Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:27]=[C:28]([N:30]5[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]5)[CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(NC5CCCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.2 mmol) and cyclopentylamine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A yellow solid (13 mg); Mp: 88-90° C.; 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=6.6 Hz, 3H), 1.23-1.87 (m, 13H), 2.77-2.85 (m, 2H), 3.76 (d, J=12.3 Hz, 2H), 4.08-4.15 (m, 1H), 5.15 (bs, 1H), 6.04 (s, 1H), 6.76 (d, J=12.3 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 7.26-7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.87-7.97 (m, 3H), 8.07-8.11 (m, 1H), 8.20 (s, 1H); MS 540 (M+1).
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CS(C)=O>[CH:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)=[CH:16][CH:17]=1)([CH3:25])[CH3:24]
Reactant: CC(C)OCc1ccc(Cc2ccc(NC(=O)OCC[Si](C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)OCc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid 2-trimethylsilanyl-ethyl ester (734 mg, 1.84 mmol) in dry dimethyl sulfoxide at 20° C. under argon atmosphere was added tetra-n-butylammonium fluoride in tetrahydrofuran (5.52 mL, 5.52 mmol). After the mixture was stirred for 1 hour, the solution was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous phase was extracted with diethyl ether (2×20 mL), and the, combined organic layers were washed with water and brine, dried (Mg2SO4), and evaporated in vacuo. The crude product was purified by flash chromatography to give pure 4-(4-isopropoxymethyl-benzyl)-phenylamine (405 mg, 86%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[CH:4][CH:3]=1>Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(O[C@H]3CCNC3)n2)[nH]1
Yield: 117.2 %

Procedure:
A solution of (S)-tert-butyl 3-((7-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (200 mg, 0.463 mmol) in 4M HCl/EtOAc (5 mL) was stirred at RT for 2 hours. The reaction mixture was subsequently concentrated in vacuo to give the title compound (180 mg, 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][CH2:2][C:3]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(=O)CCl)cc1
Temperature: 60 °C

Procedure:
23.5 mmol of chloroacetyl chloride and, in portions, 18.1 mmol of acetanilide, are added slowly, under an argon atmosphere, to 108 mmol of aluminium chloride in 90 ml of 1,2-dichloroethane. The reaction mixture is heated at 60° C. for 2 hours and then cooled with an ice bath. After slow hydrolysis using ice, and filtration, the precipitate obtained is washed with ethyl ether and dried. The expected product so obtained is used in the following without being purified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccc(NCc3ccccc3)cc2)c1C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a mixture of 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (1.0 g, 3.74 mmol) and sodium bicarbonate (310 mg, 4.48 mmol) suspended in ethanol was added benzyl bromide (770 mg, 4.48 mmol). After 10 min of stirring at 70° C., the mixture became homogeneous. The reaction was stirred at 70° C. for 2 h and the solvent and volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine (2×25 ml). After drying over magnesium sulfate, evaporation of the solvent left a viscous yellow oil which was chromatographed on silica gel to give 960 mg (72% yield) clear, colorless oil. Further purification by HPLC gave a white solid, m.p. 47°-8° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>>[C:9]([O:8][C:7]([NH:6][C:2]1[CH:3]=[CH:4][C:5]([OH:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]=1[C:14]([O:22][CH3:23])=[O:21])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ccco1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC

Procedure:
reacting tert-butyl furan-2-ylcarbamate with dimethyl but-2-ynedioate via the Diels-Alder reaction to form dimethyl 3-(tert-butoxycarbonylamino)-6-hydroxyphthalate;
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C:16](=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(F)ccc1-3
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the foregoing alcohol (from Step 3) in DCM (0.06 M) was added DMP (1.5 eq.), and the mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed with a 1:1 (v/v) mixture of sodium thiosulfate and sodium hydrogen carbonate (both saturated aqueous solutions), then with brine. Drying over Na2SO4, filtration and concentration i. vac. gave the crude product, which was used without further purification (92%); MS (ES+) m/z 422 (M+H)+.
Reaction SMILES: [Na].[CH:2]([C:14]([O:16]CC)=O)([C:9]([O:11]CC)=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:19][C:20]([NH2:22])=[O:21]>C(O)C>[O:21]=[C:20]1[NH:22][C:9](=[O:11])[CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:14](=[O:16])[NH:19]1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of anhydrous ethanol (1500 mL) was added sodium (25.2 g, 1.1 mol) in pieces. After all the sodium dissolved, triethyl ethane-1,1,2-tricarboxylate (180.0 g, 733 mmol) and urea (43.9 g, 733 mmol) was added respectively. The reaction mixture was heated at reflux overnight and cooled to room temperature, evaporated to dryness. The residue was diluted with water and acidified by diluted hydrochloric acid (2 N). The mixture was evaporated and purified by silica gel chromatography to afford the product ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate as a pale-yellow solid (82.8 g, yield 35.0%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>C(#N)C.CCOC(C)=O>[C:32]([O:35][CH2:36][C:37]([NH:14][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:11]=2)[N:6]([CH3:30])[C:5](=[O:31])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 90 °C

Procedure:
To the product of Example 2 (120 mg) in acetonitrile (2 mL) was added acetoxyacetyl chloride (0.2 mL). The reaction was heated to 90° C. in a CEM microwave reactor for a total of 34 minutes. The reaction was diluted with EtOAc and was washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane affording the title compound. HPLC/MS: 572.1 (M+1), 574.1 (M+3); Rt=4.06 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH2:15][C:14]([F:18])([F:17])[F:13])[CH2:11]2
Reactant: NCC(F)(F)F
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 2,2,2-trifluoroethylamine (Aldrich Cat No. 269042). LCMS (M+H)+=294.0/296.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[O:9]CCO1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:5]([CH2:4][CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=2)([OH:32])[CH2:31][CH2:30]1)=[O:9]
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: Cc1cc(F)ccc1C1(CCCCl)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C(=O)CCCN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C

Procedure:
A mixture of 3 g of 4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.5 g of 4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, 1.4 g of anhydrous potassium carbonate, 0.05 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 3 hours. The resulting mixture was poured into ice water and was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residual oil were added 60 ml of methanol, 21 ml of water and 10.5 ml of concentrated hydrochloric acid. The mixture was refluxed for 50 minutes and concentrated in vacuo. The residual oil was made alkaline with 28% aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residual solid was recrystallized from isopropyl ether to give 1-[γ-(2-methyl-4-fluorobenzoyl)-propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, melting at about 63.5°-64.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(NCCOC(=O)NC(COCc2ccccc2)C(=O)O)n1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1cccc(C)n1)c1cc(Cl)cc(Cl)c1

Procedure:
Analogously to Example 2, ethyl 3-amino-3-(3,5-dichlorophenyl)propionate is reacted with 3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propionic acid and purified by chromatography, giving ethyl 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]-propanoylamino}-3-(3,5-dichlorophenyl)propionate, RT 1.765 min, FAB-MS (M+H)+ 618.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:21][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1ccccc1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: CN1CCN(CC(O)COC2c3ccccc3C(=O)N2c2ccccc2)CC1
Yield: 127.3 %

Procedure:
A solution of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (8.4 g.) and 1-methylpiperazine (3.6 g.) in anhydrous toluene (84 cc.) is heated under reflux for 3 days. After cooling, the reaction mixture is washed with water (2 × 50 cc.) and then the organic solution is extracted with 1N hydrochloric acid (55 cc.) and water (3 × 20 cc.). The aqueous and acid solutions are combined and are rendered alkaline by addition of 1N sodium hydroxide solution (55 cc.). The oil which separates out is extracted with methylene chloride (150 cc.) and then the organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residual oil is dissolved in ethanol (20 cc.) and the resulting solution is added to a hot solution of fumaric acid (5.85 g.) in ethanol (80 cc.). The product which crystallises on cooling is filtered off and then washed with ethanol (30 cc.) and di-isopropyl ether (40 cc.). After drying, 3-[2-hydroxy-3-(4-methylpiperazin-1-yl)-propoxy]-2-phenyl-isoindolin-1-one acid difumarate (14.5 g.), melting at 194° C., is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][C@H:59]([C:64](O)=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][C@H:59]([C:64]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])=[O:57])([CH3:53])([CH3:54])[CH3:52]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 56 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-leucine. Yield 56%. [α]D =-2.7° (c=0.86, tetrahydrofuran).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)ccc1F
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(N2CCOCC2)ccc1F
Yield: 73.3 %

Procedure:
A mixture of 1-(5-amino-2-fluoro-phenyl)-ethanone (3.5 g), bromoethyl ether (5.929 g), and i-Pr2NEt (7.121 g) in toluene (20 mL) was refluxed for 16 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 3.74 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:42]([O:43][CH3:44])[CH3:41])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To the solution of compound 4-bromo-2-methylbenzoic acid D-1 (50 g, 0.23 mol) in DCM (500 mL) was added EDCI (48 g, 0.25 mol), HOBt (34.1 g, 0.25 mol), NMM (50.5 g, 0.50 mol) and N,O-dimethylhydroxylamine hydrochloride (24.3 g, 0.25 mol). The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with H2O (300 mL), 1 N HCl (300 mL), and saturated sodium bicarbonate solution (300 mL), dried over sodium sulfate, and concentrated to give the desired product D-2 (55 g, yield 91.6%) as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:26])=[O:27])=[CH:20][CH:19]=2)[N:7]=1
Reactant: COc1ccccc1-c1cc(C)nc(Cl)n1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(C)nc(Nc2ccc(CS(N)(=O)=O)cc2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-6-methyl-pyrimidine (0.939 g, 0.004 mol) (Cocuzza, Anthony J. et al., PCT Int. Appl. (1999), WO 9901439 A1, 19990114.), and (4-amino-phenyl)-methanesulfonamide (0.745 g, 0.004 mol) in DMF (12 ml) is stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to give {4-[4-(2-methoxy-phenyl)-6-methyl-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:9]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
140 g of 3-hydroxy-6-methylpyridine was dissolved in 1.4 L of dimethylformamide, and with cooling with ice, 178 ml of benzyl chloride was added to it and stirred overnight at room temperature. The reaction liquid was poured into water with ice, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1 to 2/1) to obtain 246.7 g of the entitled compound as an orange oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[O:10]([CH2:9][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([Cl:19])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC(COc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)OC(COc1ccccc1)C(=O)Cl

Procedure:
To 22.42 g (0.1 mole) of 2-acetoxy 3-phenoxy propanoic acid, was added 24 g of thionyl chloride and the mixture was heated under reflux for 2 hours. The excess of thionyl chloride was driven off on a rotary evaporator and the residue was distilled under nitrogen. B.P.14 =163°-8° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C:20](=[O:22])[NH:19][S:18]3(=[O:24])=[O:23])=[C:13]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=2)[CH:5]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:26]([O:25][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N:17]1[CH2:21][C:20](=[O:22])[NH:19][S:18]1(=[O:23])=[O:24])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:33])=[O:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cccc(Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN(c2ccc(Cc3cccc(C(=O)O)c3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzoic acid methyl ester (intermediate from Example LBY596) (0.3 g, 0.643 mmol) in THF is added a solution of LiOH (0.081 g, 1.929 mmol) in H2O. The reaction is stirred at ambient temperature overnight. The mixture is poured into 1 M HCl and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a brown oil. The oil is place under high vacuum to afford solid 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzoic acid: MS (M−H)−=451.2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[C:6]([OH:8])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CC(C)CC1C=CC(C2O[N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=CC=1>CN(C=O)C>[CH3:14][C@H:13]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=[CH:4][C:3]=1[C:2]([F:1])([F:18])[F:17])[CH2:15][CH3:16]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Reactant: CC[C@H](C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 59.1 %

Procedure:
A solution of 600 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)-methylpropyloxy)benzoic acid (from Step B), 542 mg (2.2 mmol) of EDC and 357 mg (2.2 mmol) of HOBT in 6 mL of DMF were stirred at rt for 1 h. The reaction was subsequently treated with 350 mg (2.2 mmol) of N-hydroxy-4-(hydroxymethyl)benzamidine (from Aldehyde 1, Step A) and heated to 80° C. for 12 h. The reaction mixture was cooled and purified via chromatography on a Biotage 40M cartridge using 2:1 v/v hexanes/EtOAc as the eluant affording 510 mg of the title compound: 1H NMR (500 MHz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73–1.83 (m, 2H), 4.55 (septet, 1H), 4.79 (s, 2H), 7.12 (d, J=8.9, 1H), 7.51 (d, J=8.2, 2H), 8.15 (d, J=8.2, 2H), 8.30 (d, J=8.9, 1H), 8.43 (s, 1H).