Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][C:13]1[S:14][C:15](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:18])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:12][C:13]1[S:14][C:15]([C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=[O:5])=[C:16]([CH3:18])[N:17]=1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc(C)nc2C)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a solution of 2-bromo-5-methoxybenzaldehyde (200 mg, 0.93 mmol) in DMF (10 mL) and H2O (2 mL) are added 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (333 mg, 1.4 mmol), Pd(PPh3)4 (107 mg, 0.09 mmol) and K2CO3 (257 mg, 1.9 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×10 mL). The combined organic layer is dried, (MgSO4), filtered and is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2,4-Dimethyl-thiazol-5-yl)-5-methoxy-benzaldehyde (150 mg, 65%) as a white foam.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.CC(C)=O.[CH3:31][CH2:32][C:33](Cl)=[S:34].[OH-].[Na+]>C(=O)(O)[O-].[Na+]>[CH3:31][CH2:32][C:33]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:34]
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(=S)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(C(CCNC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a sitrred, cooled (-20°) solution of 10.4 g. (0.026 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml. of acetone is added dropwise a solution of 3.66 g. (0.029 mol.) of methylthioacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A mixture of 4-phenoxybenzoic acid (0.136 g, 0.634 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.146 g; 0.635 mmol), HATU (0.265 g; 0.698 mmol) and N,N-diisopropylethyldiamine (0.273 mL; 1.59 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.070 g (28%) of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([O:24]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:23]>>[F:21][C:18]([F:19])([F:20])[C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][NH:8][CH2:9]2)=[CH:14][C:13]=1[C:22](=[O:24])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Product: CC(=O)c1cc2c(cc1C(F)(F)F)CNC2

Procedure:
Prepared in analogy to Example A47 from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and 1-ethoxyvinyltributylstannane. White solid. MS (m/e): 230.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Cl-:10].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:10][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:9]
Reactant: [Cl-]
Reactant: Cc1cc(C)cc(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)c(Cl)c(C)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
Mesitylene (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 6 h. The product was purified by column chromatography to give chloromesitylene (40%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCOCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and morpholine (0.26 mL; 3.0 mmol) under microwave irradiation for 4 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-morpholin-4-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (76 mg, 74%) as an off-white powder. ES-HRMS m/e calcd for C19H28N4O2 (M+H+) 345.2285, found 345.2282.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:9]I>C1COCC1>[I:9]/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: II
Reactant: C#CCCCCCC
Solvent: C1CCOC1
Product: CCCCCC/C=C/I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of oct-1-yne (113 mg, 1 mmol, available from Lancaster, Pelham, N.H., USA) and Cp2ZrCl2 (413 mg, 1.4 mmol, 1.4 eq.) in THF (4 mL) at RT was rapidly added a 1 M THF solution of LiAlH(Ot-Bu)3 (1.4 mL, 1.4 mmol, 1.4 eq.). A resulting dark red solution was stirred at RT for 15 min. Then, a solution of iodine (355 mg, 1.4 mmol, 1.4 eq., Aldrich) in THF (2 mL) was added. After additional stirring at RT for 15 min., the reaction mixture was quenched with 1 N HCl, and extracted with diethyl ether (3×10 mL). The organic extracts were combined and washed successively with saturated Na2SO3, H2O, and brine. The organic residue was then dried over MgSO4 and concentrated via evaporation under reduced pressure. Purification of the residue was performed using a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent. (E)-1-iodooct-1-ene (217 mg, 91% yield) was obtained as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm: 6.51 (dt, J=14.30, 7.12 Hz, 1H), 5.97 (d, J=14.31 Hz, 1H), 2.05 (dt, J=7.01, 6.96 Hz, 2H), 1.45-1.34 (m, 2H), 1.33-1.18 (m, 6H), 0.88 (t, J=6.66 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ ppm: 146.78, 74.21, 36.03, 31.56, 28.58, 28.32, 22.54, 14.04. The physical and spectral data are consistent with those previously reported (see Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215-4217).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccccc1B(O)O
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: COc1ccccc1-c1ccc(S(=O)(=O)NCCCCCO)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2-methoxyphenyl boronic acid were reacted to give the title compound as a clear oil. δC (DMSO, 62.9 MHz): 22.7, 29.0, 32.0, 42.7, 55.6, 60.6, 115.5, 121.4, 125.3, 126.1, 128.2, 129.8, 130.2, 138.8, 142.1 and 156.1.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[Br:17]Br>O1CCOCC1>[Br:17][CH2:2][C:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])=[O:3]
Reactant: COc1cc(OC)c(C(=O)O)cc1C(C)=O
Reactant: BrBr
Solvent: C1COCCO1
Product: COc1cc(OC)c(C(=O)CBr)cc1C(=O)O

Procedure:
5-Acetyl-2,4-dimethoxybenzoic acid (Ber. 41, 1607, 1908) (21.1 g, 0.094 mole) was stirred in dioxane (200 ml.) at room temperature and bromine (5 ml., ca 0.1 mole) was added dropwise. The bromine colour gradually disappeared over 30 minutes and the mixture was then gently warmed in a steambath for 30 minutes, cooled and the dioxane removed in vacuo. The solid product was treated with boiling ethyl acetate, filtered hot and the filtrate evaporated to give 5-bromoacetyl-2,4-dimethoxybenzoic acid, m.p. 236° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][F:15])[N:9]=1)(C)(C)C.[OH-].[Na+]>Cl>[F:15][CH2:14][C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CF)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(CF)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
A suspension of (6-fluoromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.10 g, 0.43 mmol) in 6N HCl (2.00 ml) was warmed to 100° C. and stirred for 6 h. The clear solution was then cooled to room temperature and neutralized with 5N NaOH. The aqueousaqueous phase was extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to yield 6-fluoromethyl-pyridin-2-ylamine (0.04 g, 78%) as colorless oil, which was used crude.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:9]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(C2CCCC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCC2)n1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
300 mg of 3-methylsulfonyl-5-cyclopentyl-1,2,4-thiadiazole and 99 mg of 2-butyn-1-ol were dissolved in 3 g of N,N-dimethylformamide, 62 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 155 mg of 5-cyclopentyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (3)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:48](=[O:57])([O:53][CH:54]([CH3:56])[CH3:55])[O:49][CH:50]([CH3:52])[CH3:51])P(=O)(OC(C)C)OC(C)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]/[P:48](=[O:57])([O:49][CH:50]([CH3:51])[CH3:52])[O:53][CH:54]([CH3:55])[CH3:56])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OC(C)C)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), tetraisopropyl methylenediphosphonate (0.59 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diisopropyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.61 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].C([O-])(=O)C.[NH4+]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:40]([C:39]3[C:38]([CH3:37])=[N:46][CH:45]=[CH:44][CH:43]=3)=[O:41])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 75 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 2-methyl-nicotinic acid in 75% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.22 (d,3H), 1.36 (s,3H), 2.10 (d,1H), 2.42 (m,1H), 2.60 (m,1H), 2.99 (d,1H), 3.20 (m,1H), 3.92 (m,2H), 4.22 (m,1H), 7.22 (dd,1H), 7.65 (d,1H), 7.90 (s,1H), 8.16 (d,1H), 8.23 (s,1H), 8.31 (d,1H), 8.38 (d,1H), 8.45 (d,1H), 9.02 (s,1H), 10.04 (s,1H), 11.26 (s,1H). Retention Time (LC, method: ammonium acetate standard): 2.16 min. MS (M+H+): 535.5.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][C:14](=[O:16])[CH3:15])=[CH:7][CH:8]=1
Reactant: NCCc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccc(C(F)(F)F)cc1
Yield: 29 %

Procedure:
In close analogy to the procedure described above, 2-(4-trifluoromethyl-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([Si:24]([CH3:26])([CH3:25])[O:11][CH2:10][CH2:9][S:8][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc(SCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
A mixture of 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol (60% pure, 3.25 g, 9.1 mmol), 1H-imidazole (1.24 g, 18.2 mmol), and tert-butylchlorodimethylsilane (2.75 g, 18.2 mmol) in 20 mL DMF was stirred at room temperature for 4 h. Solution was concentrated and residue was extracted with water and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (hexane/AcOEt 30:1) to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-3-nitro-pyridine as a yellow oil (2.39 g, 48%). 1HNMR (CDCl3, 400 MHz) δ 0.8 (s, 6H), 0.90 (s, 9H), 2.85 (s, 3H), 3.39-3.42 (t, J=6.7 Hz, 2H), 3.85-3.89 (t, J=6.7 Hz, 2H), 7.13-7.15 (d, J=8.7 Hz, 1H), 8.10-8.13 (d, 1H). Exact mass calculated for C14H24N2O3SSi 328.13 found 329.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH3:32][C:33]([CH3:62])([O:35][C:36](=[O:61])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:55]([C:54]3[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][C:36]([O:35][C:33]([CH3:62])([CH3:34])[CH3:32])=[O:61])[CH:60]=[CH:59][CH:58]=3)=[O:56])=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21][CH2:20]4)[CH:29]=[CH:30][N:31]=3)[CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 132b (0.048 mmol, 20 mg), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (0.053 mmol, 24 mg) and DIEA (0.29 mmol, 38 mg) in DMF (0.16 mL) was added HATU (0.053 mmol, 20 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. TLC to give a yellow syrup (13.8 mg, 34%). MS (ES, m/z): 836.07 [M+H]+.
Reaction SMILES: C([O:8][C@:9]12[C@@H:16]([CH2:17][O:18]CC3C=CC=CC=3)[O:15][C@@H:14]([N:26]3[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[C@@:13]1([O:35][CH3:36])[O:12][CH2:11][CH2:10]2)C1C=CC=CC=1.C>CO.[OH-].[Pd+2].[OH-]>[OH:8][C@:9]12[C@@H:16]([CH2:17][OH:18])[O:15][C@@H:14]([N:26]3[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[C@@:13]1([O:35][CH3:36])[O:12][CH2:11][CH2:10]2
Reactant: CO[C@]12OCC[C@@]1(OCc1ccccc1)[C@@H](COCc1ccccc1)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CO[C@]12OCC[C@@]1(O)[C@@H](CO)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of nucleoside 16 (1.20 g, 2.43 mmol) in methanol (10 cm3) was added 20% palladium hydroxide over charcoal (250 mg) and the mixture was carefully degassed under reduced pressure. An atmosphere of hydrogen was applied and stirring was continued for 12 h. The catalyst was removed by filtration of the reaction mixture through a glass column (1×8 cm) packed with silica gel in methanol. The column was additionally washed with methanol (20 cm3). All fractions were collected, evaporated to dryness and co-evaporated with petroleum ether to yield a glass-like solid. This residue was purified by silica gel chromatography eluting with a gradient of 5-10% methanol in dichloromethane (v/v). The fractions containing the product were collected, combined and evaporated to dryness. The residue was dissolved in anhydrous methanol (5 cm3) and anhydrous benzene (100 cm3) was added. Lyophilisation yielded nucleoside 17 (0.61 g, 79%) as a white solid material. δH (CD3OD) 7.45 (1H, s, 6-H), 5.93 (1H, s, 1′-H), 4.15-3.81 (5H, m, 5′-Ha, 5′-Hb, 2″-Ha, 2″-Hb, 4′-H), 3.43 (3H, s, CH3—O), 2.47-2.40 (1H, m, 1″-Ha), 2.03-1.93 (1H, m, 1″-Hb), 1.92 (3H, s, CH3). δC (CD3OD) 164.1 (C-4), 150.1 (C-2), 138.3 (C-6), 109.6 (C-5), 108.3 (C-2′), 84.4, 84.1, 82.4 (C-1′, C-3′, C-4′), 68.0, 59.5 (C-5′, C-2″), 49.6 (CH3—O), 34.0 (C-1″), 10.5 (CH3). FAB-MS m/z 315.13 [M+H]+, 337.09 [M+Na]+ (Found: C, 49.9; H, 5.7; N, 8.2; C13H18O7N2 requires C, 49.7; H, 5.8; N, 8.9%).
Reaction SMILES: [Na+].[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O-:15])=[O:14])=[O:8])([CH3:5])([CH3:4])[CH3:3].CN(C=O)C.[I-].[K+].[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)[O-])c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCOC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
3-(t-Butyloxycarbonylamino)benzoic acid sodium salt (10 g), DMF (60 ml) and potassium iodide (6.3 g) are mixed, and thereto is added dropwise pivaloyloxymethyl chloride (6 g) under ice cooling. The mixture is stirred at room temperature for 15 hours, and thereto is added ethyl acetate (200 ml). The mixture is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 70% aqueous acetonitrile to give pivaloyloxymethyl 3-(t-butyloxycarbonylamino)benzoate (11.9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: NOCC1CCO[C@@H](c2ccccc2)O1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@H](O)CCO)c(=O)n(C)c1=O
Yield: 60 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O-((R)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1 H) 11.97 (s, 1 H) 7.80 (dd, J=10.11, 1.77 Hz, 1 H) 7.58 (d, J=8.84 Hz, 1 H) 7.15 (t, J=8.59 Hz, 1 H) 4.90 (d, J=4.29 Hz, 1 H) 4.38 (t, J=5.05 Hz, 1 H) 3.71-3.90 (m, 2 H) 3.56-3.67 (m, 1 H) 3.44-3.53 (m, 2 H) 3.21 (s, 3 H) 2.96 (s, 3 H) 1.30-1.59 (m, 2 H). [M+H] calc'd for C17H20FIN4O6, 523; found, 523.