Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[CH2:9][N:8]([CH:10](C2C=CC=CC=2)C2C=CC=CC=2)C1)(=[O:3])[CH3:2].Cl>[Pd].C(O)C>[C:1]([NH:4][CH:5]1[CH2:6][CH2:9][NH:8][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)NC1CCNC1
Yield: 89 %

Procedure:
A mixture of 12.5 g (0.057 mol) of the compound obtained in stage c) above, 1.3 g of 10% Pd/C, 80 ml of 95% ethanol and a drop of concentrated hydrochloric acid is hydrogenated at 40° C. When the theoretical quantity of hydrogen has been consumed, it is filtered and the filtrate is concentrated to obtain 6.5 g of the title compound in the form of an oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13].[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13])#[N:15]
Reactant: CC(=O)Nc1ccc(Br)c(F)c1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(F)c1C
Temperature: 150 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
To a solution of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide (72B) (2.18 g, 8.86 mmol) in DMF (20 mL) was added CuCN (2.61 g, 29.1 mmol). The mixture was stirred at 150° C. for 12 h and was then poured into ice (50 g). After warming to rt, the product was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified via flash chromatography eluting with a solution of 5% methanol in 95% of EtOAc/hexane (1:1) to provide the title compound (1.51 g) as a white solid. LCMS: m/z 193 [M+H]+
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)[CH3:17]
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCOc2ccccc21
Product: CN(C)C=C1COc2ccccc2C1=O

Procedure:
The 3-(dimethylaminomethylene)-chroman-4-one starting material was prepared from 4-chromanone (5.0 g, 33.7 mmol) and N,N-dimethyl-formamide diethyl acetal (15 ml, 87.5 mmol) to give the desired product as orange crystals (4.3 g) m.p. 135.8°. MS (ES+) 204 (100%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:26][CH3:27])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1)=[O:4].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:26]([N:5]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1)[C:3](=[O:4])[CH2:2][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:27]
Reactant: CCN(C(=O)CCl)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C(=O)CN1CCCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (129 mg) in N,N-dimethylformamide (5 ml) were sequentially added piperidine (0.07 ml) and potassium carbonate (184 mg), and the solution was stirred overnight at 60° C. The solution was let to cool, then a saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous potassium carbonate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (139 mg).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([CH3:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([CH3:14])[C:8]=2[S:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:28][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([CH3:14])=[C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(C)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(C)c2c(CC(=O)O)csc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl(4,7-dimethyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (124.6 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (0.883 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was crystallized from EtOAc-hexane to give the title compound (108 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C:5](=S)[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]([NH:24][NH2:25])=O>C(O)CCC>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[N:24][N:25]=[C:5]2[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C[C@H]1CNC(=S)CN1C(=O)OC(C)(C)C
Reactant: NNC(=O)c1cnccn1
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43.5 %

Procedure:
To a suspension of (S)-tert-butyl 2-methyl-5-thioxopiperazine-1-carboxylate (2.5 g, 10.9 mmol) in n-butanol (10 mL) was added pyrazine-2-carbohydrazide (1.6 g, 11.9 mmol) and the reaction mixture was heated to 120° C. for 12 hours. The reaction mixture as cooled to room temperature, concentrated onto silica gel and purified by flash column chromatography (0-20% MeOH in EtOAc) to provide the desired compound (1.5 g, 43%). 1H NMR (400 MHz, DMSO) δ 9.36 (d, J=1.4 Hz, 1H), 8.78-8.74 (m, 2H), 5.02 (d, J=17.4 Hz, 1H), 4.72 (d, J=12.6 Hz, 2H), 4.53 (d, J=17.4 Hz, 1H), 4.36-4.28 (m, 1H), 1.48 (s, 9H), 1.10 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl-].[F:2][C:3]([F:15])([F:14])[S:4]([O:7][C:8]1[CH2:9][CH2:10][NH2+:11][CH2:12][CH:13]=1)(=[O:6])=[O:5].[CH3:16][C@@:17]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]1>>[F:15][C:3]([F:2])([F:14])[S:4]([O:7][C:8]1[CH2:13][CH2:12][N:11]([S:25]([CH2:24][C@:17]2([CH3:16])[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)(=[O:26])=[O:27])[CH2:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(OC1=CC[NH2+]CC1)C(F)(F)F
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: [Cl-]
Product: C[C@]1(CS(=O)(=O)N2CC=C(OS(=O)(=O)C(F)(F)F)CC2)NC(=O)NC1=O

Procedure:
4-{[(Trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydropyridinium chloride was reacted with [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (Example 1f) in the same way as for Example 1c.
Reaction SMILES: ClCCl.[C:4]([OH:9])(=[O:8])[C:5]([CH3:7])=[CH2:6].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CS(O)(=O)=O.C(N(CC)CC)C>[C:4]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][O:10]1)(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCC1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCCO1
Temperature: -40 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, nitrogen inlet and a magnetic stirrer was added 300 mL of dichloromethane, 24.5 g (0.29 mol) of methacrylic acid and 21.4 g (0.305 mol) of 2,3-dihydrofuran. The flask was cooled under Nitrogen to −40° C. and 0.05 g of methanesulfonic acid was added. The mixture was warmed to 0° C. and stirred for 6 hours at which time it was recooled to −40° C. and an excess (1 mL) of triethylamine was added. The solution was then washed with saturated sodium bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Distillation from sodium carbonate at reduced pressure resulted in 26 g (58%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[N:12]([O-])=[O:13].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7](=[N:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: COC(=O)Cc1ccccn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(=NO)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of methyl 2-pyridylacetate (3.78 g) in acetic acid (15 mL) was added dropwise an aqueous solution (5 mL) of sodium nitrite (1.75 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=75/25 to 25/75) to give methyl(hydroxyimino)(2-pyridyl)acetate (3.72 g, yield: 83%) as a colorless solid.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:17]([O:21][C:22](=[O:32])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O>[C:17]([O:21][C:22](=[O:32])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][CH2:2]4)[CH2:16][CH2:15]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.58 g (15 mmol) of 1-(indan-4-yl)-piperazine hydrochloride and 3.41 g (15 mmol) of trans-(4-formyl-cyclohexyl)-carbamic acid tert-butylester were dissolved in dichloroethane (120 ml), 2.1 ml (15 mmol) triethylamine was added, then 4.6 g (22 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20% potassium carbonate solution in water (40 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 5.1 g (yield: 82.2%), m.p.: 131-4° C.
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[CH3:38][C:39]1[S:40]C(B2OC(C)(C)C(C)(C)O2)=C[N:43]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[S:40][C:39]([CH3:38])=[N:43][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1ncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)s1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-methylthiazol-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=518, obsd.=518).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C([O-])([O-])=O.[K+].[K+].[N:24](S(C(F)(F)F)(=O)=O)=[N+:25]=[N-:26]>O.CO>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][N:24]=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNN=[N+]=[N-])C(=O)O
Reaction time: 8 h
Yield: 50 %

Procedure:
Boc-Lys(N3)OH was synthesized from Boc-LysOH by using procedures for Cu(II)-catalyzed diazo-transfer to amines. (Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 6029-6032.) Boc-LysOH (4.38 g, 17.8 mmol), CuSO4.5H2O (44.7 mg, 178.2 □mol) and K2CO3 (3.69 g, 26.8 mmol) were dissolved in H2O (57 mL) and MeOH (114 mL). N3Tf (triflyl azide, 17.8 mmol in 150 mL CH2Cl2) was added, and the reaction mixture was stirred overnight. MeOH was removed under reduced pressure. The resulting aqueous solution (50 mL) was diluted with H2O (0.10 L), and the pH was adjusted to 6.0 with HCl. Sodium phosphate buffer (150 mL, 0.25 M, pH 6.2) was added, and the solution was washed with EtOAc (3×) to remove the triflic amine byproduct. The pH of the washed aqueous layer was adjusted to 2.0 with HCl, and the resulting solution was washed with EtOAc (4×) to extract the desired product. The organic layer was then dried over MgSO4(s) and filtered, and the solvent was removed under reduced pressure to yield Boc-Lys(N3)OH as a clear oil (50%). Spectral data. 1H NMR (500 MHz, CDCl3) δ:10.93 (broad s, 1H), 5.11 (d, J=8.3 Hz, 1H), 4.34 (m, 1H), 3.30 (d, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.49 (m, 2H), 1.46 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ:179.96, 156.30, 97.44, 55.79, 53.79, 34.66, 31.07, 30.96, 25.20 ppm; MS (ESI) m/z 295.1383 (MNa+[C11H20N4O4Na]=295.1382).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C@H:16]([CH2:21][N:22]([CH2:30][C@H:31]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:39]([O:38][C@H:31]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][N:22]([CH2:21][C@@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])(=[O:4])=[O:3])[CH:6]=3)[CH:12]=2)[O:17]1)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41]
Reactant: COCC(=O)O
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3cccc(S(N)(=O)=O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1

Procedure:
A solution of the compound of Example 281 (60 mg, 0.091 mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCI (26 mg, 0.14 mmol), and DMAP (11 mg, 0.091 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down and the crude product was purified by preparative TLC plate with CH2Cl2:MeOH:NH4OH (90:15:2) to obtain (60 mg). ESLC-MS: m/z=725 (MH+); 1H NMR (MeOH-d4): 8.566˜8.439 (m, 2H), 8.077 (s, 1H), 7.889˜7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313 (m, 2H), 6.767 (d, 1H), 5.180˜5.035 (m, 1H), 4.220 (s, b, 1H), 3.907 (s, 2H), 3.760˜3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m, 1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H), −0.109 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:4]=1[NH2:5].[I-].C[N+]1(CC2C=CC=CC=2)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.C(Cl)Cl>CCO.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:4]=1[N:5]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: CCCOc1ccc(N)c(OC)c1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc(N2CCC(=O)CC2)c(OC)c1
Reaction time: 1 h

Procedure:
1.20 g (6.62 mmol) 2-methoxy-4-propoxyaniline (Example XXXI) in 8.5 mL EtOH and 1.8 mL water are stirred under reflux. During 30 min 2.19 g (6.62 mmol) N-methyl-N-benzyl-4-oxopiperidinium iodide (Org. Lett. 1999, 1, 1261-1262) are added by several portions. Stirring under reflux is continued for 1 h. Then the reaction mixture is cooled down to rt before water and DCM are added. The layers are separated and the org. layer is dried with MgSO4, filtered and the solvent is removed in vacuo. The resulting residue is purified by column chromatography (silica gel, PE/EtOAc 8/2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(=O)(O)[O-].[Na+].[C:23](O)(=O)[CH2:24]C(CC(O)=O)(C(O)=O)O>C(O)C>[CH2:23]([O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)=[O:10])[CH3:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)c1ccc(O)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(O)cn1
Temperature: 0 °C
Yield: 55 %

Procedure:
To a stirred solution of 5-hydroxy-pyridine-2-carboxylic acid (1.25 g, 9.0 mmol) in ethanol (40 mL) was added concentrated sulfuric acid (3 mL, 56.3 mmol) and the resulting solution heated at reflux under an atmosphere of argon for 20 h. The solution was then cooled to 0° C. then sodium hydroxide (2 N, 55 mL) was added. Saturated aqueous sodium bicarbonate and 10% w/w citric acid solution were then added to bring the pH to 7 and the resulting solution concentrated to ˜70 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts dried, filtered and concentrated to afford the title compound (829 mg, 55%) as an off white solid. MS: m/e=168.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH2:59]([O:66][C:67]([C@@H:69]1[CH2:73][C@H:72]([NH:74][C:75]([O:77][CH2:78][CH:79]2[C:91]3[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=3[C:85]3[C:80]2=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:76])[CH2:71][NH:70]1)=[O:68])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[CH2:59]([O:66][C:67]([C@@H:69]1[CH2:73][C@H:72]([NH:74][C:75]([O:77][CH2:78][CH:79]2[C:91]3[CH:90]=[CH:89][CH:88]=[CH:87][C:86]=3[C:85]3[C:80]2=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:76])[CH2:71][N:70]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:68])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (435 mg, 1.69 mmol) in DMF at 0° C. was added DIPEA (1.18 mL, 6.76 mmol) and HATU (674 mg, 1.77 mmol). After 30 minutes (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94 g, 1.69 mmol) was added in one portion. The cooling bath was removed and the mixture stirred for 1 h, diluted with water, the resulting white precipitate collected, washed with water and air-dried to give (2S,4S)-1-((S)-2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.07 g, 93%).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:21]1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[F:19][C@@H:20]1[C@@H:24]([CH2:25][O:26][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:23][C@@H:22]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:21]1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C

Procedure:
At 0° C., 1.2 equivalents of palmitoyl chloride are added to a solution of 3'-deoxy-3'-fluorothymidine in pyridine. The solution is warmed slowly to room temperature. As soon as a thin layer chromatographic control (CHCl3 /methanol=95/5 on silica gel) shows a complete reaction, the solution is poured into ice water. The aqueous phase is decanted, the resulting oil is chromatographed on silica gel with chloroform eluent. The title compound is recovered from the suitable fractions by evaporation of the solvent. M.P. 65°-66° C. (cyclohexane).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[OH:11][CH2:12][CH:13]1[CH2:17]OC(=O)[O:14]1>>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:14][CH:13]([CH2:12][OH:11])[CH2:17][O:4]1
Reactant: O=C1OCC(CO)O1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Yield: 66 %

Procedure:
8.5 grams of this hydroxyethyl hemiketal of hexafluoroacetone is then reacted with 3 grams of glycerol carbonate at 115°-141° C. for 103 hours. The yield is 66% 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].ClC1C=CC(SC)=CC=1C(O)=O.[CH3:36][N:37]([C:39](ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:38].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:36][N:37]([CH3:39])[C:38]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CSc1ccc(Cl)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(N(C)C)n1
Temperature: 150 °C
Yield: 231.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylthio)benzoic acid (0.404 g, 2.0 mmol), HATU (1.50 g, 0.040 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.035 g (42% yield) of pure product as the undesired product: MS (ES) m/z 377 (M+).