Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1>CN(C)C=O>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:14][CH:13]=1
Reactant: NCc1ccncc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Yield: 71.4 %

Procedure:
A mixture of 74 g (0.5 mole) of phthalic anhydride, 60 g (0.56 mole) of 4-pyridinemethylamine and 200 mL of dimethylformamide was heated under reflux for 2 hours. The cooled mixture was filtered and the solids were washed with ether and dried to give 85.1 g of 2-(4-pyridinylmethyl)-1H-isoindole-1,3(2H)-dione, m.p. 164°-165°. Another 24.0 g was obtained by crystallization of the concentrated mother liquors from dimethylformamide. Combined yield: 99.1 g (83%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C1CCCCC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:28]([O-:33])=[O:29])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Solvent: ClC(Cl)Cl
Solvent: C1=CCCCC1
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)-phenylacetic acid in chloroform with 1.5 equivalents of cyclohexene is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([Mg]Br)C=C.[F:14][C:15]1[CH:16]=[CH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:25]=3[O:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[O:21][C:20](=[O:43])[C:19]=2[CH:44]=1.[N-]=C=O>C1COCC1.C(OCC)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH:23][C:22](=[O:21])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:26][C:25]=2[O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[C:19]([CH:44]=1)[C:20]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:43]
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Reactant: Nc1ccccc1F
Agent: C=CC[Mg]Br
Agent: [N-]=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccccc2F)CC1
Reaction time: 0.08 h

Procedure:
A solution of 2-fluoroaniline (22.1 mg, 0.18 mmol) in dry THF (1 mL) was treated with a 1 M diethyl ether solution of allyl magnesium bromide (0.2 mL). The reaction was stirred for 5 minutes before adding 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one (25 mg, 0.06 mmol) in THF (1 mL). The reaction was stirred overnight at ambient temperature, concentrated to dryness and mixed with saturated aqueous NaHCO3 (1 mL) and CH2Cl2 (2 mL). The mixture was filtered through a plug of diatomaceous earth and treated with an isocyanate resin (methylisocyanate polystyrene HL, 0.360 mmol) overnight. Purification consisted of applying this mixture directly onto a column of silica and eluting with 1% MeOH in CHCl3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:17]2[N:16]3[C:11]([C:12]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[CH:13][CH:14]=[CH:15]3)=[CH:10][C:9]=2[N:8]=[C:7]([CH3:27])[N:6]=1.[C:28]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:28]1([NH:1][CH2:2][CH2:3][NH:4][C:5]2[C:17]3[N:16]4[C:11]([C:12]([C:18]5[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=5[CH3:26])=[CH:13][CH:14]=[CH:15]4)=[CH:10][C:9]=3[N:8]=[C:7]([CH3:27])[N:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCNC4CCCC4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Treat a solution of (2-aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-yl]amine (0.07 g, 0.19 mmol), cyclopentanone (0.02 mL, 0.19 mmol) and acetic acid (0.01 mL, 0.19 mmol) in dry dichloroethane (3 mL) with sodium triacetoxyborohydride (0.06 g, 0.27 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL) and wash with saturated aq NaCl (50 mL). Dry the organic portion over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC (10% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]3[CH:13]=[C:12]([NH2:9])[CH:28]=[CH:27][C:15]=3[O:16][C:17]=2[CH:23]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: Nc1ccc2c(c1)Oc1ccc(N)cc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a mixture of 1200 ml of anisole and 800 ml of THF were added 69.7 g (0.254 mole) of 2,7-dinitrodibenzodioxin and 22.2 g of 10% palladium/carbon and hydrogen gas was passed through the mixture with stirring at room temperature for 8 hours. The 10% palladium/carbon was removed by filtration, then a precipitate containing the 10% palladium/carbon was collected by filtration, and the precipitate was rinsed with THF. The rinsings were concentrated and dried under reduced pressure to give 25.0 g (0.117 mole, 46.0% yield) of 2,7-diaminodibenzodioxin. The product showed a purity of 98.1% (HPLC, 254 nm).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](Cl)=[O:16].[Cl:23][C:24]1[CH:25]=[C:26]([NH2:33])[C:27](=[CH:31][CH:32]=1)[C:28]([OH:30])=[O:29]>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([NH:33][C:26]1[C:27](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=1)[C:28]([OH:30])=[O:29])=[O:16]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)Nc2cc(Cl)ccc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
In a mixture of 3.4 g of 4-chloroanthranilic acid in 50 ml of tetrahydrofuran is dissolved 3 ml of triethylamine, to this mixture is added slowly a solution of 4.5 g of 3,4-dimethoxycinnamoylchloride in tetrahydrofuran under room temperature, and this solution is stirred at room temperature for 5 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration and recrystallized from a mixture of dimethylformamide and water to obtain 5.9 g of N-(3,4-dimethoxycinnamoyl)-4-chloroanthranilic acid as colorless prisms.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](Br)[CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][N:26]([CH3:30])[C:25]2=[O:31])[CH:20]=[C:21]([Cl:23])[CH:22]=1.O>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:11][CH2:12][CH2:13][C@:27]32[N:26]([CH3:30])[C:25](=[O:31])[N:24]([C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)[C:28]3=[O:29])=[CH:6][CH:5]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reaction time: 30 h
Yield: 110.8 %

Procedure:
KOH flakes (1.3 g, 23.2 mmol) were added at RT to a solution of 1-bromo-4-(1,4-dibromobutyl)benzene (4.08 g, 10.6 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.5 g, 9.6 mmol, prepared according to Fujinami et al. cited above) in dry DMSO (40 ml). After 30 h at RT, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to yield an orange oil (4.98 g) which was chromatographed over silica gel (DCM/pentane 50/50) to give 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (2.1 g) as a white solid having the relative stereochemistry depicted above. 1H NMR (CDCl3): 7.45 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.03 (2H, d, J=8.4 Hz), 6.65 (2H, m), 3.36 (1H, dd, J1=12.9 Hz, J2=6.2 Hz), 3.13 (3H, s), 2.4-2.65 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[CH3:26]C[O-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:26])[C:16]2=[O:25])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1[N+](=O)[O-]

Procedure:
using ethyl 2-nitro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate with sodium ethylate in ethanol there is obtained ethyl 2-nitro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 188°-190° C.,
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:3]1=[O:4].[BrH:10].S(=O)(=O)(O)O>O>[Br:10][CH2:6][CH2:7][CH2:8][CH2:9][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC1CCCCOC1=O
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(CCCCBr)C(=O)O
Temperature: 130 °C
Yield: 53.3 %

Procedure:
To 2-methylcaprolactone (1.8 g, 14 mmole) was added a solution mixture of 47% aqueous hydrobromic acid (10.5 ml) and concentrated sulfuric acid (2.6 ml), and the reaction was conducted under heating at 130° C. for 3 hours. After the reaction solution was cooled, water was added, and the product was extracted with ether. The organic layer was washed with water, dried and the solvent was evaporated in vacuo. The residue was chromatographed on a column of silica gel using isopropyl ether to give 6-bromo-2-methylhexanoic acid (1.56 g, 53.3%) [NMR (δ value): 1.18 (3H,d,6 Hz), 2.25-2.8 (1H,m), 3.40 (2H,t,6 Hz), 11.56 (1H,COOH)].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])([CH3:3])[CH3:2].N#C[Br:19]>CCOCC>[Br:19][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: N#CBr
Reactant: COCCOCOc1ccccc1C(C)C
Solvent: CCOCC
Product: COCCOCOc1c(Br)cccc1C(C)C
Temperature: 7.5 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
In dry ether (100 mL) was dissolved 5.18 g (23.1 mmol) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene obtained in Example 18(1), 22.3 mL (35.7 mmol) of n-butyl lithium-hexane solution (1.60M) was added dropwise to the solution in an ice bath (reaction solution temperature: 5-10° C.), and the mixture was stirred in an ice bath for 5 hours. To the reaction mixture was added 8.20 g (69.7 mmol) of 90% cyanogen bromide while maintaining the reaction solution temperature to 5-10° C. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (300 mL), and extracted with ether. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=100:1) to obtain 3.40 g (11.2 mmol, Yield: 48.5%) of 1-bromo-3-isopropyl-2-[(2-methoxyethoxy)-methoxy]benzene.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[CH:13][C:14]=1[CH2:15][CH3:16])(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[NH2:7][CH2:8][C:9]1[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[CH:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(C)[nH]c(=O)c1CN
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Tert-butyl((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (1.00 g, 3.75 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (20 mL). The mixture was stirred for 2 hr. The reaction mixture was filtered. The residue was washed with dichloromethane, dried to afford 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one hydrochloride (593 mg, 77.9%) as a light yellow solid. LRMS (M+H+) m/z: calcd 166.11. found 167.1. 1H NMR (400 MHz, D2O): δ ppm 6.31 (s, 1H), 4.06 (s, 2H), 2.57 (q, J=7.86 Hz, 2H), 2.25 (s, 3H), 1.10 (t, J=7.53 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:24]=1[NH2:25]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:25][C:24]4[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:23]=4[F:22])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Solvent: CC(C)O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)ccc3F)ncc21

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (50 mg, 0.16 mmol), 2,5-difluoroaniline (31 mg, 0.24 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (20 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.85 (m, 11H) 4.02 (t, J=14 Hz, 2H) 4.68 (d, J=8 Hz, 1H) 6.88 (t, J=8 Hz, 1H) 7.26 (td, J=10, 6 Hz, 1H) 7.74-7.96 (m, 1H) 8.24 (s, 1H) 9.04 (br. s., 1H). [M+H] calc'd for C19H19F4N5O, 410. found 410.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[CH2:16][CH:15]=[CH:14][C@H:13]1[C@@H:17]([OH:30])[CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:30][C@H:17]([C@@H:13]2[CH:14]=[CH:15][CH2:16][O:12]2)[CH2:18][NH:19][C:20]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:29])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(NC[C@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H](CNC(=O)OCc2ccccc2)[C@@H]2C=CCO2)cc1
Yield: 61.4 %

Procedure:
A solution of p-toluenesulfonyl chloride (252 mg, 1.32 mmol) in pyridine (7.0 mL), alcohol (17) (290 mg, 1.10 mmol) was stirred at 24° C. for 2 days then diluted with water (15 mL). The product was extracted into tert-butyl methyl ether (3×20 mL) then dried (MgSO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 7:93 to 20:80 gave tosylate (32) (282 mg, 61%) as a colourless oil. TLC (Rf=0.35, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=19.02 min., HPLC-MS 418.2 [M+H]+, 857.3 [2M+Na]+; [α]D11 −86.1° (c=1.103, CHCl3; δH (500 MHz, CDCl3) 2.37 (3H, s, aryl-CH3), 3.29-3.37 and 3.50-3.56 (2H total, m, CH2NH), 4.53-4.56 (2H total, m, OCH2CH═CH), 4.62-4.66 m, OCHCH═CH), 4.85-4.90 (1H, m, CHOTs), 5.02-5.08 (2H, m, OCH2Ph), 5.02 (1H, brs, NH), 5.65-5.70 and 5.94-5.98 (2H total, m, CH2CH═CH), 7.27 (2H, d, J=8.12 Hz, aromatic CH3CCH), 7.29-7.37 (5H, m, phenyl CH), 7.76 (2H, d, J=8.23 Hz, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.609 (aryl-CH3), 41.749 (CH2NHCbz), 66.833 (CH2Ph), 75.939 (OCH2CH═CH), 81.235 (CHOTs), 85.203 (OCHCH═CH), 124.702, 127.887, 128.026, 128.128, 128.504, 129.687 and 129.757 (OCH2CH═CH and aromatic CH), 133.591 (CHOSO2C quaternary), 136.368 (Cbz quaternary), 144.906 (CH3C quaternary), 156.271 (Cbz C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:27](=[O:28])[CH2:26][C:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:31])[CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (prepared in a similar manner as described in International Patent Application No. WO 04/043965, 0.949 g, 3.96 mmol), 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.86 g, 3.96 mmol), HOBt (1.334 g, 8.71 mmol), and Hunig's base (2.074 mL, 11.88 mmol) in methylene chloride (20 mL) was treated with EDC (1.669 g, 8.71 mmol), and the reaction was allowed to stir for about 16 h at room temperature. The mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with 1M NaOH, 3× with 1M HCl, once with water, and once with brine, dried over sodium sulfate, and concentrated in vacuo to yield an amber solid which was used as-is in the next step.
Reaction SMILES: [CH2:1]([O:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25](OC(=O)C)(=[O:27])[CH3:26].B(F)(F)F.CCOCC>>[C:25]([C:22]1[S:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccs1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
When in Example 2, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:22][CH2:21][C:18]2[CH:19]=[N:20][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]=1[CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: COc1cc(NCCc2ccc(C(F)(F)F)nc2)ccc1C
Yield: 31.3 %

Procedure:
In analogy to example 6, step 1, 2-methoxy-1-methyl-4-nitro-benzene (988 mg, 5.91 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.0 g, 5.37 mmol, prepared in example 1, step 1) to give the title compound (521 mg, 31%) as an orange oil MS m/e: 311.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1cc(Br)cc(OCC(F)(F)F)c1
Yield: 77 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with 2,2,2-trifluoro-ethanol using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a white solid (yield: 77% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.[BH3-][C:40]#N.[Na+].CC(O)=O.C=O>CO.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:40])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (3.76 g, 7.2 mmol) and NaBH3CN (5.9 g, 93.6 mmol) in MeOH (40 mL) was added AcOH to adjust to pH=6. Then, 37% HCHO (8.7 mL, 122.4 mmol) was added and the mixture was stirred at 30° C. for 1.5 h. Water (15 mL) was added and the mixture was concentrated in vacuo. Then, the mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=100:1-20:1) to obtain the target (2.4 g, yield: 67%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.35-7.30 (m, 5H), 6.22 (s, 1H), 5.55-5.52 (m, 1H), 5.09 (s, 2H), 5.04-5.01 (m, 1H), 4.40-4.38 (m, 1H), 2.76-2.65 (m, 3H), 2.29-2.22 (m, 2H), 2.18 (s, 3H), 2.11-1.95 (m, 2H), 1.78-1.71 (m, 2H), 1.64-1.61 (m, 2H), 1.59 (s, 3H), 1.41-1.39 (m, 1H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 537.3 [M+1]+.
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.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41](Cl)(=[O:43])=[O:42])=[C:36]([CH3:45])[C:35]=1[CH3:46]>>[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:41]([C:37]4[C:38]([CH3:40])=[CH:39][C:34]([O:33][CH3:32])=[C:35]([CH3:46])[C:36]=4[CH3:45])(=[O:43])=[O:42])=[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: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)cc(OC)c(C)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=633.7)=80%.