4-(N,N-dimethylamino)pyridine (DMAP, 4.5 mg, 37 μmol) and dicyclohexylcarbodiimide (DCC, 75.4 mg, 0.37 mmol) were added to the solution and stirred for 84 hours at room temperature in darkness. The mixture was chromatographed on a silica gel flash column using CHCl3 --MeOH (30/1 v/v) as the eluent. The residue was dried at room temperature in vacuo to give a purple product, 2-(8-imidazol-1-yloctanoyloxymethyl)-5,10,15,20-tetrakis(o-pivalamidophenyl)porphyrin (80 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)Cl)c1
Temperature: 170 °C

Procedure:
3-Bromo-4-fluoro-benzoic acid (2.0 g) was dissolved in chlorosulfonic acid (97%, 35 ml) and heated at 170° C. for 72 h. The reaction mixture was cooled to RT and added dropwise to an ice-water mixture. Extraction with EtOAc, drying (MgSO4) and concentration in vacuo gave the desired compound. Yield: 2.5 g.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:12][O-:13].[Na+].C[C:16]([OH:18])=O>CO>[CH3:12][O:13][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:18][CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: CC(=O)O
Reactant: C[O-]
Reactant: Cc1cc(Cl)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(OC)c1C#N
Temperature: 25 °C
Yield: 95 %

Procedure:
2,4-dichloro-6-methylnicotinonitrile (45 g, 240 mmol) was dissolved in CH3OH (300 ml). NaOMe (30% in MeOH, 100 ml, 1680 mmol) was added. The mixture was refluxed for 4 h. After cooled to r.t., the reaction mixture was neutralized by HOAc. The solvent was removed under vacuum and the residue was washed with H2O (300 ml) and MTBE (100 ml). The resulting solid was coevaporated with dry THF (300 ml) to give 2,4-dimethoxy-6-methylnicotinonitrile as a dark-yellow solid. (40 g, yield 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:18]2[CH2:21][N:20]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>O1CCCC1.CO>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]2[CH2:21][CH:18]([CH:16]([OH:17])[C:13]3[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:9])=[CH:11][CH:12]=3)[CH2:19]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.3 %

Procedure:
9.94 g of the compound [88-1] was dissolved in 100 mL of tetrahydrofuran and 20 mL of methanol, 799 mg of sodium borohydride was added thereto at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture, water was added, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate. Then, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 to 30/70) to obtain 632 mg of tert-butyl ((1S)-1-{4-[[1-(diphenyl methyl)azetidin-3-yl](hydroxy)methyl]phenyl}ethyl)carbamate [88-2] (hereinafter, referred to as the compound [88-2]).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in MeOH (100 mL) at 0° C. was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0° C. for 30 min, the reaction was quenched by addition of 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to afford the pure faster eluting isomer and a mixture containing both the faster eluting isomer and the slower eluting isomer. Faster eluting isomer: 1H NMR (500 MHz, CD3OD): δ 7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.10 (d, 3H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(O)C>CN(C)C=O>[CH2:19]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:18][CH2:17][CH2:16][C:15]#[CH:14]
Reactant: C#CCCCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: C#CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 40.1 %

Procedure:
To potassium phthalimide (37.5 g) in dimethylformamide (400 ml) at 100° C,. was added dropwise 1-chloro-5-hexyne (23.67 g) in dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for a further hour, cooled and stirred at room temperature overnight. The mixture was poured on to ice/water to give an oil, which on trituration gave as a white solid N-5-hexynyl phthalimide (18.35 g), m.p. 74°-6° C. (recrystallisation from ethanol).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:20][CH2:19][NH:18][NH:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:40]([NH:39][CH2:37][CH3:38])=[O:41])[NH:18][CH2:19][CH2:20]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(C(CCCN2CCNNCC2)c2ccc(F)cc2)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-[4,4-bis(4-fluorophenyl)butyl]hexahydro-1H-1,2,5-triazepine dihydrochloride (3.25 g, prepared as in example 13), N,N-diisopropylethylamine (3.38 ml) in dry dichloromethane (10 ml) at 5° under nitrogen was added ethyl isocyanate (0.62 ml) in dichloromethane (10 ml) and the solution was stirred at room temperature overnight. After extraction of the mixture with water, the dichloromethane solution was dried (Na2SO4) and evaporated to an oil. The crude product was chromatographed on a column of silica gel prepacked in dichloromethane. Successive elution with ethyl acetate-dichloromethane (4:1) and ethanol-ethyl acetate-dichloromethane (1:4:5) allowed a separation of a major component from impurities. The hydrobromide salt of the titled compound was formed from the material in 2-propanol and was recrystallized from 2-propanol-ethyl acetate; wt. 2.18 g (49%), mp=130°-134° dec.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][C:8]1C=CC(S(O)(=O)=O)=C[CH:13]=1.C(=O)CCC>C(Cl)Cl>[CH2:8]([CH:13]1[S:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5]1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)CCO
Solvent: ClCCl
Solvent: CCCC=O
Product: CCC1OCCC(C)S1
Temperature: 25 °C

Procedure:
A solution of 3-mercapto-1-butanol (106 g, 1 mol, synthesized as above) and PTSA (paratoluenesulfonic acid monohydrate, 38 g, 0.2 mol, commercially available from Sigma-Aldrich, Inc.) in 400 mL of CH2Cl2 (dichloromethane) were cooled with an ice bath. Butyraldehyde (106 mL, 1.2 mol, commercially available from Sigma-Aldrich, Inc.) was added drop wise to the solution, and the reaction mixture was stirred with cooling for half an hour and at room temperature for another 1 hour. The reaction mixture was washed twice with saturated sodium bicarbonate solution and once with brine. The organic phase was then dried with anhydrous magnesium sulfate. The solvent was removed with a rotary evaporator and the crude product was distilled under vacuum to provide 2-ethyl-4-methyl-1,3-oxathiane (98 g), which had a boiling point of 80° C. at a pressure of 10.4 mmHg.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][O:54][C@@H:55]1[C@@H:61]([CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=2[Cl:72])[O:60][C@H:57](OC)[C@:56]1([CH3:74])[OH:73]>CC#N.O.C(Cl)Cl>[O:1]([CH2:9][CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[N:13]([C@@H:57]2[O:60][C@H:61]([CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=3[Cl:72])[C@@H:55]([O:54][CH2:53][C:47]3[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=3[Cl:45])[C@@:56]2([CH3:74])[OH:73])[CH:12]=1)[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ncnc(Cl)c12
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
Compound 2.3 (2.5 g, 8.00 mmol) was suspended in CH3CN (50 mL), and powdered 85% KOH, (1.3 g, 19.73 mmol) followed by TDA -1 (tris[2-(2-methoxyethoxy)ethyl]amine) (0.2 mL, 0.62 mmol) were added. After stirring at room temperature for 10 min, a freshly prepared solution of bromo sugar 2.4 (prepared from commercially available 3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-1-O-methyl-α-D-ribofuranose; (i) Helv. Chim. Acta, 1995, 78, 486; (ii) WO 02/057287, 2002) (10.1 mmol) in anhydrous acetonitrile (50 mL) was added via cannula, and the reaction stirred for 24 hr at room temperature then cooled in an ice/water bath and treated with CH2Cl2 (100 mL) and water (80 mL). The aqueous material was extracted three times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered and evaporated The crude product was purified on a silica gel column using 20% ethyl acetate/hexanes as eluent to give the desired nucleoside 2.5 (1.03 g, 13%). Further elution with 25% EtOAc/hexanes as eluent gave a mixture of the desired nucleoside 2.5 and starting base 2.3 (350 mg).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][NH2:39]>>[CH3:37][O:38][N:39]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:33][CH:34]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CON
Product: CCOC(=O)C(CC)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.