Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=[O:12].C[S-].[Na+]>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:12]
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1ccc2ccccc2c1
Yield: 85.5 %

Procedure:
4-Methoxyphenyl 2-naphthyl ketone (735 mg) obtained in Example 35 was dissolved in N,N-dimethylformamide (20 ml), sodium thiomethoxide (491 mg) was added, and the admixture was refluxed under argon for 5 hours. The reaction mixture was treated in the same manner as described in Example 33 to obtain 595 mg of the title compound (yield: 86%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][C:12]1([CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[O:16][CH2:15][CH2:14][O:13]1.C(OCC)(=O)C>O1CCCC1>[CH3:11][CH:12]([O:13][CH2:14][CH2:15][OH:16])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)CCCC1(C)OCCO1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCCC(C)OCCO
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (600 mL) was charged to 2 L flask fitted with condenser, nitrogen, thermocouple and mechanical stirrer. The flask was cooled to <10° C. and the flask was inerted with dry nitrogen fed a slow rate. Aluminium chloride (112 g, 840 mmol) was slowly added to the reaction flask whilst maintaining a temperature of <10° C. Then lithium aluminium hydride powder (15.9 g, 420 mmol) was added slowly over 30 minutes. The reaction mixture was stirred for a further 30 minutes at <10° C. To the reaction flask was added slowly a solution of 2-methyl-2-(4-methylpentyl)-1,3-dioxolane (72 g, 420 mmol) in tetrahydrofuran (50 mL) over 30 minutes. The reaction mixtures as stirred for 2 hours at <10° C. Ethyl acetate (200 g) was then added slowly to the reaction mixture to neutralise the excess lithium aluminium hydride—cooling was necessary to counteract the large exotherm. The crude reaction mixture was extracted into methyltert-butyl ether (2×300 mL) and the organic phase washed with water (200 mL). The organic phase was dried over magnesium sulphate, filtered and the solvent removed by evaporation to yield the desired product suitable for the next synthetic step as a colourless oil (100% pure by GC rpa, 70 g, 400 mmol, 96% chemical yield). A small sample was Kugelrohr distilled to give material suitable for olfactive analysis.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:21])[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[CH:9][NH:8][N:7]=1)=[O:5])C>[OH-].[Na+].CO>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[C:12]([NH:11][C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][NH:8][CH:9]=1)=[O:21]
Reactant: CCOC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.7 %

Procedure:
A mixture of 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid ethyl ester (10.2 g) in 2 M aqueous NaOH/MeOH (1:1, 250 ml) was stirred at ambient temperature for 14 h. Volatile materials were removed in vacuo, water (300 ml) added and the mixture taken to pH 5 using 1M aqueous HCl. The resultant precipitate was collected by filtration and dried through azeotrope with toluene to afford 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pink solid (5.70 g). (LC/MS: Rt 2.33, [M+H]+267.96).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7])=[O:5]
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)N(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1N2CN3CN(C2)CN1C3.[C:29](O)(C(F)(F)F)=[O:30].Cl>O.CO>[CH:29]([C:17]1[C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCc1cc(=O)c2ccccc2[nH]1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCCCCc1[nH]c2ccccc2c(=O)c1C=O
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-heptyl-4(1H)-quinolone (5 mmol), hexamine (2.5 mmol), and TFA (7.5 ml) was stirred at reflux under nitrogen for 30 hours. MeOH (15 ml) and water (15 ml) were added, and heating was continued for 1 hour. 3 M HCl (5 ml) was added and the heating was continued for a further period of 30 minutes. The mixture was cooled and the precipitate removed by filtration and washed with water. The solid on trituration with acetone afforded the title compound in 40% yield. Recrystallisation from MeOH/EtOAc gave colourless needles, mp 245-248° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:17])=[C:13]([NH2:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.O1CCO[CH:23](O)[CH:22]1O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]3[N:17]=[CH:23][CH:22]=[N:16][C:13]=3[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Reactant: OC1OCCOC1O
Solvent: CO
Product: Brc1cccc(Nc2ncnc3cc4nccnc4cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 4-(3-bromoanilino)-6,7-diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane-2,3-diol (0.2 g, 1.6 mmol) [Venuti, M. C.; Synthesis, 1982, 61-63] in MeOH (20 mL) is stirred at room temperature overnight to give a precipitate of 4-(3-bromoanilino)pyrazino[2,3-g]quinazoline (80 mg, 83%). 1H NMR (DMSO) δ10.45 (1H, brs), 9.52 (1H, s), 9.09 (1H, d, J=1.6 Hz), 9.06 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.44 (1H, s), 8.32 (1H, brs), 7.99 (1H, m), 7.45-7.34 (2H, m). ##STR24##
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-[(9-{(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate (500 mg) was dissolved in trifluoroacetic acid : dichloromethane (1:9, 20 ml) and the mixture kept at 3° C. for 16 h. The mixture was then quenched with saturated sodium bicarbonate solution (100 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 ml) and evaporated to dryness in vacuo to afford the title compound (407 mg) as a yellow glassy solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(Cl)c1Cl
Yield: 87.9 %

Procedure:
A solution of 4.0 grams (0.013 mole) of N-(2,3-dichloro-4-methylphenyl)phthalimide, 2.3 grams (0.013 mole) of N-bromosuccinimide and 0.3 gram of benzoyl peroxide in 200 ml of carbon tetrachloride was heated under reflux for 22 hours. The cooled reaction mixture was poured into 500 ml of ethyl acetate. The solution was washed with three 100 ml portions of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using ethyl acetate:heptane (1:4). The appropriate fractions were combined and concentrated under reduced pressure to yield 4.4 grams of N-(4-bromomethyl-2,3-dichlorophenyl)phthalimide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:14][CH2:13][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[C:4]=1[F:12])(=[O:18])=[O:17]
Reactant: CC(=O)Nc1ccc(Cl)c(CO)c1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A 0° C. of N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1.05 g, 4.82 mmol) and TEA (1.003 mL, 7.24 mmol) in DCM (30 mL) was treated slowly with methanesulfonyl chloride (0.414 mL, 5.31 mmol), warmed to RT and stirred for 2 h. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 3-acetamido-6-chloro-2-fluorobenzyl methanesulfonate (1.31 g, 74% yield) as an off-white solid. MS (ESI) m/z: 296.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=C.C[N+]1([O-])CC[O:16]CC1.CCCCCC>O1CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:11][C:5]1[C:4]([CH2:1][CH:2]=[O:16])=[C:9]([Cl:10])[N:8]=[CH:7][N:6]=1
Reactant: C=CCc1c(Cl)ncnc1Cl
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=CCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a stirred solution of 5-allyl-4,6-dichloropyrimidine (2.5 g) in dry dioxane (25 mL), N-methyl morpholine N-oxide (2.3 g) and osmium tetroxide (0.85 mL, 25% solution in water) were added. The reaction mixture was stirred at room temperature for 2 hours before being quenched by solid sodium bisulphate. The reaction mixture was filtered through celite bed. The celite bed was washed with dioxane (10 mL). The combined filtrate was taken into a 100 mL three necked round bottom flask and sodium metaperiodate (6 g, in 5 mL water) was added. The reaction mixture was stirred at room temperature for about 3 hours, then diluted with water (30 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude product, which was treated with hexane to offer a solid. The solid obtained was filtered, washed with cold hexane (50 mL) and dried under vacuum to get 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.7 g) as white solid. 1H NMR (DMSO-d6): δ 4.21 (s, 2H), 8.86 (s, 1H), 9.7 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[Cl:28])[N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:23]=[C:22]2[NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41]>O1CCOCC1.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.O.C(OCC)(=O)C>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:23][N:24]2[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:19]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Reactant: CCc1ccc(B(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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(CC)cc3)cc12
Yield: 104.1 %

Procedure:
504 mg of 4-ethylphenylboronic acid, 664 mg of sodium carbonate in 20 cm 3 of distilled water and 202 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 75 cm3 of dioxane. The mixture is refluxed for 18 hours and then the temperature is allowed to return to room temperature to add 75 cm3 of ethyl acetate and 50 cm3 of water, and the reaction medium is filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the organic phase is washed successively with 50 cm3 of water, with 50 cm3 of saturated aqueous sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), and then dried (90 Pa; 50° C.) to give 1.1 g of N-[6-chloro-5-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][C@H:26]([CH3:45])[C@H:27]([NH:37]C(=O)OC(C)(C)C)[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:8]([O:25][C@H:26]([CH3:45])[C@H:27]([NH2:37])[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.1 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl [(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (370 mg) in methylene chloride (2 ml), and the reaction solution was stirred at room temperature for 11 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and brine, and then the solvent was evaporated under reduced pressure to obtain 275 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1COCC1>O>[CH2:27]([O:26][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (2.28 g, 11.4 mmol), sodium bicarbonate (1.26 g, 15 mmol), benzyl chloroformate (2.69 g, 15 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 4.34 g of the title compound as a colorless solid (100%).
Reaction SMILES: [NH3:1].S(O[N:13]=[C:14]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:21][CH:20]=1)[C:15]([F:18])([F:17])[F:16])(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[C:30]([Si:27]([CH3:28])([CH3:29])[O:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2([C:15]([F:16])([F:18])[F:17])[NH:13][NH:1]2)=[CH:20][CH:21]=1)([CH3:32])([CH3:33])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)C(F)(F)F)cc1
Reactant: N
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2(C(F)(F)F)NN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
Liquid ammonia (2 mL) was added a −78° C. to an ether (15 mL) solution of 1-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone O-tosyl oxime (4.00 g, 8.2 mmol) in a sealed tube. The solution was stirred at rt (16 h). The mixture was carefully cooled at −78° C. and the sealed tube was opened. The ammonia was evaporated and the white precipitate was filtered and washed with ether. The filtrate was concentrated in vacuum to obtain 2.4 g of a colorless oil (87%); NMR (CDCl3): δ 0.10 (s, (CH3)2Si), 0.95 (s, CH3)3C), 2.21 (d, J=8.1 Hz, NH), 2.77 (d, J=8.1 Hz, NH), 4.76 (s, CH2), 7.38 (d, J=8.4 Hz, 2 C6H4), 7.58 (d, J=8.4 Hz, 2 C6H4); 13C NMR (CDCl3): δ −5.3 (CH3Si), 18.4 (C(CH3)3), 25.9 (C(CH3)3), 58.0 (q, J=35.8 Hz, C diaziridine), 64.4 (CH2O), 123.6 (q, J=276.0 Hz, CF3), 126.2 (C6H2), 128.0 (C6H2), 130.2 (C6H2), 143.8 (C6H2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:30]1([O:20][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[S:15][CH:16]=2)=[O:21])[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)Oc3cccc4ccccc34)cs2)CC1

Procedure:
A solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 12.0 g) is reacted analogously to Example IX-1 with 1-naphthol (7.20 g). This gives, after chromatographic purification, tert-butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (12.3 g, 73%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl.CS(C)=O>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(NC4CCNCC4)ncc3Cl)n2)c1
Reactant: CCS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 5′-chloro-N6-(3-fluorobenzyl)-N2′-(piperidin-4-yl)-2,4′-bipyridine-2′,6-diamine (Example 6, 16 mg, 0.039 mmol), dichloromethane (0.5 ml), and TEA (0.022 ml, 0.155 mmol) was cooled to 0° C. This cooled mixture was then diluted with a solution of 0.03 ml of dichlormethane with ethanesulfonyl chloride (6.99 mg, 0.054 mmol). The reaction mixture then was warmed to ambient temperature and stirred for 1 hour, followed by LCMS. The reaction mixture solvent was removed under reduced pressure, to yield a residue which was dissolved in 0.75 ml DMSO, filtered, purified by prep LC and then lyophilized to yield 9.9 mg of the title compound, as a TFA salt. LCMS (m/z): 504.2 (MH+), retention time=0.77 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32 (t, J=7.33 Hz, 3 H) 1.47-1.67 (m, 2 H) 2.08 (d, J=10.84 Hz, 2 H) 2.96-3.12 (m, 4 H) 3.75 (d, J=12.89 Hz, 2 H) 3.80-3.92 (m, 1 H) 4.65 (s, 2 H) 6.83 (s, 1 H) 6.92 (d, J=9.08 Hz, 1 H) 6.95 (d, J=7.62 Hz, 1 H) 7.01 (t, J=8.64 Hz, 1 H) 7.11 (d, J=9.96 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 7.30-7.41 (m, 1 H) 7.75-7.85 (m, 1 H) 8.06 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([OH:21])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=CC=CC=1.CO[CH:31](OC)[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[O:40][CH3:41].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:21][CH:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[N:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Reactant: COC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzoyl-βphenyl isoserine methyl ester (3A, 0.5 g, 1.67 mM) is dissolved in dry THF (10 mL) and benzene (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (4, 0.420 g, 1.98 mM) and pyridinium p-toluenesulfonate (12 mg) and the solution warmed to reflux. After 30 minutes the reaction is cooled to RT and allowed to stand overnight. It is then again warmed to slowly distill off ½ of the solvent over 1 hr. TLC shows the reaction to be finished at this point. The reaction is concentrated in vacuo and the residue chromatographed over 50 g silica gel packed in (5-95) methanol-toluene. The column is eluted with methanol-toluene (5-95). Fractions of 12 mL are collected. The product elutes as a mixture. Thus, fractions containing both 5Aa & 5Ab are recombined and evaporated. The residue (0.90 g) is rechromatographed over silica gel (100 g) The column is eluted with ethyl acetate-toluene (500 mL of 15-85 and 500 mL of 20-80). Fractions of 20 mL are collected and analyzed by TLC. The fractions containing each 5Aa & 5Ab are combined and evaporated under vacuum.