Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.S(=O)(=O)(O)O.[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:8]([CH:17]=[CH:18][C:19]([CH3:21])([CH3:20])[O:11]2)=[CH:9][CH:10]=1
Reactant: C=CC(=C)C
Reactant: COCOc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COCOc1ccc2c(c1)OC(C)(C)C=C2
Reaction time: 3 h
Yield: 69 %

Procedure:
7.7 g (50 millimoles) of 3-methoxymethoxy-phenol and 110 g of 50% sulfuric acid are dissolved in 150 g of chloroform, whereupon 6.8 g of isoprene are added at 60° C. within 20 minutes. The reaction mixture is allowed to stated at 60° C. for 3 hours, separated, the organic phase is evaporated and the residue is heated to boiling in the presence of 2.5 g of dichloro-dicyano-benzoquinone in 100 ml of dioxane for 10 hours. Then one proceeds as described in Example 8. Thus 7.6 g of the desired compound are obtained in the form of a light yellow oil, yield 69%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[CH2:22][OH:23])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=1[CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:24][CH3:25])=[CH:21]/[CH:22]=[O:23])[CH:16]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC/C(=C\CO)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CC/C(=C\C=O)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Yield: 86 %

Procedure:
In a manner similar to that of Example 7(c), by reaction of 2.1 g (3.7 mmol) of (E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}pent-2-en-1-ol with 4.9 g (56 mmol) of manganese dioxide, the crude product (1.8 g) is the expected aldehyde, obtained in a yield of 86%.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN1CCCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCCN(C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-methyl-1,4-diazepane as starting raw materials, to produce an intended compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:30])[CH:21]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[N:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:30])[C:21]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: Cc1cccc(C(O)C(O)c2ccncc2)c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C(=O)C(=O)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylsufoxide (2.85 mL, 40 mmole) was dropwise added into a solution of trifluoroacetic anhydride (4.24 mL, 30 mmole) in methylene chloride (100 mL) at 78° C. The reaction mixture was stirred at that temperature for 10 min before the addition of 1-pyridine-4-yl-2-m-tolyl-ethane-1,2-diol (2.29 g, 10 mmole) in methylene chloride (50 mL). The mixture was stirred additional 1 hr at that temperature. Finally, the mixture was quenched with triethylamine (8.5 mL, 60 mmole) and the resulting mixture was allowed to warmed to r.t. The reaction was diluted with methylene chloride, washed with NH4Cl and brine, dried with MgSO4, evaporated, and finally, purified through a silica column (ethyl acetate/hexane) to give the title compound. MS (m/z): Calcd. C14H11NO2(M+): 225, found (M+H)+: 226.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13](OC)=[O:14])[C:6](=[O:17])[N:5]([CH3:18])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C)=O>C(Cl)Cl>[OH:14][CH2:13][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[N:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:18])[C:6]1=[O:17]
Reactant: COC(=O)c1sccc1-n1c(OC)nn(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1nn(C)c(=O)n1-c1ccsc1CO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of the title compound of Step D (1.8 g) in methylene chloride (23 mL) under N2 at -78° C. was added a solution of diisobutylaluminum hydride (18.3 mL, 1 M) in methylene chloride. The resulting solution was allowed to stir at -78° C. for 15 min, warmed to room temperature and then stirred for 1.5 h. After cooling the reaction mixture to -78° C., acetone was added and after about 10 min, the reaction mixture was quenched with 1N HCl. The reaction mixture was allowed to warm to room temperature, was diluted further with methylene chloride, and was then washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield 1.3 g of the title compound of Step E as an off-white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][CH:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:9][CH:10]1[CH2:15][CH2:14][CH:13]([O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH2:12][CH2:11]1
Reactant: CC1CCC(O)CC1
Reactant: Oc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(Oc2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
In a four necked flask (2 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, resorcinol (110 g, 1.0 mol), 4-methylcyclohexanol (114 g, 1.0 mol) and triphenylphosphine (393 g, 1.5 mol) were dissolved in dried tetrahydrofuran (500 ml) under a nitrogen gas stream, and a mixed solution of diisopropyl azodicarboxylate (269 g, 1.3 mol) and dried tetrahydrofuran (400 ml) was dropped for 1 hour while cooling with iced saline solution. Next, it was stirred at room temperature for 12 hours. After the reaction terminated, 30% hydrogen peroxide (200 ml) was dropped through the dropping funnel for 10 minutes, then the reaction solution was dissolved in 2 L toluene, and washed three times with 1 L water. Toluene was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-2A) (45.0 g, 22% yield, 97% GC purity).
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[N:7]([C@H:16]([CH2:51][OH:52])[C@@H:17]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:18]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH2:8][C@@H:9](O)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:16]([C@@H:17]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:18]([N:28]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:51][O:52][C@@H:9]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:8]1)=[O:53])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC[C@H](O)CN(C(=O)OC(C)(C)C)[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
Dissolve [2-(S)-benzyloxy-3-(S)-dibenzylamino-4-(3,5-difluorophenyl)-1-(R)-hydroxymethylbutyl]-(2-(S)-hydroxy-5-methylhexyl)-carbamic acid tert-butyl ester (253 mg, 347 mmol) in benzene (3 mL). Deoxygenate the reaction mixture. Add tributyl phosphine (130 μL, 520 mmol), N,N-tetramethyl azodicarboxamide (TMAD) (89.5 mg, 520 mmol) and stir at room temperature 2.5 hours. Add deoxygenated tetrahydrofuran (5 mL), more tributyl phosphate (130 μL), more TMAD (90 mg) and stir 1.5 hours. Filter, rinse with hexanes, concentrate and purify (silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes) to give the desired compound (191.7 mg, 77%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([F:15])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>ClCCl>[F:15][C:9]1[CH:8]=[C:7]([OH:6])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1
Reactant: COc1cc(F)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Boron tribromide (1M in dichloromethane, 9 mL, 89.985 mmol) was added drop wise to an ice-cooled solution of 3,5-dimethoxy fluorobenzene (3 ml, 22.496 mmol) in dichloromethane (20 mL) and the mixture was stirred at 0° C. to room temperature for 4 hours. The solution was cooled to 0° C., further boron tribromide (4 ml, 44.992 mmol) was added and stirring continued, warming to room temperature for an additional 18 hours. The reaction was quenched with 0.88 ammonia solution and stirred at room temperature for 90 minutes. The organic layer was separated and extracted with 2N sodium hydroxide (30 ml), which was then acidified to pH1 by drop wise addition of concentrated hydrochloric acid. The aqueous layer was then re-extracted with dichloromethane (3×15 mL), the combined organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 54% yield, 1.72 g.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][N:22]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A reaction vessel was charged with 0.5 g of 1 -benzyloxy-3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)propyloxy)benzene and 50 ml of ethyl acetate, and the air in the vessel was- replaced with nitrogen. Then, 0.3 g of 10% palladium carbon was added, and the nitrogen in the vessel was replaced with hydrogen, followed by stirring at room temperature for 24 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered through Celite, and the filtrate was concentrated, which afforded 0.36 g of 3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)propyloxy)phenol (92% yield).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH2:33])([CH3:27])([CH3:26])[CH3:25].CC(O)=O>CCO>[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH:33][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (62 mg, 0.39 mmol) in EtOH (9 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.2 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 113 mg of the title compound as an off-white solid. MS: (−) m/z 437.33 (M−1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([CH2:7][OH:8])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1CNC[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,4R)-(4-Hydroxypyrrolidin-3-yl)methanol (1.18 g) was dissolved in ethanol (25 mL). To this solution, triethylamine (1.40 mL) was added and while the mixture was chilled in a salt/ice water bath, benzyl bromide (1.10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=20:1) to give (3R,4R)-(1-benzyl-4-hydroxypyrrolidin-3-yl)methanol as a milky white syrup (1.02 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:31])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([C:18]4[CH:19]=[C:20](C(OCC)=O)[CH:21]=[N:22][CH:23]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]([CH3:29])[C:6]1=[O:30].[CH3:32][Mg+].[Br-].C([O:38][CH2:39][CH3:40])(=O)C>O1CCCC1>[OH:38][C:39]([C:20]1[CH:19]=[C:18]([C:14]2[CH:13]=[CH:12][C:11]3[N:10]=[CH:9][C:8]4[N:7]([CH3:29])[C:6](=[O:30])[N:5]([CH2:4][C@@H:3]([O:2][CH3:1])[CH3:31])[C:17]=4[C:16]=3[CH:15]=2)[CH:23]=[N:22][CH:21]=1)([CH3:40])[CH3:32]
Reactant: CCOC(=O)c1cncc(-c2ccc3ncc4c(c3c2)n(C[C@H](C)OC)c(=O)n4C)c1
Reactant: C[Mg+]
Reactant: CCOC(C)=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CO[C@@H](C)Cn1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)O)c4)cc3c21
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of ethyl 5-[1-[(2S)-2-methoxypropyl]-3-methyl-2-oxo-imidazo[4,5-c]quinolin-8-yl]pyridine-3-carboxylate (32.0 g, 76.1 mmol) in tetrahydrofuran (320 mL), slowly add MeMgBr (1.4M in tetrahydrofuran/toluene, 221.4 g, 6.92×) solution under N2 protection with temperature below 0° C. Stir the mixture at −5˜0° C. for one hour under N2 protection. Add NH4Cl solution (15%, 320 mL) slowly to quench the reaction while keeping the temperature below 25° C. Then add ethyl acetate (320 mL). Warm up the mixture to 25˜30° C. and stir for half hour. After separation of two layers, back extract the aqueous layer with tetrahydrofuran (160 mL). Wash the combined organic with brine (192 mL). Add active charcoal (1.6 g) to the organic layer and stir at 65˜75° C. for 4-5 hours. Filter the mixture with Kieselguhr® Silica-Thiol (1.6 g). Stir the organic layer at 65˜75° C. for 2-3 hours; the mixture is then filtered by Kieselguhr® Silica-Thiol. The organic layer is removed under vacuum and the re-crystallized with ethyl acetate/tetrahydrofuran to give 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one as a light yellow solid (22.34 g, 72.2%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[O:13][C:14]1[S:18][C:17]([NH:19][C:20](=[O:41])[CH:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:16][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>C1COCC1>[CH:38]1([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH:21]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:20]([NH:19][C:17]3[S:18][C:14]([O:13][C:12]4[CH:42]=[CH:43][CH:44]=[C:10]([CH2:9][OH:8])[CH:11]=4)=[CH:15][N:16]=3)=[O:41])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:40][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ncc(Oc2cccc(CO)c2)s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
N-[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenoxy]thiazol-2-yl]-2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetamide (0.05 g, 0.0758 mmol) was taken in 3 mL of dry THF and to it tetra-n-butylammonium fluoride (0.16 mL, 0.16 mmol, 1M solution in THF) was added in inert atmosphere at 0° C. After complete addition the reaction was stirred for overnight at room temperature. TLC showed complete reaction. The reaction mixture was portioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed on vacuo to get the crude product which was purified by preparative TLC to get the solid product (0.020 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@H:12]([CH2:31][O:32][CH2:33]C2C=CC=CC=2)[O:11][C@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[C:44]([Cl:56])=[CH:43][C:42]=1[O:57][CH3:58])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:59]([Si](C)(C)C)[CH:60]=[CH2:61]>>[CH2:59]([C@:10]1([C:41]2[CH:46]=[C:45]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([CH2:54][CH3:55])=[CH:52][CH:53]=3)[C:44]([Cl:56])=[CH:43][C:42]=2[O:57][CH3:58])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:13]([O:23][CH2:24][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:11]1)[CH:60]=[CH2:61]
Reactant: C=CC[Si](C)(C)C
Reactant: CCc1ccc(Cc2cc([C@]3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)cc2Cl)cc1
Product: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 159.5 %

Procedure:
The title compound (230 mg, 80%) was prepared from 23 (280 mg) and allyltrimethylsilane (167 μL, 120 mg, 3.0 eq.) using the method described for preparing 24.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:18].O>C1COCC1>[CH3:18][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[C:12](=[O:14])[CH3:13]
Reactant: CI
Reactant: CC(=O)Nc1ccc2nccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a solution of N-(quinoxalin-6-yl)acetamide (8.0 g, 0.043 mol) in THF (120 mL) was added sodium hydride (60% wt in mineral oil, 3.42 g, 0.086 mol). The mixture was stirred at room temperature for 10 min. Then iodomethane (7.28 g, 0.051 mol) was added. The mixture was stirred at room temperature for 2 h. Water (60 mL) was added carefully. The mixture was extracted with EtOAc (3×150 mL). The extracts were dried over sodium sulfate, concentrated to give N-methyl-N-(quinoxalin-6-yl)acetamide as a brown solid (8.04 g, yield 93%). ESI MS: m/z 202.1 [M+H]+.
Reaction SMILES: COC(=O)[O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[C:7]([F:15])[C:6]=1[F:16].B(Br)(Br)Br>ClCCl>[F:16][C:6]1[C:7]([F:15])=[C:8]([CH3:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[OH:4]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of carbonic acid 2,3-difluoro-4-methyl-5-nitro-phenyl ester methyl ester (2.3 g, 9.3 mmol) in dichloromethane (30 ml) was cooled to 0° C. in an ice bath, and 1.0M boron tribromide in dichloromethane (9.3 ml, 9.3 mmol) was added. The ice-bath was removed and the mixture was stirred at room temperature for 18 hours. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 9:1) gave 1.02 g (58%) of 2,3-difluoro-4-methyl-5-nitro-phenol as a white solid.
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:25][NH:26][C:27]([NH2:29])=[O:28].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:21])[F:22])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:3]([NH:29][C:27]([NH:26][CH3:25])=[O:28])=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 28 %

Procedure:
3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid methyl ester (383.8 mg, 1.05 mmol) and methyl urea (234.1 mg, 3.16 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 6.0 mL, 4.21 mmol). The resulting reaction mixture was then heated under reflux for 2 d. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate until the solvent passing through the celite showed absence of desired product by thin layer chromatography. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl urea (119.3 mg, 28%) as a white solid: mp 191-192° C.; FAB-HRMS m/e calcd for C17H21F3N2O4S (M+H)+407.1252, found 407.1247.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]3[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][C@H:29]([CH3:33])[CH2:28]1)=[CH:9][C:8]2=[O:34])=[O:4]>CO.[Rh]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][C@H:29]([CH3:33])[CH2:28]1)=[CH:9][C:8]2=[O:34])=[O:4]
Reactant: COC(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: [Rh]
Solvent: CO
Product: COC(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
(R)-tert-Butyl 2-(6-(methoxycarbonyl)-2-(2-methylmorpholino)-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate (2 g, 4.27 mmol) and 5% Rhodium on Alumina (50% wet) (0.4 g, 0.09 mmol) in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 65° C. for 2 h. More catalyst was added and stirring continued overnight. 2 g of 5% Rh/C was then added followed by the same amount after 1 h then after another 2 h. The catalyst was filtered through celite and washed with MeOH/DCM and the solvent evaporated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 15% MeOH in EtAc. The solvent was evaporated to dryness to afford tert-butyl 2-(6-(methoxycarbonyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (1.18 g, 59%) as a white solid. Mass Spectrum: m/z [M+H]+=473.