Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]([CH3:30])([CH3:29])[CH3:28]>CCO>[CH3:26][S:23]([O-:25])(=[O:24])=[O:22].[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:21][N+:27]([CH3:30])([CH3:29])[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)CC(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C[N+](C)(C)C
Product: CS(=O)(=O)[O-]
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a suspension of (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)-butanoate (149 mg, 0.38 mmol) in EtOH (2 mL) at 0° C. was added xs Me3N in EtOH (4.2 M, 2 mL, 8.4 mmol). The reaction was sealed and stirred at the temperature for 15 min and then at rt for 3 d. Later, the reaction was concentrated to dryness and purified by preparative TLC (silica gel, 5% MeOH/DCM) to afford the title compound as a colorless gum (43 mg, 37%). 1H NMR (300 MHz, CDCl3): δ=7.35-7.20 (m, 5H), 5.14-5.00 (AB quartet, J=12 Hz, 2H), 4.46 (br, 1H), 3.50-3.25 (m, 2H), 3.24 (s, 9H), 2.85-2.65 (m 2H), 2.70 (s, 3H), 1.38 (s, 9H); MS ESI [M]+, calcd for [C19H31N2O4]+ 351.5 found 351.2 m/z (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:33])[C:23]=2[C:22](F)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:33])[C:23]=2[C:22]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c2ccccc2sc2c(OCc3ccccc3)ccc(F)c12
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2ccc(OCc3ccccc3)c3sc4ccccc4c(=O)c23)cc1
Temperature: 140 °C
Yield: 100.2 %

Procedure:
To a solution of 4-methoxybenzyl amine (1.63 g, 11.89 mmol) in dry pyridine (10 ml) was added 4-Benzyloxy-1-fluoro-thioxanthen-9-one (1 g, 2.97 mmol) in a single portion. The mixture was then heated to reflux (140° C.) for 18 hrs. The resulting hot orange suspension was allowed to cool to room temperature before being poured onto 100 ml of crushed ice. The precipitate was filtered off and washed with copious amounts of water to give the title compound as a red/orange solid (1.35 g, 89.6%). m/z (LC-MS, ESP): 454 [M+H]+ R/T=6.09 mins.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([O-])(=O)=O)=[CH:3][CH:2]=1.[NH+]1C=[CH:16][CH:15]=[CH:14][CH:13]=1.C([OH:20])C>>[C:4]1([S:7][CH2:13][C:14]#[C:15][CH2:16][OH:20])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1cc[nH+]cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCO
Product: OCC#CCSc1ccccc1

Procedure:
A stirred solution of sodium ethoxide in ethanol, obtained from 1.3 g of sodium and 50 ml of absolute ethanol was treated dropwise with 5.5 g (0.05mol) of thiophenol in 15 ml of absolute ethanol. The reaction mixture was refluxed for 1 hour and then treated with 5.84 g (0.025 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether, refluxing the mixture for 2 additional hours. It was then cooled, poured into water and extracted withmethylene chloride. The organic extract was washed with water, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, to produce 4-phenylthiobut-2-yn-1-ol tetrahydropyranyl ether, as an oil. Upon hydrolysis of the ether group with pyridinium p-toluenesulfonate in ethanol, in accordance with the method of Example 16, part E, there was obtained 4-phenylthiobut-2-yn-1-ol.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19]>C(O)C>[C:1]1([CH2:11][C:12]2[C:13]([NH2:14])=[N:18][NH:19][C:15]=2[NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: N#CC(C#N)Cc1cccc2ccccc12
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1Cc1cccc2ccccc12
Yield: 57.2 %

Procedure:
To a mixture of malononitrile (1.32 g, 20 mmol) in Ethanol (50 mL) and Water (2.50 mL) was added 1-naphthalenecarbaldehyde (3.12 g, 20 mmol). The reaction was stirred at rt for 7 days. The mixture was cooled to 0° C. in an ice bath. Sodium borohydride (0.204 g, 5.40 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (20 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave (1-naphthalenylmethyl)propanedinitrile (3.3 g, 80%). To a solution of (1-naphthalenylmethyl)propanedinitrile (3.3 g, 16 mmol) in Ethanol (80 mL) was added hydrazine hydrate (0.785 mL, 16.00 mmol). The mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (2.18 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 7.26 (d, J=7.07 Hz, 1H) 7.31-7.44 (m, 1H) 7.45-7.58 (m, 2H) 7.74 (d, J=8.08 Hz, 1H) 7.85-7.97 (m, 1H) 8.12-8.26 (m, 1H) 10.05 (bs, 1H). LC/MS: MS (ES+) m/e 239.0 [M+H]+.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1([C:17]([O-:19])=[O:18])C(C)=CC=CC=1O.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Reactant: [O-]c1ccccc1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 80 %

Procedure:
A pressure vessel was charged with 6.98 g of potassium phenolate, 7.54 g of potassium meta cresolate and 25 g of NeoSK 1400. With stirring at 1,000 r.p.m., reaction was carried out at a carbon dioxide pressure of 7 kg/cm2 (G) and at 300° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 80.0% on the basis of potassium phenolate, with 3.6% salicylic acid forming as a by product.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Fc1ccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5ccc(F)nc5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-8-(6-fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazoline (70 mg, 0.000203 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2] dioxaborolan-2-yl)-phenyl]-ureido]-benzamide (100 mg, 0.0002436 mol), cesium carbonate (133 mg, 0.000406 mol), DMF (3.5 mL) and water (0.9 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (7 mg, 0.0000101 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the title compound as a light yellow solid [8 mg, 7%]. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.43 (m, 1H), 8.28 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.58 (m, 3H), 7.49 (m, 2H), 7.39 (m, 3H), 3.84 (s, 8H), 2.95 (s, 6H); LC-MS (ESI): Calculated mass: 591.2; Observed mass: 591.9 [M+H]+ (RT: 1.53 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (134.8 g) in N,N-dimethylformamide (850 m) was cooled in an ice bath under a nitrogen atmosphere. Potassium tert butoxide (75.2 g) was added in portions such that the temperature did not exceed 22° C. and the resulting mixture was maintained at 0° C. for a further 1.5 hours when 4-fluorobenzotrifluoride (100 g) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (200 ml) was added and the mixture was extracted with tert butyl methyl ether (1×400 ml, 1×300 ml, 1×200 ml). The combined organic extracts were washed with water (2×400 ml), brine (200 ml) and then dried over magnesium sulphate and evaporated in vacuo to leave the title compound as an off-white/pale yellow solid (206.4 g)
Reaction SMILES: C(O)(=O)C.C(N=C1CC(C)CCN1)C.[ClH:15].[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH3:26])[CH:18]=1>>[ClH:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][C:19](=[N:23][CH2:24][CH2:25][CH3:26])[CH2:18]1
Reactant: CCCNc1cc(C)ccn1
Agent: CCN=C1CC(C)CCN1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN=C1CC(C)CCN1

Procedure:
The method of preparation of 2-(ethylimino)-4-methylpiperidine acetate was used to convert 4-methyl-2-(propylamino)pyridine hydrochloride to the title compound. The product was obtained as a clear colorless oil which crystallized under EtOAc. The analysis of the product was found to be consistent with the proposed structure. MH+=155; 1H NMR (D2O): 3.45-3.20 (m, 2H); 3.05 (t, J=6 Hz, 2H); 2.60-2.45 (m, 1H); 2.20-2.00 (m, 1.95-1.70 (m, 2H); 1.60-1.40 (m, 2H); 1.40-1.25 (m, 1H); 0.90 (d, J=6 Hz, 3H); 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:15]
Reactant: CO
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 80 °C
Yield: 94 %

Procedure:
To a solution of 6-methoxy-naphthalene-2-carboxylic acid (1.01 g, 5 mmol) in methanol (10 mL), a catalytic amount of sulphuric acid was added. The mixture was then heated at 80° C. for 8 hours. Upon reaction completion (as monitored by LcMS), the solution was slowly cooled and the precipitation of the product was observed. Filtration of the white solid afforded 1.01 g (94% yield) of title compound
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc(Br)c2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cccc2c1OCCN(Cc1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 4-benzyl-9-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (8.00 g, 24.1 mmol) in tetrahydrofuran (80 ml) was added 1M borane-tetrahydrofuran solution (96.4 ml, 96.4 mmol), and the mixture was stirred at 60° C. for 2 hr. Under ice-cooling, methanol (240 ml) and sodium hydroxide (20.8 g, 519 mmol) were added, and the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (6.20 g, 80.8%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:12]3[CH:7]4[C:8]5([C:13]([O:15]C)=[O:14])[CH:11]3[CH:10]1[CH:9]5[CH:6]24)=[O:4].[OH-].[Na+]>CO.O>[C:13]([C:8]12[CH:7]3[CH:6]4[C:5]5([C:3]([O:2][CH3:1])=[O:4])[CH:12]3[CH:11]1[CH:10]5[CH:9]24)([OH:15])=[O:14]
Reactant: COC(=O)C12C3C4C1C1C2C3C41C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12C3C4C1C1C2C3C41C(=O)O
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Cubane-1,4-dicarboxylic acid dimethyl ester (3.10 g, 14.1 mmol) purchased from Enichem Sintesi SpA, was dissolved in 75 ml of hot methanol in a 250 ml, round-bottomed flask equipped with a condenser. Solid NaOH (ACS grade 0.560 g, 14.1 mmol) was added, and the reaction mixture was refluxed under N2 for 13-15 h, then cooled to room temperature. The reaction mixture was diluted with 120 ml of water and extracted with ether (1×75 ml, 3×25 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated, leaving 373 mg (12%) of recovered starting material. The aqueous layer was acidified to pH 3 with 6N HCl and then extracted with chloroform (4×50 ml). The combined organic phase was dried over sodium sulfate, filtered, and concentrated furnishing 2.25 g (77%) of 1-carboxy-4-carbomethoxycubane as a white powder having a melting point of 178°-179° C. An NMR spectrum of the product at 500 MHz, dissolved in deuterated chloroform, had peaks assigned the following sigma values: 4.27 ppm (multiplet, 6 hydrogens) and 3.71 ppm (singlet, 3 hydrogens).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](I)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>O1CCCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:23]=[CH2:24])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
Temperature: 80 °C
Yield: 84.1 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (5.00 g, 11.48 mmol) in anhydrous tetrahydrofuran (115 ml) was added tributyl(vinyl)stannane (3.52 ml, 12.05 mmol). The mixture was degassed for 15 minutes using argon, dichlorobis(triphenylphosphine)palladium (0.40 g, 0.57 mmol) was then added. The resulting solution was heated at 80° C. overnight under argon, then evaporated under reduced pressure. Ethyl acetate and a 5% aqueous potassium fluoride solution were added to the residue, the resulting precipitate was filtered. The filtrate was recovered and the two layers separated, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-10%) in cyclohexane to afford the title compound as a yellow solid (3.24 g, 84%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(C)(C)CC(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)CC(=O)Cl)cc1
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A solution containing 3-methyl-3-(4-methylphenyl)butyric acid (8.5 g, 44.2 mmol) and anhydrous DMF (5 drops) in anhydrous benzene (110 mL) was refluxed under nitrogen as thionyl chloride (8.1 mL, 110 mmol)was added dropwise under nitrogen. The solution was refluxed an additional 15 h after complete addition of thionyl chloride. The dark brownish reaction mixture was allowed to cool to room temperature and concentrated under vacuum. TLC analysis of the crude material showed complete disappearance of the starting material. Presence of DMF was evident from the proton NMR. The crude material, 3-methyl-3-(4-methylphenyl)butyric acid chloride (305) (about 10 g), thus obtained was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>C(Cl)Cl>[C:1]([NH:4][NH:5][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NNC(C)=O
Yield: 47.3 %

Procedure:
To a solution of acetohydrazide (36.0 g, 486 mmol) in CH2Cl2 (250 mL) stirring at 0° C. under N2, was added triethylamine (250 mL, 1.46 mol) followed by ethyl chlorooxoacetate (65.0 mL, 584 mmol) over 1 h. The reaction mixture was stirred at rt for 8 h at which time ethyl acetate was added and the salts were removed by filtration. The filtrate was concentrated in vacuo and the residue purified by column chromatography using a gradient of 5-15% EtOAc/hexane to afford the product as an off-white solid (40.0 g, 47%). 1H NMR (300 MHz, CDCl3): δ 9.85 (1H, bs), 9.29 (1H, bs), 4.35 (2H, q, J=7 Hz), 2.10 (3H, s), 1.36 (3H, t, J=7 Hz). MS (M+H): 175.0.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[ClH:14]>C1(C)C=CC=CC=1>[ClH:14].[N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCCC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CN1CCCCC1
Yield: 83 %

Procedure:
Ethyl 2-(piperidin-1-yl)-acetate (5.5 g, 32.2 mmol), water (12 ml) and c HCl (3 ml) were heated under reflux for 20 hours. Volatile components were evaporated under reduced pressure to leave an off white solid. This solid was co-evaporated with toluene (50 ml×3) and dried in vacuo to give an off white powder (Yield 4.8 g, 83%).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.CC(C)([O-])C.[K+].Br[C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1.Cl>C1COCC1.O>[CH3:10][C:6]1[CH:5]=[CH:4][C:3]([Si:2]([CH3:11])([CH3:12])[CH3:1])=[CH:8][C:7]=1[O:9][C:20]1[O:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc([Si](C)(C)C)cc1O
Reactant: COC(=O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Oc2cc([Si](C)(C)C)ccc2C)o1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of 5-trimethylsilyl-2-methylphenol (Intermediate 3; 653 mg, 3.6 mmol) in THF was added potassium tert-butoxide (407 mg, 3.6 mmol) and the reaction heated at reflux for 1.5 hours. The resulting solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in dimethyl sulphoxide (10 mL), treated with methyl 5-bromo-2-furoate (632 mg, 3.1 mmol) and heated at 85° C. for 18 hours. The dark brown mixture was allowed to cool to room temperature, diluted with water (10 mL) and then acidified by the addition of hydrochloric acid (1 M). The mixture was extracted with diethyl ether (3×30 mL) and the combined organic extracts were dried (magnesium sulphate), concentrated under reduced pressure and purified by column chromatography (SiO2; light petroleum to 95:5 light petroleum-diethyl ether) to give the title compound as a colourless oil (534 mg, 57%). Rf=0.21 (9:1 light petroleum-diethyl ether). LCMS Rt=4.9 mins, m/z=305 (MH+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10]N1C=CN=C1.C[N:20]([CH3:26])[CH2:21][CH2:22][N:23](C)C.[CH:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[C:28]1=[O:37])[CH2:34]2>CCCCCC.O1CCCC1.O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]([C:28]2([OH:37])[CH:29]3[CH2:35][CH:33]4[CH2:32][CH:31]([CH2:36][CH:27]2[CH2:34]4)[CH2:30]3)[C:26]2[NH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: Fc1cccc(Cn2ccnc2)c1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OC1(C(c2cccc(F)c2)c2ncc[nH]2)C2CC3CC(C2)CC1C3
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
55 ml (85 mmol) of a 1.55 molar solution of n-butyllithium in hexane were added dropwise to a solution of 7.04 g (40 mmol) of N-(3-fluorobenzyl)-imidazole and 4.65 g (40 mmol) of N,N,N',N'-tetramethylethylenediamine (TMEDA) in 90 ml of absolute tetrahydrofuran (THF) at -70° C. The mixture was stirred for a further 20 minutes at -70° C., and a solution of 6.01 g (40 mmol) of adamantanone in 30 ml of absolute tetrahydrofuran (THF) was then added dropwise at -70° C. in the course of about 15 minutes. Stirring was then continued for 15 minutes at about -70° C., the reaction mixture was allowed to warm up to room temperature in the course of about 2 hours, 200 ml of water were added at about 5°-18° C., while cooling, and the mixtures was extracted with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered, and evaporated down in vacuo. The residue of the extract was dissolved in acetonitrile, after which crystalline 3-fluorophenyl-(2-hydroxy-2-adamantyl)-imidazolylmethane was precipitated in pure form. After the crystalline product had been filtered off under suction and washed thoroughly with acetonitrile, 8.70 g of pure product of melting point 191° C. were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]([C@@:18]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH2:20][O:19]2)[CH3:17])=[C:9](Cl)[N:8]=1>>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]([CH3:17])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])([OH:19])[CH2:20][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[C:9]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Product: C[C@@H](n1cnc2c(-n3cncn3)nc(-n3cncn3)nc21)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 14.6 %

Procedure:
Using 1H-1,2,4-triazole (59 mg) and (2S)-2-[(1R)-1-[2,6-dichloro-9(9H) -purinyl]ethyl]-2-(2,4-difluorophenyl) oxirane (168 mg), Compound 50 (21 mg) was obtained as a white powder by the same way as in Example 1.