Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[CH3:22][S:19]([C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Agent: Cl
Product: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Yield: 99 %

Procedure:
Prepared in analogy to example 4 (d) from 4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as a light brown crystalline solid (yield 99%). MS (m/e): 248.1 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)c(OC)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(CC(=O)O)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)-acetate (0.260 g, 0.736 mmol) in THF (1.5 ml), lithium hydroxide 1N (0.883 ml, 0.883 mmol) was added, and the reaction was stirred at RT for 4 hours. The mixture was diluted with EtOAc (15 ml) and acidified with HCl 1M. The organic phase was washed with brine and dried over Na2SO4; the solvent was evaporated to dryness affording 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)acetic acid as a yellow oil (0.233 g, 0.716 mmol, 97% yield, MS/ESI+ 348.1 [MNa]+). This product was used without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1csc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of the product of step 3 (90 mg, 0.21 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (0.5 ml, 2.1 mmol), and stirred at room temperature for 4 h. After the solvent was removed, the crude material was triturated with ether to afford the title product (60 mg, 83%); 1HNMR (400 MHz, CD3OD) δ 7.90 (d, J=8.4 Hz, 2H), 7.82 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.07 (s, 4H), 7.00 (d, J=8.8 Hz, 2H), 4.22 (dd, J=10.4, 3.2, 1H), 4.14 (m, 1H), 4.04 (m, 1H), 3.38 (m, 2H), 2.28 (m, 1H), 2.14 (m, 2H), 1.92 (m, 1H); LC/MS (ESI+) 88%; m/z: 353 (M+1, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][C:15](=[O:17])[NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][C:15](=[O:17])[N:14]([CH3:20])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C)C(=O)O2)cc1OC
Temperature: 25 °C

Procedure:
To a solution of the 6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (1.20 g, 5.06 mM) produced in Example 1 in dried N,N-dimethylformamide (30 ml) were added sodium hydride (60%) (0.41 g, 10.12 mM) and methyl iodide (1.44 g, 10.12 mM). The solution was then stirred at room temperature for one night. The reaction solution was carefully poured into ice water, then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to obtain a residue as a brown oil. The residue was purified by flash chromatography (SiO2; eluted by 0.5% methanol/chloroform) to obtain the above-described compound 0.28 g (yield 22.3%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-:22].[Na+].Cl>C(O)(C)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]3[C:20]([CH3:21])=[N:19][N:18]([CH:7]4[CH2:6][CH2:5][CH2:10][CH2:9][O:22]4)[C:7]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (10.9 g) and sodium hydroxide solution (1N, 80 mL) in isopropanol (80 mL) was stirred at r.t. for 90 min. The pH was adjusted to 3 with 1N HCl and the mixture was poured onto water. The precipitate formed was filtered off and dried in air to give 6-(4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (10.2 g, 97% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CO)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
A suspension of N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 50 (14.0 g, 37 mmol) in toluene (120 mL) was treated with 4-(hydroxymethyl) phenylboronic acid (7.87 g, 51.8 mmol, 1.4 equiv), potassium carbonate (K2CO3, 15.32 g, 111 mmol, 3.0 equiv), ethanol (EtOH, 40 mL), and H2O (40 mL) at 25° C., and the resulting mixture was degassed three times under a steady stream of argon at 25° C. Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 2.14 g, 1.85 mmol, 0.05 equiv) was subsequently added to the reaction mixture, and the resulting reaction mixture was degassed three times again before being warmed to gentle reflux for 6 h. When thin layer chromatography (TLC) and HPLC showed the coupling reaction was complete, the reaction mixture was cooled to room temperature before being treated with H2O (240 mL). The resulting mixture was then stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% ethyl acetate (EtOAc)/hexane (2 X 50 mL), and dried in vacuo. The crude desired N-[3-(2-Fluoro4′ -hydroxymethyl-biphenyl4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 51 (12.50 g, 94% yield) was obtained as off-white solids. This material was found to be essentially pure by HPLC and 1H NMR and was directly used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ1.76 (s, 3H, COCH3), 3.35 (t, 2H, J=5.4 Hz), 3.69 (dd, 1 H, J=6.4, 9.2 Hz), 4.08 (t, 1H, J =9.1 Hz), 4.46 (d, 2 H, J=5.7 Hz, CH2OH), 4.68 (m, 1 H), 5.16 (t, 1 H, J=5.7 Hz, OH), 7.25-7.52 (m, 7 H, aromatic-H), 8.18 (t, 1 H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C=O.[OH:8][CH2:9][C:10]1[N:14]2CCCCC2=[CH:12][N:11]=1>>[CH3:12][N:11]1[CH:3]=[C:2]([CH3:1])[N:14]=[C:10]1[CH2:9][OH:8]
Reactant: [Li]CCCC
Reactant: OCc1ncc2n1CCCC2
Agent: C=O
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylamidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde (according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in Example 243) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:42][C:43]2[CH:48]=[C:47]([CH2:49][CH2:50][C:51]([O:53]C)=[O:52])[CH:46]=[CH:45][C:44]=2[OH:55])[C:10]([OH:41])=[C:11]([CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH:17]=[C:16]([CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])[CH:30]=[CH:29][C:28]=3[OH:39])[C:15]=2[OH:40])[CH:12]=1)=[O:4].[OH-].[Na+].[OH-].[NH4+]>CO>[C:22]([CH2:21][CH2:20][C:18]1[CH:17]=[C:16]([CH2:26][C:27]2[CH:32]=[C:31]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:30]=[CH:29][C:28]=2[OH:39])[C:15]([OH:40])=[C:14]([CH2:13][C:11]2[CH:12]=[C:7]([CH2:6][CH2:5][C:3]([OH:4])=[O:2])[CH:8]=[C:9]([CH2:42][C:43]3[CH:48]=[C:47]([CH2:49][CH2:50][C:51]([OH:53])=[O:52])[CH:46]=[CH:45][C:44]=3[OH:55])[C:10]=2[OH:41])[CH:19]=1)([OH:24])=[O:23]
Reactant: COC(=O)CCc1ccc(O)c(Cc2cc(CCC(=O)OC)cc(Cc3cc(CCC(=O)OC)cc(Cc4cc(CCC(=O)OC)ccc4O)c3O)c2O)c1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(O)c(Cc2cc(CCC(=O)O)cc(Cc3cc(CCC(=O)O)cc(Cc4cc(CCC(=O)O)ccc4O)c3O)c2O)c1

Procedure:
A solution of bis-[5-(2-methoxycarbonylethyl)-3-[5-(2-methoxycarbonylethyl)-2-hydroxybenzyl]2-hydroxyphenyl]methane (0.10 g) in methanol (2 ml) is stirred with 10% aqueous sodium hydroxide (NaOH) (1 ml) at room temperature. The mixture is quenched with dilute aqueous hydrochloric acid (HCl) and the organic soluble material retreated as above. The mixture is quenched as above and the organic soluble material flash chromatographed, eluting with 10% methanol in chloroform. The product so obtained is treated with ammonium hydroxide solution and lyophilized to give the desired product as the ammonium salt, m.p. 150° C. (dec.).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([N:36]3[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46][CH2:45][CH2:44]4)[CH2:39][Si:38]([CH3:55])([CH3:54])[CH2:37]3)=[O:35])[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([N:36]3[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46][CH2:45][CH2:44]4)[CH2:39][Si:38]([CH3:54])([CH3:55])[CH2:37]3)=[O:35])[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2C[Si](C)(C)C[C@H]2C(=O)N[C@@H]2CCCc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si]1(C)C[C@@H](C(=O)N[C@@H]2CCCc3ccccc32)N(C(=O)[C@H](Cc2ccc(C(=O)O)cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C1
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)benzoate (0.17 g, 0.22 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL) at rt. After 4 h, the reaction mixture was concentrated in vacuo to obtain the title compound (150 mg, 82% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.37 (br. s., 1H), 8.05 (d, J=8.4 Hz, 2H), 7.76 (d, J=7.5 Hz, 2H), 7.56 (dd, J=7.3, 4.4 Hz, 2H), 7.44-7.05 (m, 11H), 6.62-6.52 (m, 2H), 5.23-5.09 (m, 2H), 4.94 (t, J=6.9 Hz, 1H), 4.38-4.11 (m, 3H), 3.33 (d, J=13.2 Hz, 1H), 3.20 (dd, J=14.1, 4.8 Hz, 1H), 3.03-2.93 (m, 2H), 2.86-2.74 (m, 2H), 2.11-2.01 (m, 1H), 1.92-1.79 (m, 3H), 1.27 (d, J=6.6 Hz, 2H), 0.45 (s, 3H), 0.32 (s, 3H); MS(ESI+) m/z 702.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.Br[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][C:22]#[N:23])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: N#CCBr
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-Bromoacetonitrile (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (53 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1ccccc1F
Product: O=C(NCCc1ccccc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-fluoro-phenethylamine (67.9 mg, 0.49 mmol). The title compound was obtained as a solid (35 mg, 18% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.97 (1H, m), 8.37 (1H, s), 7.27 (2H, m), 7.16 (2H, m), 3.44 (2H, m), 2.82 (2H, m). MS m/z: 470.00, 472.01 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:58])([CH3:57])[C@H:42]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:58])([CH3:57])[C@H:42]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@H](NC(=O)COc1ccccc1)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)COc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 54B (0.038 mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.011 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (d, J=2.94 Hz, 18 H), 1.53 (m, 2 H), 2.55 (m, 1 H), 2.73 (m, 3 H), 3.49 (s, 3 H), 3.65 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 4.05 (m, 1 H), 4.15 (m, 1 H), 4.33 (d, J=9.56 Hz, 1 H), 4.53 (m, 2 H), 4.81 (d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.95 (m, 3 H), 7.11 (m, 1 H), 7.18 (m, 6 H), 7.31 (m, 3 H), 7.48 (d, 9.56 Hz, 1 H), 7.84 (m, 6 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:40])[N:24]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:28]2[CH2:27][CH2:26][CH:25]([N:24]([CH2:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:23](=[O:40])[O:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:30][CH2:29]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccccc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CCCc4ccccc4)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To 3 mL of dichloromethane solution containing 95 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 81 mg of tert-butyl(3-phenylpropyl)(piperidin-4-yl)carbamate, 18 μl of acetic acid and 98 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 1 hour. To the reaction mixture, water, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added. The organic layer was separated, and washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.16 g of tert-butyl (1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(3-phenylpropyl)carbamate as a brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](N)=[N:6][CH:7]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:18]>>[Cl:18][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
5-Fluoro-3-nitropyridine-2-amine (2.66 g) suspended in concentrated hydrochloric acid (35 ml) was cooled to −15° C., and an aqueous solution (7 ml) of sodium nitrite (2.57 g) was added dropwise over 10 minutes. After stirring at −10° C. for 1 hour, and further stirring at room temperature for 1 hour, under ice cooling a 30% aqueous sodium hydroxide solution was added for neutralization. The insolubles were collected by filtration, washed with water, air-dried, and then redissolved in ethyl acetate, before the insolubles were filtered off. The filtrate was concentrated under reduced pressure to afford 2-chloro-5-fluoro-3-nitropyridine (1.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:33][CH2:34]O)(=[N:29][C:30](=[O:32])[CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:33][CH2:34][Br:56])(=[N:29][C:30](=[O:32])[CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N=S(=O)(CCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Yield: 49.7 %

Procedure:
To a suspension of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-hydroxy ethyl)-N-acetyl sulfoximide (90 mg, 0.000168 mol) in DCM (15 mL) was added triphenyl phosphine (44 mg, 0.000168 mol) with stirring followed by carbon tetrabromide (55 mg, 0.000168 mol) at 25-30° C. Reaction mixture was stirred at same temperature for 3 hr. Subsequent work up and column purification (100-200 mesh silica gel, 50% ethyl acetate in hexane) gave 50 mg of titled product in 50% yield.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[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][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[C:37](Cl)(=[O:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1.C1(C)C=CC=CC=1.C(O)(C)C>[CH:20]1([N:19]([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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37](=[O:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
10 g of the compound from Example 1 are suspended in 20 ml of tetrahydrofuran and, after addition of 10 g of sodium carbonate, 10 g of dodecanoyl chloride in 10 ml of tetrahydrofuran are added dropwise. When the reaction has ended (control by thin layer chromatography on silica gel 60 in toluene/isopropanol 6:1), the solid is filtered off, the filtrate is evaporated to a syrup in vacuo and the crude product is purified by column chromatography on silica gel 60 with the eluting agent toluene/isopropanol 10:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(OC(C)(C)C)=O)[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[CH2:19][O:18]1.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][N:17]2[C:21](=[O:22])[C:20]([CH3:23])([CH3:24])[CH2:19][O:18]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.1 %

Procedure:
To a stirred solution of 2.0 grams (0.006 mole) of 2-[2-chloro-4-(1,1-dimethylethoxycarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone in 10 ml of methylene chloride was added dropwise a solution of 10 ml of trifluoroacetic acid in 10 ml of methylene chloride. Upon completion of addition the reaction mixture stirred at ambient temperature for 3.5 hours. The reaction mixture was slurried with 50 ml of water and neutralized with a saturated aqueous solution of potassium carbonate. A solid precipitate was collected by filtration to give 1.3 grams of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 106°-108° C.