Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.5 %

Procedure:
(2S,4R)-tert-Butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 2.3 mmol) in pyridine (20 mL) was cooled to 0° C. and treated with a solution of p-toluenesulfonyl chloride (483 mg, 2.53 mmol) in pyridine (5 mL) added over a period of 1 hour. The reaction was allowed to slowly warm to ambient temperature with continued stirring for 48 hours. The resulting material was triturated with ethyl acetate and purified by flash chromatography on a 12 g silica gel column, eluting with 5% ethyl acetate/hexanes for 3 minutes followed by a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as an oil (397 mg; 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.69 (m, 2H), 7.48 (d, J=7.9 Hz, 2H), 4.92 (d, J=2.8 Hz, 1H), 4.23-3.82 (m, 4H), 3.12 (dd, J=25.5, 13.9 Hz, 2H), 2.42 (d, J=3.6 Hz, 3H), 1.87 (d, J=20.3 Hz, 2H), 1.35 (dd, J=23.0, 13.0 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][CH2:19][CH:18]1[C:25](O)=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:25]([CH:18]3[CH2:19][O:20][C:21]([CH3:23])([CH3:24])[CH2:22][N:17]3[CH3:16])=[O:26])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CN1CC(C)(C)OCC1C(=O)O
Product: CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 61 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 4,6,6-trimethyl-morpholine-3-carboxylic acid in 61% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH2:5][CH2:6]O)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:4]([CH2:5][CH2:6][Cl:30])[CH2:8][C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH:2]=[CH2:3].[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: C=CCN(CCO)Cc1ccoc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCN(CCCl)Cc1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9.255 g (51.07 mmol) of the above 2-[allyl-(3-furylmethyl)amino]ethanol, 10.7 ml (76.6 mmol) of triethylamine and 0.1 g of 4-dimethylaminopyridine in 150 ml of dichloromethane, 11.7 g (61.3 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield N-allyl-N-(3-furylmethyl)-2-chloroethylamine as a mixture with p-toluenesulfonyl chloride.
Reaction SMILES: COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(Cl)=CC=2)=CC=1.C[O:56][C:57](=[O:117])[C@@H:58]([NH:73][C:74]([C@@H:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@H:83]([C:92]4[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]5[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=5)=[CH:94][CH:93]=4)[C:84](=[O:91])[N:85]3[CH3:90])=[CH:80][C:79]=2[CH2:78][N:77]1[C@H:108]([C:111]1[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=1)[CH2:109][CH3:110])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>>[Cl:72][C:69]1[CH:70]=[CH:71][C:66]([C:63]2[CH:62]=[CH:61][C:60]([CH2:59][C@H:58]([NH:73][C:74]([C@@H:76]3[CH2:89][C:88]4[CH:87]=[C:86]5[C:81]([O:82][C@H:83]([C:92]6[CH:97]=[CH:96][C:95]([O:98][CH2:99][C:100]7[CH:105]=[CH:104][C:103]([Cl:106])=[C:102]([Cl:107])[CH:101]=7)=[CH:94][CH:93]=6)[C:84](=[O:91])[N:85]5[CH3:90])=[CH:80][C:79]=4[CH2:78][N:77]3[C@H:108]([C:111]3[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=3)[CH2:109][CH3:110])=[O:75])[C:57]([OH:117])=[O:56])=[CH:65][CH:64]=2)=[CH:67][CH:68]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 88 %

Procedure:
(S)-3-(4′-chloro, —biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (74 mg) was converted to (S)-3-(4′-chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (60 mg) using general procedure K. This ester upon hydrolysis furnished title compound (52 mg) using general procedures B. LC-MS (m/z): 888.
Reaction SMILES: C1(C)C=CC=CC=1.C(C1C=CC=CC=1O)C=C.C[SiH](C)O[SiH](C)C.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][CH2:34][Si:35]([CH3:51])([CH3:50])[O:36][Si:37](CCCC1C=CC=CC=1O)([CH3:39])[CH3:38]>C(O)(CC)(C)C>[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][CH2:34][Si:35]([CH3:51])([CH3:50])[O:36][SiH:37]([CH3:39])[CH3:38]
Reactant: C[Si](C)(CCCc1ccccc1O)O[Si](C)(C)CCCc1ccccc1O
Agent: C=CCc1ccccc1O
Agent: C[SiH](C)O[SiH](C)C
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: C[SiH](C)O[Si](C)(C)CCCc1ccccc1O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a 85 ml toluene solution containing 67.1 g (0.5 mole) of 2-allylphenol and 0.4 g of a 5% solution of H2PtCl6 in t-amyl alcohol is added a solution consisting of 15 ml of toluene and 38.8 g (0.25 mole) of 1,1,3,3-tetramethyldisiloxane at 75° C. The addition is complete in 1 hour. The mixture is heated at 85° C. for 1 hour and then at 105° C. for 3 hours. After washing successively three times with 100 ml portions of water, 101 g of the 2:1 molar adduct, 1,3-bis-(3-(2-hydroxylphenyl)-propyl)-1,1,3,3-tetramethyldisiloxane (>92% pure by gel chromatography, GC) having a light straw color is obtained after stripping off solvent. The structure of the product 1,3-bis-(3-(2-hydroxylphenyl)-propyl)-1,1,3,3-tetramethyldisiloxane is confirmed by 1H NMR and IR (neat).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](C(O)=O)[C:8]([F:15])=[C:7]([F:16])[C:3]=1[C:4]([OH:6])=[O:5]>O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:15])=[C:7]([F:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Solvent: O
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: 130 °C

Procedure:
80 g of 80% strength by weight 2,3,5,6-tetrafluoroterephthalic acid (containing 8% by weight of sulfuric acid and 12% by weight of water) were mixed with 300 g of water in a 0.6 l enamelled autoclave and heated for 40 hours at 130° C. After cooling to 20° C. and depressurizing, the suspension then present was filtered, washed with 60 g of water and the white solid was dried. 42 g of 2,3,5,6-tetrafluorobenzoic acid having a content of 98% by weight and a melting point of 151° C. were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:16]=12)[CH3:14].[CH3:29][C:30]1[N:34]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:32][C:31]=1[CH:54]=[O:55].C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[CH2:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[C:24](=[O:28])[CH:25]([CH:54]([OH:55])[C:31]3[N:32]=[CH:33][N:34]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:30]=3[CH3:29])[CH2:26][CH2:27][C:16]=12)[CH3:14]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1c2n(c3ccccc13)C(=O)CCC2
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 0.58 h
Yield: 80.1 %

Procedure:
To a solution of diisopropylamine (1.85 g) in tetrahydrofuran (15 ml) at -70° C. under a nitrogen atmosphere was added 1.49M butyllithium in hexane (11.5 ml). After being stirred at the same temperature for 35 minutes, the mixture was treated with a solution of 10-ethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (3.2 g) in tetrahydrofuran (20 ml) over 5 minutes. The mixture was stirred at -70° C. for 40 minutes, and a solution of 5-methyl-1-trityl-1H-imidazol-4-carbaldehyde (5.81 g) in tetrahydrofuran (65 ml) was added dropwise over 30 minutes. After the mixture was stirred at -70° C. for 2 hours and then at room temperature for 1 hour, it was diluted with chilled water, neutralized with aqueous oxalic acid solution, and extracted with methylene chloride three times. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The oil obtained was purified by silica gel column chromatography (1% methanol-chloroform) to give 10-ethyl-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (6.8 g) as an amorphous powder. The product was a mixture of two diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[Li+].[CH3:18]C([N-]C(C)C)C.CI.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][C:11]([CH3:18])([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CC1(C#N)CCN(c2c(Cl)cncc2Cl)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48 (90 mg, 0.35 mmol) in THF (1.5 mL), at −78° C., was added a 1M solution of LDA in THF (0.38 mL, 0.38 mmol). The mixture was stirred for 30 min at −78° C. before warming to r.t. After 60 min, methyl iodide (31 μL, 0.5 mmol) was added. The mixture was stirred for a further 60 min at r.t. for 1 h, before addition of water (5 mL). The mixture was extracted with CH2Cl2 (3×5 mL) and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 100:0-80:20, biotage 25+M) to furnish the title compound as a white solid (34 mg, 36%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile (23 mg, 25%), LC-MS (ESI, 4 min) Rt 3.09 min, m/z 270 (100%, W); m/z (ESI) C12H13Cl2N3 requires 269.0487 found [M+H]+ 289.0488.
Reaction SMILES: C[O-].[Na+].C(OCC)(=O)[CH2:5][C:6]([CH3:8])=[O:7].[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26](=O)[C:27](=[CH2:33])[CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]>C(O)C>[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26]2[CH:27]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:33][CH2:8][C:6](=[O:7])[CH:5]=2)[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=C(C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl)C1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)COc1ccc(C2=CC(=O)CCC2C2CCCC2)c(Cl)c1Cl
Yield: 35.7 %

Procedure:
To a stirred solution of sodium methoxide (2.3 g, 0.043 mole) in ethanol (50 ml) and ethyl acetoacetate (5.56 g, 0.043 mole) was added [2,3-dichloro-4-(2-methylene-2-cyclopentyl-1-oxoethyl)phenoxy]acetic acid (6.5 g, 0.019 mole). The reaction mixture was heated at reflux for 2 hours, then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified, extracted into ether, washed with water, extracted into sodium bicarbonate, acidified, extracted into ether, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 2.6 g of [2,3-dichloro-4-(6-cyclopentyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 206°-207° C. after recrystallization from 300 ml of toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([N+:23]([O-])=O)=[CH:21][N:22]=2)[N:19]=1>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1
Reactant: O=[N+]([O-])c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Solvent: CCO
Product: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 70 °C
Yield: 78.6 %

Procedure:
To a mixture of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitroimidazo[1,2-b]pyridazine (4.17 g, 12.1 mmol) and SnCl2 dihydrate (10.9 g, 48.4 mmol) in a flask was added 200 mL EtOH to form a suspension. The reaction was heated at 70° C. for 1 hour to reach completion. After cooling to ambient temperature, the reaction mixture was concentrated. Water (200 mL) was added to the resulting crude solid residue, and the mixture was briefly sonicated and then vacuum-filtered. The filtrate pH was neutralized with 6N NaOH solution and extracted with DCM (3×250 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated to yield the crude product as a yellowish foamy solid. The crude material was purified by C-18 reverse-phase column chromatography (eluent=5 to 60% acetonitrile/water) to provide the pure product as a light yellowish powder (3 g, 78% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:36][CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([C:24]2[NH:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([C:16]4[C:12]([C:9]5[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:47])[CH3:1])=[CH:11][CH:10]=5)=[N:13][N:14]([CH2:36][CH2:37][NH:38][CH3:39])[CH:15]=4)=[C:18]3[CH:25]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:35]
Reactant: CN(C)Cc1cccc(-c2cc3c(-c4cn(CCN(C)C(=O)OC(C)(C)C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157 %

Procedure:
To 1,1-dimethylethyl {2-[3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate (1.05 g, 1.65 mmol) was added 25% TFA in CH2Cl2 (25 mL). The reaction was stirred at RT for 1 h and evaporated to dryness under vacuum. Trituration with (1:1) Et2O/Pet. Ether, filtration, and drying under vacuum gave the title compound (1.39 g, 95%) as a yellow solid. ESMS [M+H]+: 537.3
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([N:30]1[CH2:34][CH:33]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:32][C:31]1=[O:44])[CH3:29])(C(C)(C)C)(C)C.O.[Cl-].[Na+]>O1CCCC1>[Cl:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[O:36][CH2:35][CH:33]1[O:32][C:31](=[O:44])[N:30]([CH:28]([CH3:29])[CH2:27][OH:26])[CH2:34]1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
1.2 ml of a 1.0M solution of tetrabutyl ammonium fluoride in tetrahydrofuran were added dropwise to a solution of 152 mg of 3-(2-t-butyldimethylsilyloxy-1-methylethyl)-5-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 11) in 1 ml of tetrahydrofuran, whilst ice-cooling. The mixture was then stirred at room temperature for 1.5 hours. At the end of this time, water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the ethyl acetate was removed from the extract by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 20:1 by volume as the eluent, to give 97 mg of the title compound having an Rf value of 0.28 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
Stir a solution of 4-bromobenzyl alcohol (50 g, 267.3 mmol), DBU (48 ml, 320.8 mmol) and dichloromethane (600 mL) in an ice/water bath. Add triisopropylsilylchloride (63 mL, 294 mmol) over 10 min via an addition funnel and stir the reaction mixture for 20 hours at room temperature. Wash the mixture with water (2×600 mL), dry over anhydrous magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with 9:1 hexanes:ethyl acetate to give the title compound (91.5 g, 99%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.50 (m, 2H), 7.28-7.30 (m, 2H), 4.81 (s, 1.11-1.24 (m, 21H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added drop wise. The mixture was stirred an additional 0.5 h at −20° C. HPLC indicated the reaction was ˜30% complete. The addition of NaH and bromoacetonitrile was repeated two more times. HPLC indicated the reaction was ˜60% completed. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated to give the crude product as brown oil (36.8 g), which was used for the next step without purification.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[N:27]([CH2:30][CH3:31])[C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH2:33][CH3:34])[C:26](=[O:32])[N:27]([CH2:30][CH3:31])[C:28]=2[CH3:29])=[CH:21][CH:22]=1)=[O:7]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(C)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(C)cccc3Cl)C(=O)O)cc2)c(=O)n(CC)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (0.82 mmol, 420 mg) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (1.6 mL) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred for 2 h. The ethanol was removed under reduced pressure and the residue was diluted with water (25 mL) and NaOH (3 mL, 1.0N) to dissolve the sodium salt. The aqueous solution was washed with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 277 mg (68% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1611, found 520.1616.
Reaction SMILES: [N+](=C)=[N-].[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[C:18](O)(=O)C>C(OCC)C>[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([O:11][CH3:18])=[O:10]
Reactant: COc1ccc(C(=O)O)c(O)c1OC
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)c(OC)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of diazomethane in diethyl ether (30 ml, 0.25M, 0.0075 mol) was added to a solution of 3,4-dimethoxy-2-hydroxybenzoic acid (1.5 g, 0.0075 mol) in diethyl ether (50 ml) and the reaction stirred at room temperature for 10 minutes. Glacial acetic acid was then added and stirring continued for a further 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (40 ml) and aqueous sodium hydrogen carbonate solution (40 ml). The aqueous phase was further extracted with dichloromethane (100 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a white crystalline solid (1.5 g, 94%). 1H-NMR (CDCl3): Γ=3.82 (9H, m), 6.48 (1H, d), 7.58 (1H, d), 10.84 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[CH:27]=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1cnc2ccccc2n1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnc3ccccc3n2)n1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (245 mg, 1.7 mmol) was dissolved in anhydrous DMF (10 mL), and then were added potassium carbonate (357 mg, 2.6 mmol) and 2-(bromomethyl)quinoxaline (500 mg, 2.2 mmol) in anhydrous DMF (5 mL). The mixture was stirred over a weekend at room temperature. The solvent was removed by evaporation, and the residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(quinoxalin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (363 mg, 57% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.72 (s, 2H), 6.01 (bs, 1H), 7.81-7.88 (m, 2H), 8.03-8.11 (m, 2H), 9.10 (s, 1H); LRMS (ES+) m/z 285 (100%, M+1).