Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1([F:34])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)([C:16]([O:18]C)=[O:17])[CH2:5]1>CS(C)=O.O>[C:12]([O:11][C:9]([N:7]1[CH2:8][C:4]([F:3])([F:34])[CH2:5][C@@:6]1([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@]1(Cc1ccc(-c2ccc(F)cn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide (61 mg, 1.1 mmol) was added to an ambient temperature solution of 1-tert-butyl 2-methyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1,2-dicarboxylate (246 mg, 0.55 mmol) in DMSO/water (1:1) (2 mL). After stirring at ambient temperature for 1 h, the reaction mixture was extracted with chloroform and concentrated in vacuo to afford 1-(tert-butoxycarbonyl)-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]proline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 73.3 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (Example 91, step A) (0.30 g, 0.90 mmol) and methyl vinyl sulfone (0.29 g, 2.7 mmol) in dioxane (9.0 mL) was stirred under N2. The reaction was heated to 95° C. and stirred for approximately 3 h, then cooled to rt. The reaction mixture was concentrated under vacuum. The residue was taken up in DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was chromatographed on silica gel to give the title compound of step A (294 mg, 0.66 mmol, 74%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, 1H, J=9.35 Hz), 6.56 (dd, 1H, J=9.44 and 2.29 Hz), 6.49 (d, 1H, J=2.38 Hz), 4.17 (q, 2H, J=6.96 Hz), 3.36-3.41 (m, 4H), 3.25 (t, 2H, J=6.78 Hz), 3.01 (s, 3H), 2.92 (M, 2H), 2.66 (t, 2H, J=6.78 Hz), 2.57 (m, 4H), 2.15-2.25 (m, 1H), 1.89-1.97 (m, 2H), 1.75 (m, 2H), 1.32-1.40 (m, 5H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[C:39]1([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:39]1([N:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 94 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-phenylpiperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (98:2). Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Combine the appropriate fractions and concentrate to give the title compound (0.50 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=420 m/e.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.C(N([CH2:26][CH3:27])CC)C.ClCC(Cl)=[O:31]>C1COCC1>[O:31]=[C:3]1[CH2:2][O:1][CH2:27][CH2:26][N:4]1[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Reactant: O=C(OCc1ccccc1)N1CCC(NCCO)CC1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(N2CCOCC2=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Benzyl 4-[(2-hydroxyethyl)amino]piperidin-1-carboxylate (7.5 g) obtained in Example 7a) and triethylamine (4.1 mL) were dissolved in THF (70 mL), chloroacetyl chloride (2.2 mL) was added dropwise thereto with cooling at 0° C., and the mixture was stirred at 0° C. for 2 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (60 mL), the solution was cooled to 0° C., and then sodium hydride (60% in oil; 1.2 g) was added to the reaction mixture. The mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added thereto, the solution was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to ethyl acetate) to obtain the title compound (3.8g, 44%) as a colorless oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:21]>FC(F)(F)C(O)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:21]
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Reactant: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(O)cc1)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
Phenol (732 mg, 7.78 mmol) was added to a solution of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example 38-(1); 2.0 g, 7.78 mmol) in trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for five hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (1.95 g, 75%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: OCC1CCCNC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 25 g (0.22 mol) of 3-piperidinemethanol in 200 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 31.50 g (0.16 mol, 74% yield) of a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19].N1C=CC=CC=1>C(Cl)Cl>[CH:14]([CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:17])[F:1])=[CH:5][CH:6]=1)[C:11]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Reaction time: 60 h
Yield: 24.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride (4.82 g) in methylene chloride (10 ml) is added to a methylene chloride solution (10 ml) of α-cyano-m-phenoxybenzyl alcohol (4.05 g) and pyridine (1.5 ml). The mixture is stirred for approximately 60 hours and filtered. The filtrate and the washings are evaporated and the residual oil (6.29 g) is purified on a silica column using 1:1 methylenechloride-hexane as an eluant. The solvent is evaporated and the residue treated with sodium borohydride. The resulting crude material is purified on a silica gel column to yield 2.01 g of product.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=[O:14])[CH2:12][CH3:13])(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)C(CO)NC(=O)OC(C)(C)C
Yield: 97.2 %

Procedure:
tert-butyl 1-(tertbutyldimethylsilyloxy)-3-oxopentan-2-ylcarbamate (26) (900 mg, 2.7 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (14 mL). The mixture was stirred and glacial acetic acid (21 mL) was added to the reaction flask. The reaction stirred for 22 h at rt. The reaction was transferred to a 250 mL separatory funnel with sat. NaCl (50 mL) and sat. NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (3×75 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 825 mg of crude oil. The residue was purified by flash column chromatography (50% EtOAc/hexanes) to give 570 mg (96%) of 27 as a colorless oil. Rf=0.31 (50% EtOAc/hexanes); IR (film) 3420, 2976, 2937, 1686, 1498, 1365, 1163, 1056 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.78 (d, J=6.0 Hz, 1H, carbamate-NH), 4.34 (br s, 1H, Boc-NH—CH), 3.97 (d, J=10.0 Hz, 1H, CH—CH2), 3.87 (d, J=10.0 Hz, 1H, CH—CH2), 3.34 (br s, 1H, CH2—OH), 2.66 (m, 1H, O═C—CH2), 2.59 (m, 1H, O═CCH2), 1.45 (s, 9H, t-butyl-CH3), 1.09 (t, J=7.0 Hz, 3H, O═C—CH2CH3); 13C NMR (125 MHz, CDCl3) δ 209.0, 156.1, 80.3, 63.1, 61.5, 33.4, 28.4, 7.5.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>O>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[NH:24][C:25]1[C:26]([C:27]([O:29][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[O:28])=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Temperature: 50 °C
Yield: 49.5 %

Procedure:
Triethylamine (20 ml) and 3-bromophthalide (21.3 g) were added to a suspension of 2(3'-trifluormethylanilino)-nicotinic acid (28,2 g in 500 ml of acetone). The mixture was refluxed during 4 hours. The obtained greenish yellow suspension was poured into 6000 ml of water, which was previously heated at 50° C. The stirred reaction mixture was cooled to 5° C., and the formed precipitate was filtered and washed with cool water. Yield: 52% (20.5 g) of phthalidyl 2-(3'-trifluormethylanilino)-pyridin-3-carboxylate, m.p: 162°-164° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC1>>[N:22]1([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH2:27][CH2:26][CH2:23]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and azetidine and isolated as white solid (9.8 mg, 52%). MS (m/e): 357.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][S:18][C:17]1=[N:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[O:36][CH3:37])[CH2:9][C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:39]([NH2:41])[CH3:40].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][S:18][C:17]1=[N:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[O:36][CH3:37])[CH2:9][C:10]([NH:41][CH2:39][CH3:40])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a mixture of the carboxylic acid compound (1.0 g) obtained in Example 327 (1), ethylamine hydrochloride (297 mg), 1-hydroxybenzotriazole monohydrate (418 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg) and N,N-dimethylformamide (7 ml) was added dropwise N,N-diisopropylethylamine (1.27 ml), and the mixture was stirred overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (1:1)] to give the title compound (929 mg) as foam. (2) N2-{3-[2-[(4-chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3(2H)-yl]propyl}-N1-ethylglycinamide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CN(C=O)C>CCOC(C)=O>[C:22]1([NH:21][C:18]([C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: Nc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3ccccc3)ccc2C1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (0.2 g, 0.721 mmol) and aniline (0.066 mL, 0.721 mmol) and TEA (0.251 mL, 1.803 mmol) in EtOAc (5 mL) was added a 50% solution of T3P in DMF (0.408 mL, 1.442 mmol). After 24 h, the reaction was partitioned with dilute HCl (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (10 mL) and dried (MgSO4). Purification by silica gel chromatography afforded 0.238 g of Intermediate 19A. MS (ESI) m/z: 352.9 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:28])[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)=[CH:17][C:11]=2[N:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.O.CS(C)=O>[Cl:28][C:15]1[C:16]([C:18]#[C:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=2)=[CH:17][C:11]2[N:10]=[C:9]([S:8][CH2:7][C:6]([OH:29])=[O:5])[NH:13][C:12]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(CO)cc3)c(Cl)cc2[nH]1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CSc1nc2cc(C#Cc3ccc(CO)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 4 mL vial, compound 18-1 (25.3 mg, 0.059 mmol) was dissolved in 9:1 TFA/water (2 mL) and stirred at rt for 2 h. The solution was evaporated to dryness in vacuo to give oily brown residue, which was dissolved in DMSO (1.25 mL), filtered and purified by reverse-phase HPLC to give the title compound. LR-MS (API-ES): calculated for C18H13ClN2O3S 372.0, observed m/e 372.9 (M+H)+ (Rt 1.87 min).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][NH:24]1>>[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][N:24]1[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: c1ccc2c(c1)CNC2
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccccc4C3)cn2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and isoindoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.10 (2H, t, J=6.0 Hz), 3.99 (4H, s), 4.21 (2H, t, J=6.0 Hz), 7.17-7.24 (4H, m), 7.56 (1H, d, J=3.8 Hz), 7.82 (1H, s), 7.88 (1H, s), 8.27 (1H, s), 8.59 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H18N4O2, 335. Found, 335.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-chloro-3-nitro-pyridine (2 g, 12.61 mmol) in dioxane (15 mL) was treated with 1-methylpiperazine (1.515 g, 1.678 mL, 15.13 mmol) and DIPEA (2.445 g, 3.295 mL, 18.92 mmol). The mixture was stirred at 80° C. for 1 hour, cooled to RT. The mixture was partioned between EtOAc and an aqueous saturated solution of NaHCO3 (40 ml). Combined organic extract was dried over MgSO4 and concentrated under reduced pressure to give an orange oil which was purified by chromatography on silica eluting with 5-10% MeOH/EtOAc/0.5-1% NH4OH to give 1-methyl-4-(3-nitro-4-pyridyl)piperazine 14 as a deep yellow oil which crystallised on standing. (2.56 g, 11.52 mmol, 91.36%). MS (ES+) 223.4.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].N1C=CC=CC=1>ClCCl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Cl:3])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)CCCCC(=S)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(Cl)CCCCC(=S)OCC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
89.25 grams (0.7 mole) of thionyl chloride at +5° C. were slowly dropped into a solution of 137.0 grams (0.59 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) and 1 ml of pyridine in 300 ml of dichloromethane. After stirring for 1 hour at +10° C. the mixture was heated for 3 hours at reflux and subsequently concentrated in a vacuum. The residue was treated with 200 ml of water and extracted with dichloromethane. After drying the combined extracts with sodium sulfate the solvent was removed in a vacuum. By fractional distillation there were obtained 125.1 grams (84% of theory) of 6-chloro-8-methylthiooctanoic acid ethyl ester as a colorless oil having a boiling point of 135° C. to 145° C. at 1 mbar.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:5]([C:13]([F:16])([F:15])[F:14])=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].[O-]CC.[Na+].Cl>CCOC(C)=O.O.CN(C=O)C>[OH:1][C:2]1[C:3]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:5]([C:13]([F:14])([F:15])[F:16])=[N:6][C:7]=1[C:8]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:9]
Reactant: CCOC(=O)c1nc(C(F)(F)F)c2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1nc(C(F)(F)F)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazolo[4,5-c]pyridine-6-carboxylate (58 mg, 0.17 mmol), glycine (247 mg, 3.30 mmol), and sodium ethoxide (168 mg, 2.47 mmol) were added to 6 mL of DMF and the mixture was refluxed for 2 h. After the mixture cooled to room temperature, water (50 mL) and EtOAc (50 mL) were added. The mixture was stirred vigorously and 4M hydrochloric acid was added until pH was 3. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated sodium bicarbonate solution (20 mL) and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with 4M hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a crude solid, which was purified by flash chromatography (0-100% EtOAc/hexanes+2% acetic acid) to give 37 mg of the title compound. MS: (−) m/z 380.19 (M−1).
Reaction SMILES: [CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]CCCC)[C:16]([OH:18])=[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][CH3:14].[CH2:39](Br)[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:41].C(N(CC)CC)C.[O:56]1CCCC1>>[OH:56][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([O:18][CH2:39][C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:41])=[O:17]
Reactant: O=C(CBr)c1ccccc1
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 33 %

Procedure:
3-Hydroxy-2-n-tetradecyl-octadecanoic acid (II) prepared as described [Bulletin de la Societe chimique de France 504-510 (1954)] was dissolved in dry tetrahydrofuran (45 ml), and then phenacyl bromide (2.70 g, 13.59 millimole) and triethyl amine (1.89 ml, 13.59 millimole) were successively added thereto with ice cooling. The mixture was allowed to warm to the room temperature, and reacted for 23 hours. The insoluble mass in the reaction mixture was filtered off with suction and the solvent was distilled from the filtrate. The residue was dissolved in benzene and the obtained solution was fractionated through silicagel column chromatography (benzene). After the fractions comprising impurities were discarded, the later colorless fractions were pooled, and the solvent was distilled off from the fraction to, give white crystals of phenacyl 3-hydroxy-2-n-tetradecyl-octadecanoate (IV) (1.81 g, yield 33%).