Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[CH:30]([CH3:33])[CH:31]=[O:32])[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[NH4+].[Cl-]>CCCCCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[CH:30]([CH3:33])[CH:31]([OH:32])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CC(C=O)c1ccc(Oc2ccc(C#N)cc2)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1.6 M solution of n-BuLi in hexane (1.05 ml) was added to 4-bromo-2-methylpyridin (CAS Reg. No. 22282-99-1, 289 mg) in THF (5 ml) at −78° C. The deep red solution was stirred for 10 min. A solution of 4-[3-chloro-4-(1-methyl-2-oxo-ethyl)-phenoxy]-benzonitrile (400 mg) in THF (5 ml) was added at −78° C. The mixture was allowed to warm to 0° C. and stirred for 15 min at that temperature. Saturated aqueous NH4Cl solution was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (200 mg) as a light yellow solid. MS (m/e)=379.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH:13](C)[C:14]#[CH:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[CH3:20][C:21]1[CH:33]=[CH:32][C:24](CN2CCCCC2)=[CH:23][CH:22]=1.C#CC(CS([O-])(=O)=[O:40])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:20][C:21]3[CH:33]=[CH:32][C:24]([OH:40])=[CH:23][CH:22]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: C#CC(C)N1CCC(Cc2ccc(C)cc2)CC1
Reactant: C#CC(C)CS(=O)(=O)[O-]
Reactant: Cc1ccc(CN2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CC2CCN(CCC#Cc3ccc(O)cc3)CC2)cc1
Yield: 80 %

Procedure:
4-(4-Methylbenzyl)-1-(1-butyn-3-yl)piperidine. A mixture of 4-methylbenzylpiperidine hydrochloride (1.129 g, 5.0 mmol), 1-butyn-3-ylmethanesulfonate (0.888 g, 5.0 mmol), and potassium carbonate (2.48 g, 12.5 mmol) in 30 mL of acetonitrile is heated to reflux for 12 hr. The inorganic salt is removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). Evaporation of solvents gives a residue, which is purified by flash chromatography (50% EtOAc in hexane), giving 0.96 g (80%) of the title compound as pale yellow oil. 1H NMR (CDCl3) 1.26 (m, 3 H), 1.50 (m, 1 H), 1.61 (m, 2 H), 1.96 (m, 2 H), 2.31 (s, 3 H), 2.36 (m, 2 H), 2.47-2.59 (m, 4 H), 2.86 (d, J=11.4 Hz, 2 H), 7.07 (dd, J1==7.8 Hz, J2=10.5 Hz, 4 H).
Reaction SMILES: [C:1]([CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:2].S(C)C.CO>C1COCC1>[NH2:2][CH2:1][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: Cc1ccc(F)cc1[C@H](OCC#N)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(cyanomethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.8 g, 0.005 mol) in anhydrous THF (20 ml) was heated to reflux under nitrogen. A solution of BH3.Me2S in THF was added dropwise and stirring was continued under reflux overnight. When the resulting solution was cooled to rt, MeOH was added dropwise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.2 g, yield 66%).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:7].CC(C)=CC(CC(C)(C)C)(C)C.CC(CCC(CCC(CC=C(C)C)C)C)C.[H][H]>>[CH3:10][C:9]([CH3:12])([CH2:8][CH:6]([CH3:5])[CH2:7][C:2]([CH3:4])([CH3:3])[CH3:1])[CH3:11]
Reactant: C=C(C)CC(C)(C)C
Reactant: [H][H]
Reactant: C=C(C)C
Agent: CC(C)=CC(C)(C)CC(C)(C)C
Agent: CC(C)=CCC(C)CCC(C)CCC(C)C
Product: CC(CC(C)(C)C)CC(C)(C)C

Procedure:
Isobutanol can be converted to triisobutylene and/or isododecane as illustrated in FIG. 8. FIG. 8 depicts a typical process configuration for converting isobutanol to a higher alkane comprising predominantly 2,2,4,6,6-pentamethylheptane. Isobutanol is preheated and fed via stream 1 to a reaction vessel that contains 2.5% para toluene sulfonic acid operating at 160° C. and 50 psig. A vapor stream is generated and is passed up through a rectification column before being partially condensed and decanted into two liquid phases at 35° C. and 45 psig. The upper phase is organic comprising mostly isobutylene and is returned to the top of the column as reflux while the lower aqueous phase is removed as stream 2. Uncondensed vapors are let down in pressure across a valve and reheated by a steam exchanger to form isobutylene vapor stream 3 that is fed into a tubular oligomerization reactor packed with Amberlyst-15 catalyst in the form of 0.5 mm beads operating at 100° C. and near atmospheric pressure. At a weight hourly space velocity of 1 g isobutylene per g catalyst per hour, 8.6% of the isobutylene is converted to diisobutylene, 81.6% to triisobutylene and 5.8% to tetraisobutylene, while 4% remains unconverted. The reactor effluent stream 4 is flashed in a drum to safely vent off the unreacted isobutylene and the mixed isomers of isobutylene oligomers is pumped via stream 5 to a trickle bed hydrogenation reactor along with an excess feed of hydrogen gas stream 6 sourced from cylinder storage. The conversion of olefins is quantitative and the hydrogenation reactor effluent stream 7 is flashed in a drum to safely vent off unreacted hydrogen gas and produce a liquid product steam 8 comprising predominantly 2,2,4,6,6-pentamethylheptane. Steps for the conversion of isobutanol to triisobutylene and isododecane (2,2,4,6,6-pentamethylheptane) are known in the art, see, for e.g., Alcantara et al., Reactive Funct. Polymers 45:19-27 (2000); Ludwig et al., J. Catalysis 284:148-56 (2011); and U.S. Pat. No. 5,625,109.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[CH2:8][C:7]1=O)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].S([O:34][CH3:35])(OC)(=O)=O.[CH3:36]N(P(N(C)C)(N(C)C)=O)C>>[CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[C:8]([CH3:36])=[C:7]1[O:34][CH3:35])[CH2:4][CH3:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCC(CC)N1C(=O)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Product: CCC(CC)n1c(OC)c(C)c2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 1-(1-Ethyl-propyl)-6-methyl-4-(2,4,6-trimethyl-phenoxy)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (134 mg, 0.381 mmol) in 2 ml of HMPA was added 60% sodium hydride in oil (20 mg, 0.5 mmol) and the resulting mixture was stirred at 0° C. for 10 min. Dimethyl sulfate (66.5 mg, 0.53 mmol) was added and stirred for 30 min. The reaction mixture was quenched with dilute acid to pH4 and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a clear oil. The oil was purified through silica gel column chromatography using 3% ethyl acetate in hexane as eluent to give 70 mg of the title compound as white solid. 1H NMR (CDCl3) δ 6.88(s,2H), 6.61(s,1H), 4.0(m,1H), 3.95(s,3H), 2,44(s,3H), 2.29(s,3H), 2.26(s,3H), 2.10(s,6H), 1.95–2.1(m,2H), 1.7–1.9(m,2H), 0.78(t,6H)ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)([CH2:15]2)[C:13](=[O:26])[N:12]([CH2:27][CH2:28][CH3:29])[C:11]3=[O:30])=[CH:6][CH:5]=1)([O-])=O.CCOCC.C(Cl)Cl>C(OCC)(=O)C.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]23[CH2:16][C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)([CH2:15]2)[C:11](=[O:30])[N:12]([CH2:27][CH2:28][CH3:29])[C:13]3=[O:26])=[CH:22][CH:21]=1
Reactant: CCCN1C(=O)C2(c3ccc([N+](=O)[O-])cc3)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN1C(=O)C2(c3ccc(N)cc3)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 0.4 g of 1,5-di-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 15 ml of ethyl acetate, hydrogenated in the presence of 80 mg of 5% palladium-on-carbon and worked up. Melting point 149°-150° (from ether/methylene chloride).
Reaction SMILES: O.[C:2]1([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>[Pd].O1CCCC1.C(O)C>[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(CCCCC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc(CCCCCCc2ccccc2)cc1
Yield: 94.5 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 100.9 g of 1,6-diphenylhexane-1,6-dione in 400 milliliters of tetrahydrofuran and 400 milliliters of denatured ethanol as well as 5 milliliters of 6N-hydrochloric acid were introduced, stirred at a normal pressure and contacted with hydrogen gas. After absorption of hydrogen was stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was dissolved in ethyl acetate, washed with a dilute aqueous solution of sodium hydrogencarbonate and water, and thereafter dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, a distillation under a decreased pressure was carried out, to obtain 85.3 g of 1,6-diphenylhexane as colorless liquid.
Reaction SMILES: [NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[CH:8]=1)([CH3:6])[C:3](O)=[O:4].C1COCC1>C(OCC)(=O)C>[NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[CH:8]=1)([CH3:6])[CH2:3][OH:4]
Reactant: C[C@](N)(C(=O)O)c1cc(Br)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@](N)(CO)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Amino-2-(3-bromo-5-nitro-phenyl)-propionic acid (8.41 g, 25.8 mmol) was suspended in abs. THF (39 ml) and cooled to 0° C. BH3 in THF (103 ml, 103 mmol, 1M in THF) was added and the reaction was stirred at r.t. for 1 hr. The reaction was poured onto NaHCO3 (solid, 26 g, 12 eq.), 78 g ice and 155 ml ethyl acetate and stirred for 20 min. at r.t. Phases were separated. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure yielding the title compound as brown oil. 1H-NMR (360 MHz, DMSO-d6): 8.40 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 4.95 (t, 1H), 3.55 (m, 1H), 3.38 (m, 1H), 1.33 (s, 3H); MS: 275 [(M+H)+].
Reaction SMILES: CN(C)C=O.[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.59 g of 1-(3-piperidinopropyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.18 g of 1-(3-piperidinopropyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 54%.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([S:17][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])(=[O:18])[CH3:16]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)Cc1ccc(C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(C)cc1)SC(C)=O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of methyl 2-bromo-3-(4-methylphenyl)propionate (25.7 g), potassium thioacetate (CH3COSK) (13.7 g) and DMF (120 ml) was stirred for an hour at room temperature. The mixture was poured into water and extracted with ether. The ethereal layer was washed with water, dried (MgSO4) and concentrated to give methyl 2-acetylthio-3-(4-methylphenyl)propionate (25.2 g, 100%) as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5]>>[CH2:4]([OH:5])[C@@H:1]([C@H:4]([C@@H:1]([C@@H:4]([CH2:1][OH:2])[OH:5])[OH:2])[OH:5])[OH:2]
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S)-2,3,4,6-Tetra-0-acetyl-1,5-anhydro-1-[5-(1-benzothiophene-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucitol (381 mg) was dissolved in methanol (10 ml). Sodium methoxide (32 mg) was added to the solution, and the mixture was stirred for three hours at room temperature. The reaction mixture was neutralized with acid ion-exchange resin, and the resin was separated by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(1-benzothiene-2-yl)methyl]-2-(cyclopentyloxy)phenyl]-D-glucitol (215 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: COc1ccc(OB([O-])[O-])cc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoylamino)-benzyl)piperidine (0.4g), 4-methoxyphenyl borate (0.14g), 1 M potassium carbonate (2ml) and ethanol (1ml) in toluene (5ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-methoxyphenyl)-cinnamoylamino)benzyl)piperidine (Compound 84) (0.38g) as colorless crystals.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:18][CH2:19][CH2:20][C:21]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:22]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: O=C(Cl)CCBr
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)CCBr
Yield: 97 %

Procedure:
Step A is conducted using 2,2′-diethylhexylamine and 3-bromo-propanoyl chloride and leads to 3-bromo-N,N-bis(2-ethylhexyl)propanamide (Yield: 97%) for which the 1H and 13C NMR characterisations are given below:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: CCC(O)[C@@H](N)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CCC(O)[C@H](CC)Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4S)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 15.5 mg (58%). (57% de 4S,3R: 43% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.84-1.09 (m, 6H, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.57 (d, 6H, J=6.48 Hz, & —CH(CH3)2), 1.42-1.64 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.31 Hz, OH), 3.55-3.71 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.88-4.03 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.56-4.74 (m, 1H, —CH(CH3)2), 4.78-4.99 (m, 2H, —HNCH2-Pyr), 5.20-5.29 & 6.20-6.39 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.20-7.36 (m, 3H, 2×Pyr-H+—N═CH—N—), 7.49-7.60 (m, 1H, Pyr-H), 7.72 (d, 1H, J=7.82 Hz, Pyr-H), 8.71 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (35), 297 (15). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2500.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)c2)cc1

Procedure:
The title compound was prepared from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, and 4-methoxy-benzeneboronic acid in substantially the same manner, as described in Example 1 step c, and was obtained as a white solid, mp 93–94° C.; MS m/e 409 (M+);
Reaction SMILES: [OH-].[Na+].BrBr.[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16](=[O:18])C)[CH3:6].S(=O)(O)[O-:20].[Na+]>O1CCOCC1.O>[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([OH:18])=[O:20])[CH3:6]
Reactant: O=S([O-])O
Reactant: CCc1sc2ccccc2c1C(C)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1sc2ccccc2c1C(=O)O
Temperature: 0 °C
Yield: 92 %

Procedure:
Into a one-litre flask equipped with a mechanical stirrer and a dropping-funnel were introduced 39 g (0.97 mol) of sodium hydroxide with 270 ml of water. The solution was cooled to 0° C by means of an ice-bath and 20 ml (0.333 mol) of bromine were then added through the dropping-funnel followed by 190 ml of dioxan, care being taken to maintain the temperature at 0° C. Finally, still at the same temperature, a solution of 22.6 g (0.111 mol) of 2-ethyl-3-acetyl-benzo[b]thiophene in 25 ml of dioxan were introduced drop-by-drop. The mixture was then allowed to return to room temperature and stirring was maintained for 2 hours. A solution of sodium bisulphite was then added and the reaction medium was acidified and extracted with ether. The organic phase was washed with water, dried and evaporated to dryness to give 20.2 g of 2-ethyl-3-carboxy-benzo[b]thiophene. Yield 92%; M.P. 136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].Cl>O.C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 4-nitrophenol (14.0 g., 0.10 mol), 3-chloropropionic acid (10.8 g., 0.10 mol) and potassium hydroxide (11.2 g., 0.20 mol) in water and ethanol is heated at reflux temperature for 2 hours, cooled to ambient temperature, acidified with concentrated HCl to pH˜1, and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate. The aqueous bicarbonate phase is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The final ethyl acetate extract is washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether and hexane to afford the title compound as an off-white crystalline solid, 5.3 g (25% yield), mp 117-118° C., identified by NMR and mass spectral analyses.