Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:29])[C@H:10]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:38][C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid benzyl ester (2 g, 5 mmol) in DMF (10 mL) was added over 10 min to a slurry of NaH (240 mg 60% dispersion in mineral oil, 6 mmol) in DMF (10 mL) at 0° C. The resultant solution was stirred at this temperature for 30 min. BnBr (1.128 g, 0.785 mL, 6.5 mmol) in DMF (5 mL) was then added slowly to the solution at 0° C. and then mixture warmed to room temperature over 1.5 h. After stirring overnight the reaction was quenched and the solvent removed. The residue was taken up into EtOAc and washed with water, brine and dried with MgSO4. Filtration and removal of the solvent yielded crude material which was subject to column chromatography (silica gel, 50% EtOAc/petroleum ether, Rf 0.85) to give the ester (2.276 g, 92%). 13C NMR (CDCl3) δ 172.0, 155.2, 137.4, 136.5, 135.4, 128.7, 128.5, 128.3, 127.5, 127.4,126.9, 126.9, 126.6, 121.9, 119.4, 119.1, 109.7, 109.2, 79.7, 66.9, 54.5, 49.8, 28.3, 27.9. ISMS: 485 (M+H),
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH2:45][O:46][N:47]([CH3:49])[CH3:48])[C@@H:21]1[OH:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:31]([NH:30][C:29]1[C:28]2[N:27]=[CH:26][N:25]([C:42]=2[N:41]=[CH:40][N:39]=1)[C@@H:23]1[O:24][C@H:20]([CH2:19][OH:18])[C@@H:21]([OH:50])[C@H:22]1[O:43][CH2:44][CH2:45][O:46][N:47]([CH3:49])[CH3:48])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Solvent: C1CCOC1
Product: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Reaction time: 24 h
Yield: 86.5 %

Procedure:
5′-O-t-Butyldiphenylsilyl-N6-benzoyl-2′-O-(dimethylaminooxyethyl)adenosine (7.77 g, 11.15 mmol) was dissolved in THF (110 mL), and tetrabutylammonium fluoride (TBAF)on silica (1.0-1.5 mmol/g silica, 10.1 g) was added. After stirring for 24 hours the solid was filtered, washed with THF, and the solvent was evaporated in vacuo to give a solid which was purified by column chromatography using CH2Cl2-EtOAc-MeOH, 75:20:5, to give the title compound as a solid (4.42 g, 86%).
Reaction SMILES: [N:1]1C=C[CH:4]=[CH:3][CH:2]=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].[OH2:18]>>[OH:11][CH:3]([CH3:4])[C:2]#[N:1].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([O:18][CH2:4][CH2:3][C:2]#[N:1])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: c1ccncc1
Reactant: O
Product: CC(O)C#N
Product: N#CCCOC(=O)c1c(Cl)cccc1Cl

Procedure:
A solution of 3.7 grams (0.052 mole) of 2-hydroxypropionitrile in 8.9 grams (0.10 mole) of pyridine was prepared. To this stirred solution at ambient temperature was added 10.4 grams (0.05 mole) of 2,6-dichlorobenzoyl chloride dropwise during a 20 minute period. The exothermic reaction caused the temperature of the reaction mixture to rise to 50°. The reaction mixture was heated at 75°-80° for 75 minutes. The cooled reaction mixture was poured into 150 ml of water and the mixture was stirred. The mixture was extracted with 200 ml of diethyl ether. The extract was washed with three portions of 30 ml each of an aqueous solution of 3% hydrochloric acid, then three portions of 30 ml each of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an amber oil. The oil solidified and the solid was recrystallized from hexane-diethyl ether to give an oily semi-solid. The semi-solid and mother liquor were combined and concentrated under reduced pressure to an oil. An attempt to sublime the oil failed. The oil was distilled under reduced pressure using a short-path distilling system to give 3.1 grams of 2-cyanoethyl 2,6-dichlorobenzoate; bp 117°/0.005 mm. The oil product solidified; mp 45°-46° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:40])[F:39])[CH2:24][CH2:23]1>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([NH2:1])[CH:7]=3)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:39])[F:40])[CH2:26][CH2:27]1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1N
Yield: 74 %

Procedure:
1.04 g of 2,4-diaminotoluene, 104 mg of 4-(dimethylamino)pyridine and 4.9 ml of N,N-diisopropyl-N-ethylamine were dissolved in 40 ml of acetonitrile. Under ice-cool stirring, 3.70 g of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) was added by four portions. After stirring for 1 hour, the solvent was distilled off under reduced pressure and diluted with water. The reaction solution was alkalified with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.56 g of the objective compound as a pale brown amorphous.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1B(O)O.CCO.[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1>C1(C)C=CC=CC=1.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>[CH3:21][O:22][C:23]([C:24]1[CH:25]=[C:26]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:27]=[CH:28][CH:29]=1)=[O:31]
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Reactant: COC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
(The following reaction is done in an N2 atmosphere.) To a solution of 2,3,4-Trimethoxyphenylboronic acid (32) (1.40 g, 6.60 mmol) in toluene (15.0 mL) is added EtOH (2.0 mL), Pd(PPh3)4 (208 mg, 0.18 mmol) and Na2CO3.10H2O (4.81 g, 16.80 mmol) in water (5.2 mL). The resulting mixture is carefully degassed (5 times alternating vacuum and flushing with N2). A solution of Methyl-3-bromobenzoate (9) (1.29 g, 6.00 mmol) in toluene (9.0 mL) is added by syringe, the resulting mixture is again carefully degassed and stirred overnight at 100° C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine, dry with Na2SO4 and remove solvent. Purify crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as a yellowish oil (1.07 g, 58%). 1H NMR (400 MHz, CDCl3): 3.66 (s, 3H); 3.89 (s, 3H); 3.92 (s, 6H); 6.74 (d, 1H, J=8.6 Hz); 7.03 (d, 1H, J=8.6 Hz); 7.44 (t, 1H, J=7.8 Hz); 7.70 (d, 1H, J=7.6 Hz); 7.97 (d, 1H, J=7.8 Hz); 8.15 (br.s 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[C:19]([C:24]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[N:27][N:26]4[CH2:35][CH2:36][CH2:37][C:25]=34)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.CO.[OH-].[NH4+]>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][NH:15]3)=[C:25]2[CH2:37][CH2:36][CH2:35][N:26]2[N:27]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)cccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nn3c(c2-c2cccc4[nH]ccc24)CCC3)nc1
Temperature: 25 °C
Yield: 8 %

Procedure:
Add trifluoroacetic acid (0.4 mL) to a solution of 4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-indole-1-carboxylic acid tert-butyl ester (34 mg, 0.085 mmol) in methylene chloride (2 mL) at 0° C. Allow the reaction to warm to room temperature slowly over 19 h. Dilute the reaction with methylene chloride and methanol. Add concentrated aqueous ammonium hydroxide (2 mL) and concentrate in vacuo. Purify by flash column chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 11 mg (8% yield over 2 steps) of the title compound as a white solid. MS (APCI) m/e 301 (M+1). 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 8.30 (d, J=4 Hz, 1H), 7.65 (td, J=8, 2 Hz, 1H), 7.46 (d, J=8 Hz, H), 7.26 (d, J=8 Hz, 1H), 7.17-7.13 (m, 2H), 7.00 (t, J=8 Hz, 1H), 6.81 (d, J=7 Hz, 1H), 4.21 (t, J=7 Hz, 2H), 2.85 (dd, J=8, 7 Hz, 2H), 2.64-2.55 (m, 2H). HPLC: >99%, Rt=15.1 min. TLC (SiO2): Rf0.2 (1:1 methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3ccc(F)cc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.062 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.132 g, 0.29 mmol) and methylamine (0.092 g, 2.9 mmol). mp 179-181° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[CH2:15]1COC[CH2:16]1>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:15][CH3:16])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: C1CCOC1
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1F
Product: CCC(O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled solution of N-(2-Fluoro-4-formylphenyl)methansulfonamide (20-3, 0.424 g, 2 mmol) in THF (20 mL) at 0° C. was treated with Grignard reagent (4 mmol) and stirred at 0° C. for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant to N-[2-fluoro-4-(1-hydroxypropyl)phenyl]methanesulfonamide (20-4, LJO-337).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1cc(Cl)c(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CNCc2cc(Br)c(Cl)cc2OC)c(OC)c1
Reaction time: 1 h

Procedure:
The solution of 5-bromo-4-chloro-2-methoxybenzaldehyde (300 mg, 1.2 mmol) and 2,4-dimethoxybenzyl amine (167 mg, 1.2 mmol) in MeOH/DCM (4:1, 10 mL) was stirred at room temperature for 5 h. To this mixture, NaBH4 (100 mg, 13 mmol) was added in two portions. The mixture stirred for 1 h and then partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product. The crude product was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:29]=[C:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=1)[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1)=[O:9].C(N(CC)CC)C>CO.C1COCC1.[Pd]>[CH3:35][N:33]([CH3:34])[S:30]([C:28]1[CH:29]=[CH:2][C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[O:9])=[CH:26][CH:27]=1)(=[O:31])=[O:32]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 20 h
Yield: 32.3 %

Procedure:
To a solution of 3-{2-chloro-4-[(dimethylamino)sulfonyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.0 g, 1.9 mmol) in methanol (20 mL) and THF (20 mL) was added triethylamine (1.5 mL) and 10% palladium on carbon (100 mg). The resulting mixture was stirred under an atmosphere of hydrogen for 20 hours. The mixture was filtered through Celite® and evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with 2M hydrochloric acid (100 mL). The organic phase was separated and the aqueous reextracted with DCM (100 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford the title compound (300 mg, 32%).
Reaction SMILES: CCN(CC)CC.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][CH:17]1[C:26](=O)[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18]1.CC(OC)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][CH:17]1[C:26](=[N:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25][CH2:24][C:19]2([O:20][CH2:21][CH2:22][O:23]2)[CH2:18]1
Reactant: NCc1ccccc1
Reactant: CC1CC2(CCC1=O)OCCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC2(CCC1=NCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of NEt3 (560 mL, 4.02 mol) and benzylamine (131 mL, 1.20 mol) in CH2Cl2 (500 mL) was added TiCl4 (500 mL of 1.0 M solution in CH2Cl2, 0.500 mol) over 30 min while the internal temperature was kept below −10° C. The resulting dark red suspension was stirred at −20° C. to −30° C. for 15 min, then a solution of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (170 g, 1.00 mmol) in CH2Cl2 (500 mL) was added at −10° C. The resulting grey-yellow suspension was allowed to warm to room temperature over 2 h, then stirred at room temperature for 16 h. MTBE (1.0 L) was added to the reaction mixture, and the yellow suspension was stirred at room temperature for 30 min and filtered through a pad of Solka Floc. The cake was washed with MTBE (4×500 mL), and the combined filtrates were concentrated to provide N-(7-methyl-1,4-dioxaspiro[4.5]dec-8-ylidene)-1-phenylmethanamine, which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14]O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=NC1CCCCC1)=NC1CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([O:5][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: C=CC(C)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-methylbut-3-enoic acid (9.5 g, 95 mmol) in DCM (80 mL) was added phenylmethanol (10.26 g, 95 mmol), N,N′-methanediylidenedicyclohexanamine (19.58 g, 95 mmol) and DMAP (1.159 g, 9.49 mmol) (exothermic reaction) and the resulting mixture was stirred at rt over weekend. The reaction mixture was filtered through a pad of CELITE® to remove the solids and the filtrate was collected and concentrated. The filtrate was then concentrated and subjected to silica gel chromatography to yield the desired product as colorless oil.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:28][OH:29])[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:27])[CH2:28][O:29][N+:6]([O-:8])=[O:7])=[O:24])([CH3:20])([CH3:21])[CH3:19]
Reactant: O=[N+]=O
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In 200 ml of dry acetonitrile were suspended 17.9 g of nitronium tetrafluoroboron, and 17.5 ml of 2,4,6-collidine were added dropwise thereto at -5° C. to 0° C. under a nitrogen stream. The reaction mixture was stirred at 0° C. for 30 minutes, 10.7 g of N-t-butoxycarbonyl-L-alaninol were added thereto, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Then, the solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. The insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The thus obtained yellow oil was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (9:1) as an eluent to obtain 7.12 g of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:8][OH:9]>N1C=CC=CC=1>[CH3:1][S:2]([O:9][CH2:8][CH:7]([CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=[O:4])=[O:3]
Reactant: CC(CO)Cc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(COS(C)(=O)=O)Cc1ccc2ccccc2c1
Yield: 66 %

Procedure:
11 g (0.1 mole) of methanesulphonyl chloride are added dropwise to 14 g (0.074 mole) of 2-methyl-3-β-naphthylpropanol (crude) in 80 ml of absolute pyridine at 0° C., with stirring, the mixture is stirred for a further 16 hours at room temperature when the addition has ended, excess pyridine is removed by distillation in vacuo, the residue is taken up in water, the mixture is extracted several times with methylene chloride, the extract is dried over sodium sulphate and the solvent is removed in vacuo. 13.6 g (66% of theory) of 1-methanesulphonyloxy-2-methyl-3-β-naphthyl-propane are obtained as an oil. (IR: η=1345 and 1180 cm-1). ##STR48##
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>N1C=CC=CC=1.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([N:39]5[CH2:40][CH2:41][CH:36]([N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:37][CH2:38]5)=[N:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)n(C)c1=O
Yield: 41.7 %

Procedure:
A solution of 7-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethylxanthine (196 mg) and 4-piperidinopiperidine (102 mg) in pyridine (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: acetone: triethylamine 1:1:0.1) to provide the title compound (108 mg).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:12]1[CH:17]=[C:16](O)[C:15]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[Na+:23].C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Na+:23]
Reactant: CCCCCCCCC(=O)O
Reactant: O=S(=O)([O-])c1ccccc1O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
A 300 ml, round-bottom flask with a nitrogen inlet and a magnetic stir bar was flushed with nitrogen for ten minutes. Nonanoic acid (4.45 g, 28.0 millimoles—mmol), sodium phenolsulfonate (5.00 g, 25.0 mmol) and TFA were placed in the flask which was sealed with a septum cap and the resulting slurry was stirred while being cooled by an ice-water bath. A single rapid addition of TFAA (6.5 ml) was made via syringe. Within one minute the slurry is dissolved to yield a homogeneous solution. The stirring was continued for five minutes. The volatiles were removed by rotary evaporation yielding a white solid that was washed with 100 ml of acetone and collected on a Buchner funnel. The resulting white solid was dried under reduced pressure yielding 7.90 g (94% yield) of sodium 4-(nonanoyloxy)benzene-sulfonate (NOBS). 1H and 13C NMR show complete conversion of the SPS to NOBS.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1>C1(C)C=CC=CC=1.CCOCC>[Br:23][C:19]1[N:18]=[C:17]([C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C#N
Reactant: Brc1cccc(Br)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A dried 500 mL round bottom flask was charged with a solution of iso-butyronitrile (3.29 g, 4.27 mL, 47.6 mmol) in toluene (100 mL), the solution was cooled down to 0° C. and KHMDS 0.5 m in toluene (100 mL, 50.0 mmol) was added slowly. After complete addition, the reaction mixture was allowed to warm up to room temperature over 1 hour. The resulting mixture was added to a solution of 2,6-dibromopyridine (28.2 g, 119 mmol, available commercially from Aldrich) in toluene (100 mL) While adding, the light yellow solution became quickly dark reddish. The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was diluted with ether, washed with a saturated aqueous solution of ammonium chloride and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The semi-solid residue was suspended in a small amount of toluene and filtered off, the light brown solid corresponded to 2,6-dibromopyridine recovered. Filtrate was purified by flash chromatography (silica gel 50 μm, 220 g, Rediflash Teledyne-Isco) eluting with 0 to 50% over 20 min dichloromethane/hexanes to give 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (7.608 g, 28.4% yield) as a light yellow oil that solidified into a white solid upon standing. 1H NMR (CHLOROFORM-d) δ: 7.58-7.61 (m, 2H), 7.42-7.46 (m, 1H), 1.76 (s, 6H); LC-MS 225.0 226.9 [M+H]+.