Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]([O:13][C:14]([C@H:16]1[C@@H:21]([NH2:22])[C@H:20]2[CH2:23][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])[CH3:12].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:11]([O:13][C:14]([C@H:16]1[C@@H:21]([NH:22][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Cl:1])[CH:3]=2)[C@H:20]2[CH2:23][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])[CH3:12]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Chloro-4-fluoro-benzaldehyde (0.710 mL, 4.48 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25° C. Sodium cyanoborohydride (0.709 g, 11.3 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (1S,2R,3S,4R)-3-(3-chloro-4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.12 g, 3.44 mmol, 77%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.16 (2H, m), 1.18-1.24 (2H, m), 1.29 (3H, t, J=7.4 Hz), 1.44-1.61 (2H, m), 1.91-1.94 (1H, m), 2.27-2.28 (1H, m), 2.42-2.43 (1H, m), 2.60 (1H, d, J=7.7 Hz), 2.91 (1H, d, J=8.8 Hz), 3.64 (1H, d, J=13.9 Hz), 3.79 (1H, d, J=14.2 Hz), 4.14 (2H, q, J=7.0 Hz), 7.02-7.06 (1H, m), 7.13-7.17 (1H, m), 7.36-7.38 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccccn1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccn1)CC3
Yield: 25 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 2-pyridinecarboxaldehyde. Yield 25%; mp 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]1([NH:26][C:27]2[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN1CCOCC1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Nc2ccccc2Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a mixture of 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.34 mmol) in dichloromethane (10 mL) was added N-phenyl-benzene-1,2-diamine (148 mg, 0.4 mmol) followed by N-methylmorpholine-bound resin (300 mg). The mixture was stirred at an ambient temperature for 16 h and was then heated at reflux for an additional 2 h. Methanol (5 mL) was added and the mixture was stirred at an ambient temperature for 40 h. The mixture was filtered through a plug of celite and the filter plug was washed with hot ethyl acetate (25 mL). The resulting solution was treated with hexanes to precipitate 70 mg (0.16 mmol, 47% yield) of the titled compound as a purple-red solid. 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.29 (s, 1H), 8.74 (s, 1H), 8.10 (m, 1H), 7.58 (m, 3H), 7.25–7.05 (m, 7H), 6.79–6.679(m, 3H), 2.5(s, 3H); MS (EI) m/z 444.05 (M−H)−.
Reaction SMILES: [CH2:1]([P:16](=[O:29])([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[P:2](=[O:15])([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O.[CH2:32](NCC)C>CO>[C:1]([P:2](=[O:15])([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([P:16](=[O:29])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH2:32]
Reactant: CCNCC
Reactant: CCCCCOP(=O)(CP(=O)(OCCCCC)OCCCCC)OCCCCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCCC)OCCCCC)P(=O)(OCCCCC)OCCCCC
Yield: 68.3 %

Procedure:
20.20 g (44.0 mmol) of tetra-n-pentyl methylenebisphosphonate, 6.61 g (220.0 mmol) of paraformaldehyde and 3.22 g (64.0 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 48 hours. After the methanol is eliminated as described above in Example I. 14.08 g of tetra-n-pentyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:52])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:41])([F:40])[C:37](=C=O)[C@@H:36]3OC)=[O:34])[N:28]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-:54].C1[CH2:59][O:58]CC1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:52])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][C:38]([F:40])([F:41])[CH2:37][C@H:36]3[C:59]([OH:58])=[O:54])=[O:34])[N:28]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C(=C=O)[C@@H]3OC)n(-c3ccccc3)n2)CC1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 881 mg 4-[(S)-4-tert-butoxycarbonyl-2-({5-[2-((S)-4,4-difluoro-2-methoxy-carbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 24 ml THF and 6 ml H2O were added 30 mg LiOH at 0° C. The reaction mixture was allowed to warm to RT and was then stirred for 3 h before being acidified by using Amberlite IR-120. The reaction mixture was filtered, washed with MeOH and the combined wash solutions concentrated to give the crude product which was used in the subsequent reaction. Yield: 711 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:5]1[CH:4]=[CH:3][C:2]([C:14]#[C:13][CH2:12][CH2:11][OH:15])=[CH:7][C:6]=1[CH3:8]
Reactant: COc1ccc(Br)cc1C
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#CCCO)cc1C
Yield: 34.3 %

Procedure:
A stirred solution of 4.6 grams (0.023 mole) of 5-bromo-2-methoxytoluene (commercially available), 3 mL (0.040 mole) of 3-butyn-1-ol, 0.30 gram (0.002 mole) of copper(I) iodide, 14 mL (0.100 mole) of triethylamine, and 0.25 gram (0.0004 mole) of dichlorobis(triphenylphosphine)palladium(II) in 60 mL of DMF was heated at 90° C. for about 18 hours. After this time, the reaction mixture was poured into water and extracted with diethyl ether. The ether extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of hexane and ethyl acetate as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 1.5 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]=1.[H][H]>C(O)C.[Pt](=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1
Reactant: [H][H]
Reactant: c1ccc(C2=NCCc3ccccc32)nc1
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(C2NCCc3ccccc32)nc1
Yield: 108.9 %

Procedure:
A solution of 6.1 g of 1-pyridin-2-yl-3,4-dihydro-isoquinoline in 220 ml of absolute ethanol was hydrogenated on 1.25 g of platinum dioxide at 20° C. and 1 bar hydrogen pressure for 90 min. After removal of the catalyst by filtration, [the filtrate] was concentrated under reduced pressure. There were obtained 6.71 g of (RS)-1-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline as a colorless oil, b.p. 140° C./0.1 mbar (bulb-tube).
Reaction SMILES: [Na].[O:2]=[C:3]([CH:7]([CH3:11])[CH:8]([OH:10])[CH3:9])[C:4](O)=[O:5].P(=O)(O)(O)O>O>[OH:2][C:3]1[C:4](=[O:5])[O:10][C@@H:8]([CH3:9])[C:7]=1[CH3:11]
Reactant: CC(O)C(C)C(=O)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na]
Solvent: O
Product: CC1=C(O)C(=O)O[C@H]1C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
840 mg of the sodium salt of compound I were dissolved in 50 ml of H2O and brought to pH 2.0 with dilute phosphoric acid. The solution was held at 85° C. for 30 minutes and, after cooling, extracted with 2×50 ml of ethyl acetate. 320 mg (yield 50%) of compound III separated after removal of the solvent. Compound III, purified by preparative thin-layer chromatography (silica gel 60), exhibited an optical rotation of: [α]D20 : 21.66° (c 1.0 in chloroform).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[O:19][CH2:18][CH2:17][C:16]([C:20]([O-:22])=[O:21])=[CH:15][C:14]=4[CH:23]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].Cl>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[O:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=4[CH:23]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
In methanol (5 ml) was suspended 7-(3,4-methylenedioxy-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (399 mg, 1.23 mmol), and to the mixture was added 1N sodium hydroxide solution (3.69 ml). The mixture was stirred at room temperature for 20 hours, and to the mixture was added 1N hydrochloric acid (3.69 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and diethylether and dried under reduced pressure to give 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid(321 mg, 1.03 mmol, 84%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3]1.[ClH:13]>>[ClH:13].[CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1CC(C)CCN1
Agent: Cl
Product: CC1CCNC(C(=O)O)C1

Procedure:
Racemic ethyl 4-methyl-2-piperidinecarboxylate (trans form) was hydrolyzed by boiling with an excess of conc. HCl for 4 hrs. to give 4-methyl-2-piperidinecarboxylic acid HCl. A desalting of the amino acid HCl was carried out by chromatography using H form ion-exchange resin (Daiaion SK-112 manufactured by Mitsubishi Chemical Industries Limited) in usual method to give racemic 4-methyl-2-piperidinecarboxylic acid. To a solution of the racemic amino acid (143.2 g) in boiling 95% ethyl alcohol (2,900 ml) was added L-tartaric acid (150 g). Upon cooling, the precipitated salt (145.9 g) was collected by filtration. The crude crystals were recrystallized from 90% ethyl alcohol (1,000 ml) to give (2R,4R)-4-methyl-2-piperidinecarboxylic acid L-tartaric acid, m.p. 183.9°-185.0° C., [α]D26 =+4.4 (C=10 in H2O), Analysis Calcd. for C11H19NO8 (percent): C, 45.05, H, 6.53, N, 4.77 Found (percent): C, 45.12, H, 6.48, N, 4.70. The absolute configulation of the molecule was established by X-ray analysis of the crystal which is a 1:1 complex of the molecule with L-tartaric acid. The product was chromatographed on 2,000 ml of Diaion SK-112 ion-exchange resin packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 4% ammonium hydroxide solution was evaporated to dryness to give (2R,4R)-4-methyl-2-piperidinecarboxylic acid (63.0 g) as powdery crystal. Recrystallization of the product from EtOH-H2O yielded the corresponding amino acid, (2R,4R)-4-methyl-2-piperidinecarboxylic acid, m.p. 275.0°-277.8° C., [α]D18 =-18.0 (C=10 2N-HCl), Analysis Calcd. for C7H13NO2 (percent): C, 58.72, H, 9.15, N, 9.78 Found: C, 58.80, H, 9.09, N, 9.71.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1ccc(-n2cnc3ccc(O)nc32)cc1C

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3,4-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C#C[Si](C)(C)C)c1
Yield: 90 %

Procedure:
A mixture of ethyl 3-bromobenzoate (1.0 g, 4.37 mmol), ethynyl trimethylsilane (644 mg, 6.56 mmol), diisopropylamine (929 mg, 9.20 mmol), cuprous iodide(I) (16.6 mg, 0.0872 mmol), and bis(triphenylphosphine) palladium(II) chloride (123 mg, 0.175 mmol) was heated at 45° C. for 5 h in dried THF (8 ml) under argon atmosphere. After cooling, the reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=50/1) to give ethyl 3-[(trimethylsilyl)-ethynyl]benzoate (90%)
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]#[N:4].F[B-](F)(F)F.[CH2:19]([O:21][C:22](=[O:27])[C:23](SC)=[NH2+:24])[CH3:20]>O1CCOCC1>[NH2:4][C:3]1[NH:24][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:27])=[N:1][C:2]=1[CH2:5][CH2:6][C:7]([F:12])([F:13])[C:8]([F:10])([F:9])[F:11]
Reactant: CCOC(=O)C(=[NH2+])SC
Reactant: N#CC(N)CCC(F)(F)C(F)(F)F
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(CCC(F)(F)C(F)(F)F)c(N)[nH]1

Procedure:
A solution of 2-amino-5,5,6,6,6-pentafluorohexanenitrile (0.5722 g, 2.83 mmol) and 2-ethoxy-1-(methylsulfanyl)-2-oxoethaniminium tetrafluoroborate (0.808 g, 3.45 mmol) in dry 1,4-dioxane (5.2 mL) was stirred at 25° C. under N2 for 6 days. The solution was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using DCM/MeOH gradient to afford the desired product, as an orange oil. 1H NMR (500 MHz, CHCl3-d): δ 4.36 (q, J=7.1 Hz, 2H); 2.85 (br s, 2H); 2.41-2.16 (m, 3H); 2.11-1.94 (m, 1H); 1.35 (t, J=7.1 Hz, 3H). m/z 302.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:6]2.[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:11]([C:5]1[N:6]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:29][CH:30]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([Cl:1])[N:10]=[CH:9][N:8]=2)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2ncnc(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The titled compound was prepared by the alkylation of 6-chloro-8-butyl purine (0.063 g, 0.3 mmol) with t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.104 g, 0.3 mmol) according to the procedure described in Step 3 of Example 12. After flash-chromatographic purification of the crude product using ethyl acetate-hexane (1:1), the product was obtained as a foam (0.085 g, 60%).
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH2:15][C:16]#[C:17][CH3:18])/[CH:3]=[CH:4]/[C@H:5]1[CH2:12][CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:13])[O:9]2.[CH3:19][Mg]Br>>[OH:1][C:2]([CH3:19])([CH2:14][CH2:15][C:16]#[C:17][CH3:18])/[CH:3]=[CH:4]/[C@H:5]1[CH2:12][CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:13])[O:9]2
Reactant: CC#CCCC(=O)/C=C/[C@H]1CC[C@@H]2OC(=O)C[C@@H]21
Reactant: C[Mg]Br
Product: CC#CCCC(C)(O)/C=C/[C@H]1CC[C@@H]2OC(=O)C[C@@H]21

Procedure:
Analogously to Example 7(a), 8 g. of (1S,5R,6R)-6-[(E)-3-oxo-1-octen-6-ynyl]-2-oxabicyclo[3,3,0]octan-3-one [preparation see Example 13(a)] is reacted with methylmagnesium bromide, thus obtaining 6.8 g. of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([C:34]([N:36]5[CH2:37][CH2:38][CH2:39][CH2:40]5)=[O:35])[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C(C1CNC1)N1CCCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylpyrrolidin-1-ylmethanone (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 365 as a white solid (65 mg, 48%). LCMS (Method G): RT=6.26 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.73 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.86 (m, 6 H); 3.83 (s, 3 H); 3.69-3.63 (m, 2 H); 3.55-3.42 (m, 5 H); 3.39-3.27 (m, 4 H); 1.98-1.82 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16].C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1F)CC2
Temperature: 120 °C
Yield: 36.4 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)cyclopentanone (1.014 g, 5.17 mmol) and 50% wt. carbonisocyanatidic chloride solution in toluene (1.963 g, 9.30 mmol) was heated at 58° C. for 1 h and at 120° C. for 3 h. The reaction mixture was dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(2,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (499.3 mg, 1.883 mmol, 36.4% yield) as brown solid. LC-MS (M+H)+=265.1.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Li+].I[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26]I)=[CH:19][CH:18]=1>CN(C)C=O>[C:5]([CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])=[CH:19][CH:18]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)CC
Reactant: ICCCOc1ccc(OCCCI)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A solution of 16.1 g (0.126 m) of 3,5-heptanedione in 50 ml of dimethylformamide was added during 15 minutes to a stirred suspension of 1.2 g of lithium hydride in 100 ml of dimethylformamide. The mixture was stirred one hour at room temperature and then a solution of 27.6 g (0.0619 m) of 1,4-bis-(3-iodopropyloxy)benzene in 100ml of dimethylformaide was added. The reaction mixture was heated at 60°-70° C. for about 16 hours and then concentrated in vacuo. The residue was distilled to remove volatiles (150° C., 0.05 mm) and chromatographed on 400 g of silica with chloroform:acetonitrile 95:5. The product was distilled at 250° C. (0.02 mm) and crystallized from ether to give 4.4 g of 1,4-bis(4,4-dipropionylbutyloxy)benzene, m.p. 57°-58° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:27])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH:18]=[C:17]([CH:25]=[O:26])[CH:16]=[CH:15][C:14]1=2.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:18]1[C:19]2[C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22][C:13]([CH3:27])([CH3:12])[C:14]=2[CH:15]=[CH:16][C:17]=1[CH2:25][OH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c1ccc(CO)c2C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
17.13 ml (0.121 mol) of trimethylsilylacetylene and 100 ml of THF were introduced into a three-necked flask. A solution of 48.5 ml (0.121 mol) of n-butyllithium (2.5M in hexane) was added dropwise at −78° C. under a stream of nitrogen and the mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 23.8 g (0.11 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in 100 ml of THF at −78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and was extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 29.9 g (86%) of the expected alcohol were recovered in the form of a yellow oil.