Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:16]=[CH:15][C:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:5](C)[CH:4]=1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Br:28])[CH:22]=1)=O>O1CCCC1.BrCCBr>[Br:28][C:23]1[CH:22]=[C:21]([C:19]([C:3]2[CH:4]=[CH:5][C:6]([O:7][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10])=[CH:15][CH:16]=2)=[CH2:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: Cc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a mixture of magnesium turnings (1.5 g, 0.06 mol, 1.2 eq) in dry tetrahydrofuran (10 mL), was added a portion (⅕) of (4-bromo-2-methyl-phenoxy)-tert-butyl-dimethyl-silane (16.0 g. 0.05 mol, 1.1 eq) in dry tetrahydrofuran (50 mL) and 1,2-dibromoethane (0.5 mL). The resulting solution was refluxed and the other (⅘) portion of the above solution was added and the resulting solution was refluxed for 2 h. After cooled at 0° C. a solution of 3-bromo-4-fluoroacetophenone (11.5 g, 0.05 mol, 1 eq) in dry tetrahydrofuran (40 mL) was added dropwise and the reaction was stirred for 3 h at room temperature. The mixture was quenched with saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with dichloromethane (3×20 mL), dried (sodium sulfate) and the solvent removed in vacuo. The crude latter was dissolved in toluene (200 mL) and a catalytic amount (30 mg) of p-toluenesulfonic acid was added and refluxed for 3 h. The solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (18.5 g, 39%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH:40][CH3:41])[CH3:39]>C1COCC1>[CH2:38]([N:40]([CH3:41])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Reactant: CCNC
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.398 g, 0.742 mmol) and ethylmethylamine (2.0 mL, 23 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give ethyl-methyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a light brown gum (0.227 g, 72.3%). This was dissolved in chloroform, and etheric hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a buff-colored foam (0.254 g); Mass Spectrum (+EI, [M+H]+) m/z 424. 1HNMR (500 MHz, DMSO-d6): δ10.26-10.27 (s, br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.50-8.53 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.04 (d, 1H, J=7.56 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.38 (d, 1H, J=2.19 H) 7.22 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.43 (t, 2H, J=4.88 Hz), 4.05 (s, 3H), 3.40-3.60 (m, 3H), 3.10-3.20 (br, 1H), 2.80 (s, 3H), 1.22-1.26 ppm (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C@@:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[OH:3].S(Cl)(Cl)=O.[CH3:17]O>>[C:1]([O:12][CH3:17])(=[O:11])[C@@:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:4])[OH:3]
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g (6.0 mmol) of (S)-atrolactic acid in 7 mL of methanol was cooled in an ice-water bath and stirred while 0.70 mL (1.15 g, 9.6 mmol) of thionyl chloride was added dropwise. The resulting mixture was stirred at room temperature for one hour, then concentrated under reduced pressure to give 1.1 g of methyl (S)-atrolactate, nD 25 1.5096.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2].[NH3:19]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:19])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccn1
Reactant: N
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 63 g. (0.24 mol) of 2-(3-nitro-4-chlorobenzoyl)pyridine in 3 liters of a saturated solution of ammonia in ethanol was autoclaved at 100° C. for 24 hrs. The mixture was concentrated in vacuo and the resulting residue dissolved in 1.5 liters of warm 5N hydrochloric acid. The solution was cooled to room temperature and neutralized with concentrated ammonium hydroxide. The resulting yellow product was collected, washed with water and dried to yield 2-(3-nitro-4-aminobenzoyl)pyridine, mp. 186° -187° C. (acetone-water).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]1([CH3:34])[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31](O)=[O:32])[CH:24]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31](=[O:32])[CH2:30][O:29][C:25]3[CH:24]=[C:23]([CH3:34])[CH:28]=[CH:27][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: Cc1cccc(OCC(=O)O)c1
Product: Cc1cccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)c1
Yield: 45 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 3-tolyloxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:7][NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)[CH3:2]>O=P(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[O:16][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccccc2)o1
Yield: 95.9 %

Procedure:
A solution of (N′-benzoyl-hydrazino)-oxo-acetic acid ethyl ester (508 mg, 2.15 mmol) in POCl3 (4 mL) was heated to reflux for 3 hrs. The reaction mixture was then concentrated under reduced pressure to remove POCl3 and the resulting residue was dissolved in ethyl acetate. Subsequently, the ethyl acetate layer was washed with water and brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 450 mg (96.2% yield) of 5-phenyl[1,3,4]oxadiazole-2-carboxylic acid ethyl ester as off white solid. LCMS purity: 93.86%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=1)([C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:44]([O:48][CH3:49])(=[O:47])[CH2:45]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[N:12]([CH2:45][C:44]([O:48][CH3:49])=[O:47])[CH:13]=[N:14][CH:15]=1)([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([F:43])[CH:36]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CO
Reactant: CC(C)(C)OC(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1cncc1C(C)(NC(=O)OC(C)(C)C)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-1-(4-cyano-3-fluoro-phenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethylamine, as described above in Step B, (2.6 g, 4.5 mmol), methyl glycolate (532 mg, 5.9 mmol), and N,N-diisopropylethyl-amine (1.6 g, 11.7 mmol) in dry CH2Cl2 (100 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (1.7 g, 5.9 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (50 mL) and the solution was heated to reflux for 1 hour, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with EtOAc—2% MeOH—0.2% NH4OH. The product was further purified by preparative HPLC using a C-18 column and eluting with a gradient of H2O—0.2% triethylamine—0.1% AcOH—0% to 60% CH3CN to yield the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and -benzenesulfonyl chloride. Purity (ELSD, based on MW=561.6)=95%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([O:33][CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:36][CH2:35][CH2:34][O:33][C@H:11]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCCO[C@@H](CCO[Si](C)(C)C(C)(C)C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: OCCO[C@@H](CCO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To (S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyldimethylsilyloxyethoxy)-1-trityloxybutane (32 mg, 0.053 mmol) in dried tetrahydrofuran (THF) (2 ml) was added tetrabutylammonium fluoride (0.10 ml, 0.11 mmol, 1.1 M in THF) and the mixture was stirred for 1.5 hours at room temperature. A small amount of saturated ammonium chloride was added to the reaction mixture. The solution was dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-3-(2-hydroxyethoxy)-4-trityloxybutanol (16 mg, yield 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37](B(O)O)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59](I)=[CH:58][CH:57]=1)#[N:55].C([O-])([O-])=O.[Na+].[Na+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]([C:59]2[CH:60]=[CH:61][C:56]([C:54]#[N:55])=[CH:57][CH:58]=2)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: CCc1c(-c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(-c2ccc3c(c2)cc(-c2ccc(C#N)cc2)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of the boronic acid obtained in Step 1 (75 mg, 0.10 mmol), 4-cyanoiodobenzene (24 mg, 0.10 mmol) Pd(PPh3)4 (12 mg, 0.01 mmol), Na2CO3 (33 mg, 0.30 mmol), DME (0.9 mL) and H2O (0.1 mL) was stirred under argon at 85° C. for 2 hr. The mixture was then concentrated to dryness and chromatographed (silica gel, ethyl acetate in hexanes 0-15% gradient) to provide tert-butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-ethylpyridin-2-yl)-2-(4-cyanophenyl)-1H-indole-1-carboxylate (42 mg, yield: 55%). LC-MS 770.6 [M+H]+, RT 1.16 min. (1 min. Method). This was dissolved in diphenyl ether (1 mL) and heated to 210° C. for 0.5 hr. After cooling the mixture was chromatographed (silica gel, ethyl acetate in hexanes 0-50% gradient) to furnish 6-(2-(4-cyanophenyl)-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid (29 mg, yield: 80%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[S:30][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(-c2ccccc2)s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-c2ccccc2)s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 5-phenylthiophene-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 408.32 g/mol.
Reaction SMILES: [Cl-].[Li+].C[O:4][C:5](=O)[C@@H:6]1[CH2:10][C@@H:9]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8][N:7]1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].[BH4-].[Na+].C(O)(=O)C>O1CCCC1.C(O)C>[CH2:19]([O:18][C:16]([N:7]1[CH2:8][C@H:9]([O:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][C@H:6]1[CH2:5][OH:4])=[O:17])[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of lithium chloride (18.55 g, 437 mmol) and (2S,4R)-N-allyloxycarbonyl-4-methanesulfonyloxyproline methyl ester (67.2 g, 219 mmol) in tetrahydrofuran (280 ml) were successively added sodium borohydride (16.55 g, 437 mmol) and ethanol (420 ml) in one portion. The reaction mixture was stirred at room temperature for 5 hours, cooled to 5° C., treated carefully with acetic acid (25 ml, 437 mmol) to quench the reaction. The solvents were evaporated in vacuo, and the residue partitioned between ethyl acetate (300 ml) and water (300 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated to afford the title compound (56.26 g, 92% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Yield: 39.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) was treated with sodium hydride (8.8 g, 220 mmol) and bromononane (59 g, 54.4 ml, 285 mmol) in DMF (700 ml) as per the procedure of Example 2 (the diamino compound in DMF was cooled in an ice bath during the addition of NaH) to yield 83 g of crude product. 50 g of crude product was purified by silica gel chromatography. Fraction containing 2′-O-nonyl and 3′-O-nonyl product were combined to give a 77:23 mixture (29 g) of the 2′ and 3′ product. Pure 2′-O-nonyl product is obtained by chromatography. 1H NMR (DMSO-d6) δ 0.95 (t, 3, CH3); 1.17 [m, 12, O—CH2—CH2—(CH2)6]; 1.42 [m, 2, O—CH2CH2(CH2)6]; 3.27-3.70 (m, 2, H-5′); 3.50-3.70 [m, 2, O—CH2(CH2)7]; 3.95 (m, 1, H-4′), 4.24 (m, 1, H-3′); 4.40 (m, 1, H-2′); 5.10 (d, 1, 3′—OH, J=5 Hz); 5.50 (t, 1, 5′—OH, J=6 Hz); 5.76 (s, 2, 2—NH2); 5.83 (d, 1, H-1′, J=6.0 Hz); 6.81 (s, 2, 6—NH2); and 7.96 (s, 1, 8-H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:20])[NH:14][NH:15][C:16]=2[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33]C(C)=O)[C@@H:28]([O:37]C(C)=O)[C@@H:27]1[O:41]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:30]1([O:20][C:13]2[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:15][N:14]=2)[O:31][C@H:26]([CH2:25][OH:24])[C@@H:27]([OH:41])[C@H:28]([OH:37])[C@H:29]1[OH:33]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)Cc1ccc(Cc2c(C(C)C)[nH][nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a suspension of 4-[(4-isobutylphenyl)methyl]-5-isopropyl-1,2-dihydro-3H-pyrazole-3-one (0.082 g), acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (3 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 5-isopropyl-4-[(4-isobutylphenyl)methyl]-3-(2,3,4,6-tetraacetyl-β-D-gluco-pyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.29 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and water was added to the residue. The mixture was purified by solid phase extraction (washing solvent: water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-7/1) gave the title compound (0.080 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=2)[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28]#[N:29])=[O:22])=[CH:12][CH:11]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[NH:33]1[C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:23]2[C:21]([C:20]2[CH:30]=[CH:31][CH:32]=[C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:15][CH:14]=3)[CH:19]=2)=[O:22])=[N:29][N:35]=[N:34]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#C[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1)N1CCC[C@H]1c1nnn[nH]1
Yield: 81.1 %

Procedure:
(S)-1-[3-(2′,4′,5′-Trifluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carbonitrile (1.56 g, 3.47 mmol), sodium azide (678 mg, 10.43 mmol) and triethylammonium hydrochloride (1.43 g, 10.43 mmol) in toluene were heated at 100° C. for 17 hrs. The reaction mixture was cooled, concentrated and distributed between 20 mL 0.5N HCl and 100 mL ethyl acetate. The ethyl acetate layer was separated, washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with a 0-40% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in CH2Cl2 to give 1.35 g (81.2%) of [(S)-2-(1H-tetrazol-5-yl)-pyrrolidin-1-yl]-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanone as a white solid. LC-MS (ES) calculated for C25H20F3N5O2, 479.47; found m/z 480.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:35]=[CH:34][C:20]([CH2:21][NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:15]([NH:13][N:14]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:16])=[CH:35][CH:34]=1)=[O:33])([O-:32])=[O:31]
Reactant: NNC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)benzyl]-3-nitrobenzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 252 mg of the title compound (89%) as a orange solid in 95.4% purity by HPLC (Rt: 4.15, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[F:16][C:17]([F:21])([F:20])[CH2:18]O.S(=O)(=O)(O)O>>[F:16][C:17]([F:21])([F:20])[CH2:18][O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: OCC(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(C)Cc1ccc(C(C)C(=O)OCC(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A mixture of 4.12 g of 2-(p-isobutylphenyl)propionic acid, 15 ml of 2,2,2-trifluoroethyl alcohol and 4.9 g of concentrated sulfuric acid was heated at 100° C. for 12 hours. After the reaction was complete, the mixture was poured into ice-water and the resulting mixture was extracted with ether. The ether layer separated was washed sufficiently with successive 5% sodium carbonate solution and water, and dehydrated. The ether was removed by distillation to give an oily product. Distillation of the product in vacuo yielded 4.95 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester as a pale yellow oil, boiling at 73°-74° C./0.12 mmHg. Analysis-Calculated for C15H19F3O2 : C, 62.48; H, 6.64. Found: C, 62.31; H, 6.61.