Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:4])=[O:3].Cl>C(O)C.O=[Pt]=O>[CH3:1][S:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1ccccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)CC1CCCCN1
Reaction time: 18 h
Yield: 90.2 %

Procedure:
2-(Methylsulfonylmethyl)pyridine (4.40 g, 0.0257 moles) and PtO2 (0.50 g) were suspended in ethanol (80 mL) with 1N HCl (15 mL). The mixture was hydrogenated at 50 psi for 18 hours. The catalyst was filtered and the solvent removed. The residue was dissolved in CH2Cl2 and washed with sat. Na2CO3. The aqueous layer was extracted with CH2Cl2 (3×25 mL). The organic layers were combined and dried over Na2SO4 and evaporated to give a yellow oil (4.11 g, 90%) which solidified on standing. Further purification was unnecessary. LCMS (178, M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:38])[CH3:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=O)C.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[C:21]([CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:38])[CH3:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCCOC1CCCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C[C@H]1[C@H](C=C(CCCOC2CCCCO2)C(=O)O)OC(C)(C)N1C(=O)OCc1ccccc1

Procedure:
100 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidine-5-yl]-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate was dissolved in 0.2 ml of ethanol, and 0.5 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide was added thereto under stirring. The mixture was stirred overnight at room temperature, then cooled to 0° C. and neutralized with 1N hydrochloric acid. To the mixture, 12 ml of water was added, and the mixture was extracted three times with 12 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidine-5-yl]-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoic acid as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]3[S:11][C:7]4[C:6]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:22])=[CH:15][CH:16]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CNC(=O)C4CC4)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and cyclopropanecarbonyl chloride, the title compound was prepared as light-yellow crystals (64% yield). MS: m/e=467(M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([O:19][C:17](=[O:24])[NH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Yield: 20.4 %

Procedure:
A mixture of 4-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (200 mg, 706 μmol), tert-butyl carbamate (99.3 mg, 848 μmol) and cesium carbonate (322 mg, 989 μmol) was purged several times with argon, then tris(dibenzylideneacetone)dipalladium(0) (12.9 mg, 14.1 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16.3 mg, 28.3 μmol) were added and the mixture was purged with argon again, the vessel was then capped. The resulting mixture was refluxed for 20 hours. The mixture was evaporated to dryness under reduced pressure. Final purification by flash chromatography (20 g silicagel column using heptane/ethyl acetate 70-100 as eluent) afforded (2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-carbamic acid tert-butyl ester (46 mg, 20.4%) as yellow solid. Mp.: 166° C. MS: m/z=320.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)CC>[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:30][CH:29]=1
Reactant: NCc1ccc(O)cc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCO
Product: Oc1ccc(CNc2ncnc3c2ncn3C2CCCCO2)cc1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) 4-hydroxybenzylamine, and 5 mL of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of diethylether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane (1:1) (v:v): single spot; HPLC: purity >98%. 1H-NMR (400 MHZ, DMSO): 1.57tt (2H, Ja=11.0 Hz, Jb=3.3 Hz); 1.72qq (1H, Ja=12 Hz, Jb=3.3 Hz); 1.95tt (2H, Ja=11 Hz, Jb=2.1 Hz); 2.27qq (1H, Ja=12.0 Hz, Jb=3.3 Hz); 3.67m (1H); 4.0dd (1H, Ja=11.0 Hz, Jb=2.1 Hz); 4.6s (2H); 5.63dd (1H, Ja=11.0 Hz, Jb=2.1 Hz); 6.67d (2H, J=8.4Hz); 7.15d (2H, J=8.4 Hz); 8.02bs (1H); 8.21s (1H); 8.33s (1H); 9.21s (1H). MS (ES): [M+H]+=326 (100).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][CH2:4][C:5]1([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N+:42]([O-])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]>C(OCC)(=O)C.[Pd]>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][NH:34][C:5]1([CH2:4][CH2:3][C:2]([CH3:46])([CH3:1])[CH3:45])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: CC(C)(C)CCC1(NCc2ccccc2[N+](=O)[O-])C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CCC1(NCc2ccccc2N)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of the product of Example 98 (7 mg, 0.01 mmol) in ethyl acetate (0.5 mL) was added 10% Pd/C (2 mg). The mixture was stirred under H2 atmosphere for 1 h and filtered. The filtrate was concentrated in vacuo. Column chromatography on silica (3% methanol/dichloromethane) afforded the title compound as a yellow solid (4 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.38-0.55 (m, 1H), 0.66 (s, 9H), 0.99-1.14 (m, 1H), 1.86-2.03 (m, 1H), 2.17-2.37 (m, 1H), 3.02 (s, 3H), 3.45-3.57 (m, 1H), 6.55 (t, J=6.25 Hz, 1H), 6.72 (d, J=7.72 Hz, 1H), 6.92 (d, J=7.35 Hz, 1H), 7.00-7.77 (m, 6H), 7.90-8.01 (m, 1H), 8.20 (d, J=6.62 Hz, 1H), 9.97 (s, 1H), 13.90 (s, 1H); MS m/z 638.3 (M+H)+.
Reaction SMILES: C([CH:4]=[CH:5][CH:6]=[CH:7][C:8]1[C:9](=[O:23])[NH:10][C:11](=[O:22])[N:12]([CH:21]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1)(O)=O.[Br:24]N1C(=O)CCC1=O.C(=O)=O>CN(C=O)C>[Br:24]/[CH:4]=[CH:5]\[CH:6]=[CH:7]\[C:8]1[C:9](=[O:23])[NH:10][C:11](=[O:22])[N:12]([CH:21]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)C=CC=Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C=O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1/C=C/C=C\Br
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 5-(4-carboxy-1,3-butadienyl)-2′-deoxyuridine (VI) (0.200 g, 0.62 mmol) in DMF (1 mL) was added KHCO3 (0.185 g, 1.84 mmol) and the mixture was stirred for 20 mm at 25° C. A solution of N-bromosuccinimide (0.117 g, 0.65 mmol) in DMF (0.3 mL) was added dropwise. Smooth gas evolution (CO2) occurred throughout the addition. The resulting brown suspension was stirred for 2 h at 25° C. at which time TLC showed that (VI) was completely consumed. Water (10 mL) was added to the suspension and the resulting solution was extracted with EtOAc (2×15 mL). The extract was dried over MgSO4 and the solvent was evaporated in vacuc to give a yellow solid (178 mg, 80% yield) consisting of a mixture of two isomers as shown by 1H NMR. The crude product was separated by semi-preparative HPLC (reversed phase C18 column) using 20% acetonitrile in water as the mobile phase to give the following isomers:
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: CCC1(O)CCCCCCC1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(CC)CCCCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a 500-mL 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 32.5 g (0.208 mol) of 1-ethyl-1-cyclooctanol and 100 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 150 mL (0.239 mol, 15% excess) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 25 g (0.239 mol) of freshly distilled methacryloyl chloride in 50 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 500 mL of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled twice from Na2CO3 and phenothiazine through a based-washed 15-cm Vigreux to yield 24 g (51%) of the title compound (bp 84° C.@ 1 mmHg) as a clear, colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C[Li].[C:10]([O:14][C:15](=[O:24])[CH2:16][C@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:13])([CH3:12])[CH3:11].I[CH2:26][CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[C:10]([O:14][C:15](=[O:24])[C@H:16]([CH2:26][CH2:27][CH2:28][CH3:29])[C@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:11])([CH3:13])[CH3:12]
Reactant: CCCCI
Reactant: CCCCC[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC[C@@H](O)[C@@H](CCCC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A dried two-necked flask was cooled to −78° C., after which diisopropylamine (5.41 g, 53.5 mmol) was introduced thereto. Then, methyllithium (a 0.98M diethyl ether solution, 45 ml, 44.1 mmol) was added dropwise thereto, and stirred for 10 minutes. The resulting mixture was heated to 0° C., and stirred for another 30 minutes. The reaction solution was cooled to −48° C., the (R)-3-hydroxyoctanoic acid t-butyl ester (3.50 g, 16.2 mmol) obtained in Production Example B-1 was added dropwise thereto, and then the mixture was stirred for 30 minutes. To the obtained mixture was added hexamethylphosphoric triamide (HMPA) (7 ml), the mixture was stirred for one minute, then 1-iodobutane (3.87 g, 21.0 mmol) was added dropwise thereto. After the reaction solution was stirred at −48° C. for one hour, a saturated ammonium chloride solution was added thereto, and extracted 3 times with diethyl ether. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 150 g, n-hexane/ethyl acetate=15/1) to produce the target compound (1.98 g, 44%).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[S:8][C:9]([C:12]3[CH:13]=[C:14]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:10][N:11]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH3:18][C:16]1[CH:15]=[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:13]=[C:12]([C:9]2[S:8][C:7]([CH:4]3[CH2:3][CH2:2][S:1][CH2:6][CH2:5]3)=[N:11][CH:10]=2)[CH:17]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3=CCSCC3)s2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCSCC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
N-{3-[2-(3,6-dihydro-2H-thiopyran-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 133, 85 mg, 0.196 mmol) was dissolved in EtOAc (5 ml) and flushed with nitrogen (3×). Palladium on carbon (20.8 mg, 0.020 mmol) was added, and the reaction was flushed with hydrogen (3×) via a hydrogen balloon. The reaction was stirred at room temperature for 16 hrs under hydrogen atmosphere. A further aliquot of palladium on carbon (208 mg, 0.196 mmol) was added, the reaction was purged again with hydrogen, and stirred under hydrogen atmosphere for additional 72 hrs. The reaction mixture was subsequently filtered through a pad of Celite and concentrated under reduced pressure. Column chromatography on silica (gradient elution, 0 to 50% EtOAc in hexanes) afforded N-{3-methyl-5-[2-(tetrahydro-2H-thiopyran-4-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.041 g, 0.094 mmol, 48% yield) as a colorless foam. MS ESI: [M+H]+ m/z 437.0. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=4.9, 1H), 7.96 (m, 2H), 7.42 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.18 (bs, 1H), 3.15 (m, 2H), 2.80 (m, 1H), 2.68 (m, 2H), 2.48 (m, 5H), 1.92 (m, 2H). rhSYK activity=+++.
Reaction SMILES: [CH3:1][N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4]
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.5 %

Procedure:
To tert-Butyl 2-methyl-1-((S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido) ethyl)pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate (16 mg) was added TFA (2 mL). The mixture was stirred at rt for 30 minutes, concentrated and purified by prep. HPLC to give a yellow solid (17.6 mg, 86%). MS (ES, m/z): 946.34 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21]O.O.C([O-])(=O)C.[K+]>Br>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[O:1][CH2:21][CH2:20][CH2:19][C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCCO)c(O)c2cccnc2n1-c1ccccc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)OCCC2
Temperature: 90 °C

Procedure:
A suspension of 4-hydroxy-3-(3-hydroxypropyl)1-phenyl-1,8-naphthyridin-2(1H)-one (5.67 g.) in 47% HBr (50 ml.) was stirred in an atmosphere of nitrogen and was heated to 90° C. for 5 hrs. After cooling, the product was poured into water, and the pH was adjusted to 4.5 with potassium acetate. Chromatographic purification of the product on silica gel eluting with CH2Cl2 : 5% ether and subsequent recrystallization of the product from the relevant fractions yielded the product, m.p. 253°-255° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1Cl
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
TiCl4 (2.01 mL, 18.2 mmol) was added dropwise to a suspension of zinc powder (2.41 g, 36.9 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 71 (1.42 g, 4.56 mmol) and cyclohexanone (1.34 g, 13.7 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.61 g (93%) of compound 72 as a light green oil. 1H NMR (400 MHz, CDCl3): δ 1.59 (m, 6H), 1.97 (m, 2H), 2.28 (m, 2H), 4.93 (br s, 1H), 6.72 (d, J=8.6 Hz, 2H), 7.04 (m, 3H), 7.32 (dd, J=8.2 Hz, 2.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1COCC1.[CH3:23][C:24]1([CH3:31])[CH2:28][CH2:27][CH:26]([CH3:29])[CH:25]1O>>[CH3:23][C:24]1([CH3:31])[CH2:28][CH2:27][CH:26]([CH3:29])[CH:25]1[O:16][C:15](=[O:17])[C@@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC1CCC(C)(C)C1O
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)OCc1ccccc1

Procedure:
Into a suspension of N-Cbz-D-serine (5 g) in 50 ml of dry THF containing 1 equivalent of 2,2,5-trimethylcyclopentanol is bubbled dry hydrogen chloride gas at room temperature. Upon complete solution of the mixture, the reaction is refluxed for 5 hours, then concentrated. Ethyl acetate is added, and this is washed with saturated sodium bicarbonate, water, and dried over MgSO4. Filtration followed by concentration yields N-Cbz-D-serine-2,2,5-trimethylcyclopentyl ester. 5 g of this product is dissolved in 10 ml methanol and hydrogenated in a Paar apparatus over 1 g of 5% Pd/C to yield 2,2,5-trimethylcyclopentyl-D-serinate.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C.[Pd]>[CH2:27]([O:26][C:22]([CH2:23][CH2:24][N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C(=O)OCC)C1
Temperature: 70 °C
Yield: 57.9 %

Procedure:
A solution of (±) ethyl N-benzyl-3-pyrrolidinyl carboxylate (D1) (100 g, 0.43 mole) in ethanol (800 ml) was treated with ammonium formate (135.32 g, 2.15 mole) and 10% Pd on carbon (25 g) then heated at 70° C. for 2h. After 1h a further addition of 10% Pd on carbon (10 g) was made. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in ethanol (500 ml), treated with ethyl acrylate (51.56 g, 0.52 mole) then heated under reflux for 1h. The reaction mixture was concentrated in vacuo, treated with saturated aqueous potassium carbonate, then extracted into chloroform. The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the residue distilled to afford the title compound (D2) as an oil (60.53 g, 58%), b.p. 135°-145° C. at 4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:16][C:17]([F:27])([F:26])[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>>[F:27][C:17]([F:16])([F:26])[CH:18]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The racemate (96 mg, 83%) was separated into its enantiomers by preparative chiral HPLC (ChiralPak AD, isopropanol/heptane) and the title compound was isolated as colorless oil; LC-MS (UV peak area, m/z) 100%, 386.0882 (MH+). [α]D20=+22.4 (MeOH).