Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(F)c2)s1
Reactant: NC1CC1
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC3CC3)c2)s1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
In a closed vessel, 600 mg (1.98 mmol) of 2-fluoro-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine (described, for example, in J. Med. Chem, 2005, 48, 5966-5979) in 10 ml cyclopropylamine are heated with stirring at 150° C. After 16 h, the reaction mixture is stirred into 100 ml of water and extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 520 mg (77%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.96 (d, 1H), 7.52 (m, 2H), 7.17 (m, 2H), 6.65 (s, 1H), 6.49 (s 1H), 6.45 (d, 1H), 3.04 (q, 2H), 2.37 (m, 1H), 1.36 (t, 3H), 0.55 (m, 2H), 0.33 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[N:27]=[C:28]([O:33][CH3:34])[C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:32][C:29]2[C:28]([O:33][CH3:34])=[N:27][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:31][N:30]=2)=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1nc(P(C)(C)=O)cnc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([OH:34])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:44][C@H:45]([OH:47])[CH3:46]>CN(C)C(=O)C>[CH3:1][C:2]1([CH3:36])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[C:25]([N:27]4[C:31](=[O:32])[N:30]([CH3:33])[N:29]=[N:28]4)[C:24]([O:34][CH2:44][C@H:45]([OH:47])[CH3:46])=[CH:23][C:22]=3[F:35])[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2O)c1=O
Reactant: C[C@@H](O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)COc1cc(F)c(Nc2ncc(C#N)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 100 °C
Yield: 23.8 %

Procedure:
4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)-2-fluoro-4-hydroxyl-phenylamino)pyrimidine-5-carbonitrile (467 mg, 1.0 eq.) was added to N,N-dimethylacetamide (4.7 ml, 0.2M), followed by Cs2CO3 (922 mg, 3.0 eq.) and 3-iodo-2-(R)-propanol (0.88 g, 5.0 eq.) and heated at 100° C. under nitrogen overnight. It was cooled to room temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate (10 ml) and treated with saturated NaHCO3 (10 ml). The aqueous layer was extracted with ethyl acetate (2×10 ml), and the combined organic solution was washed with brine (10 ml), and dried with Na2SO4. Solid was filtered off, and the organic solution was concentrated under reduced pressure. 5 ml of ethyl acetate was added to the residue, silica gel was added to form a thick paste, and was concentrated under reduced pressure. This silica gel mixture was loaded onto the Combiflash chromatography and product was eluted using 2N NH3 in MeOH (0-20%)/Ethyl Acetate (100%-80%) gradient to yield 124 mg of product as a light beige solid.
Reaction SMILES: [Br:1][C:2]1(C=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH2:3]1.BrC1C=CC(F)=CC=1[CH2:22][O:23][CH2:24][O:25][CH3:26]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:22][O:23][CH2:24][O:25][CH3:26]
Reactant: O=CC1(Br)CC=Cc2ccccc21
Reactant: COCOCc1cc(F)ccc1Br
Product: COCOCc1ccc2ccccc2c1Br

Procedure:
This compound was made from 1-bromonaphthaldehyde in the same manner as compound 5b: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.42 (s, 3H), 4.75 (s, 2H), 4.81 (s, 2H), 7.5-7.7 (m, 3H), 7.99 (d, J=7.7 Hz, 2H), 8.22 (d, J=7.7 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.F[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([F:21])[N:13]=1>C1(C)C=CC=CC=1>[F:21][C:14]1[N:13]=[C:12]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: c1ccc2c(c1)CCNC2
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)nc1N1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (34.8 ml, 0.28 mol) was added to a solution of 2,6-difluoro-3-nitropyridine (44.55 g, 0.28 mol) prepared in Step 1 in toluene (200 ml). The reaction mixture was stirred overnight at 60° C. and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=1/4, v/v) to give 5.38 g of the titled compound as yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH3:23][N:15]([C:13]1[CH:14]=[C:9]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=[CH:11][C:12]=1[N+:24]([O-:26])=[O:25])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: Sc1ccccn1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1[N+](=O)[O-]
Yield: 39.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-mercaptopyridine (0.89 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.29 g), sodium hydride (55 wt. %, 0.11 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (1.13 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:10])[CH2:7][NH:8][CH3:9].[NH2:11][C:12](=[O:38])[CH2:13][N:14]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])[C:17](=[O:31])[C:16]2[S:32][C:33]([CH2:36]Cl)=[C:34]([CH3:35])[C:15]1=2>>[NH2:11][C:12](=[O:38])[CH2:13][N:14]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])[C:17](=[O:31])[C:16]2[S:32][C:33]([CH2:36][N:8]([CH2:7][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[OH:10])[CH3:9])=[C:34]([CH3:35])[C:15]1=2
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Reactant: CNCC(O)c1ccco1
Product: Cc1c(CN(C)CC(O)c2ccco2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12

Procedure:
Prepared from 1-(2-furyl)-2-(methylamino)ethanol (Preparation 8) and 4-(2-amino-2-oxoethyl)-N-(4-chlorobenzyl)-2-(chloromethyl)-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide by the procedure described for Example 2. Recrystallization from acetonitrile afforded 17 mg of the title compound as a white solid.
Reaction SMILES: C(O[CH:4]([O:18]CC)[C:5](=O)[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])C.[OH-].[Na+].[C:23]([OH:26])(=O)[CH3:24].[BH4-].[Na+]>O1CCCC1>[OH:18][CH2:4]/[C:5](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:24]/[CH2:23][OH:26]
Reactant: CCOC(OCC)C(=O)CC/C=C(/C)CCC=C(C)C
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C\CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In 125 ml of anhydrous tetrahydrofuran was suspended 18 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The resulting mixture was stirred at -20° C. for one hour and to this was further added 8.4 g of (Z)-1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 3) in 25 ml of anhydrous tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours and, after addition of ice water, extracted with n-hexane, and from the extract was obtained an oil. The oil was treated with a sodium hydroxide solution and acetic acid and reduced with 150 mg of sodium borohydride in the same manner as in Example 13, yielding 3.0 g of a mixture of the (E,Z,Z) and (E,E,Z) isomers.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][O:7][NH:8][CH:9]([CH3:29])[CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:26]([C:14]1[N:13]([CH2:12][CH2:11][CH2:10][CH:9]([N:8]([O:7][CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:29])[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=1)[CH2:27][CH3:28]
Reactant: CCN=C=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)NOC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)N(OC)C(=O)NCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Ethyl isocyanate (0.49 mL, 4.59 mmol) was added to a solution of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (0.600 g, 1.83 mmol) in tetrahydrofuran (THF) (25 mL) at 0° C. and stirred for 1 hour at ambient temperature. Analysis by LC-MS showed the reaction was incomplete and additional ethyl isocyanate (0.19 mL) was added to the reaction mixture. After 1 hour of stirring at ambient temperature, the reaction mixture was concentrated under reduced pressure to afford 0.700 g of 1-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-3-ethyl-1-methoxyurea.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 88.7 %

Procedure:
A mixture of {4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-dimethyl-amine (80 mg, 0.17 mmol) in ethanol (3 mL), tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at reflux for 36 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford {4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-dimethyl-amine (50 mg, 89%) as a white solid: LC/MS m/e calcd for C22H25N3 [M+H]+ 332.46, observed 332.1.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](S(C5C=CC=CC=5)(=O)=O)[CH:27]=[CH:28][C:21]=34)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(O)(C)C.[OH-].[Na+]>CS(C)=O>[N:47]1([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]5[NH:26][CH:27]=[CH:28][C:21]=45)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCOCC2)n1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (30 mg, 0.044 mmol) and morpholine (0.5 ml, 5.74 mmol) were mixed then heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. Isopropanol (1.5 mL) and 2M NaOH (1.500 ml) were added. The reaction mixture was stirred for 1.5 h. Further Isopropanol (1.5 mL) and 2M NaOH (1.5 mL) were added to the mixture which was stirred for 26 hours. The solvent was blown off under nitrogen. The resultant solid was dissolved in DMSO (2 mL). The salts were removed by filtration and the mixture was purified by MDAP to afford the title compound (4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C1C(=O)N([Br:21])C(=O)C1.[OH-].[K+]>OS(O)(=O)=O>[Br:21][C:4]1[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=[C:12]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc2sc(N)nc2cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cc2nc(N)sc2c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (1.0 g, 5.15 mmol) in H2SO4 at 0° C., was added NBS (550 mg, 3.07 mmol). The reaction mixture was stirred at 0° C. for 2 h. Then the reaction mixture was poured to ice-water, neutralized by 50% KOH solution to pH about 3. The precipitation was collected, washed by water and dried over high vacuum. LCMS-ESI+: calc'd for C9H9BrN2OS: 273.0 (M+H+). Found: 273.0 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>Cl>[O:1]([CH3:11])[CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: COC1O[C@@H](CO)[C@@H](O)[C@@H]1O
Yield: 95 %

Procedure:
L-Xylose (1, 25g, 167 mmol) was stirred for 5 hours in 0.5% hydrogen chloride in methanol (675 mL) at room temperature and then neutralized with Amberlite IRA-400 OH anion exchange resin. The filtrate and washings were combined and evaporated to dryness and the crude product was purified by silica gel chromatography (CHCl3/MeOH, 92:8) to afford 26.2 g of methyl L-xylofuranoside (2, 95% yield) as an α and β (1:1) mixture. MS 164 (M)+, 165 (M+H)+, 133 (M−OCH3)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C>CC(C)=O.CCCCCC>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,5-Dichloro-3-aminobenzoic acid, 206 mg (1.0 mmol), was dissolved in 4 ml of acetone, and 0.7 ml (1.4 mmol) of 2.0 M trimethylsilyl diazomethane solution in hexane was added to the solution. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed by distillation to give methyl 2,5-dichloro-3-aminobenzoate.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1>>[CH:40]1([CH2:39][O:34][C:33](=[O:35])[CH2:32][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:21][C:20]3=[O:31])[C:2]([O:1][CH2:37][CH:38]3[CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[CH2:38][CH2:37]1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Reactant: BrCC1CC1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC2CC2)ccc1OCC1CC1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and (bromomethyl)cyclopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:5][CH:4]=1.CSC.B(F)(F)F>ClCCl>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC)cc3)c2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(O)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.7 %

Procedure:
To a well-stirred solution of 1,3-bis-(4-methoxybenzoyl)benzene 14 (700 mg, 2.02 mmol) in dichloromethane (25 mL) was added boron trifluoride dimethyl sulfide complex (BF3.SMe2, 10 mL). The reaction was stirred for 16 h at room temperature, and then quenched with water, and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the pure 1-(4-hydroxybenzoyl)-3-(4-methoxybenzoyl)benzene 16 (0.2 g, 0.60 mmol) as a white solid in a 30% yield; 1H NMR (500 MHz, Acetone-d6): δ 9.19 (s, OH), 7.89 (dt, J=2 Hz, 0.5 Hz, 1H, ArH), 7.85 (dd, J=7.5 Hz, 1.5 Hz, 2H, ArH), 7.72 (ddd, J=10.0 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 7.66 (ddd, J=9.5 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 7.59 (td, J=7.5 Hz, 0.5 Hz, 1H, ArH), 6.96 (ddd, J=9.5 Hz, 4.5 Hz, 2.5 Hz, 2H, ArH), 6.86 (ddd, J=9.5 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 3.78 (s, 3H, OCH3); 13C NMR (125 MHz, Acetone-d6): δ 193.70, 193.56, 163.61, 161.941, 138.58, 138.35, 132.62, 132.41, 132.30, 130.16, 129.67, 128.75, 128.56, 115.25, 113.78, 55.12.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9]OC)=[CH:6][N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.Cl.[CH2:17]1[CH2:21]OC[CH2:18]1>[Cl-].[Na+].O>[CH:18]1([CH2:9][O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[N:5][CH:6]=2)[CH2:17][CH2:21]1
Reactant: COCOc1cnc(C(=O)OC)cc1F
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(F)c(OCC2CC2)cn1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-fluoro-5-(methoxymethoxy)pyridine-2-carboxylate (1.80 g) in THF (20 mL) was added 6 N hydrochloric acid (5 mL), and the mixture was stirred at 70° C. for 20 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL), potassium carbonate (2.31 g) and (bromomethyl)cyclopropane (1.22 mL) were added thereto, and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.07 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.Br[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9])[CH:14]=[CH2:13]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (7.50 g, 48.7 mmol), 3-bromoprop-1-ene (6.48 g, 53.5 mmol), and potassium carbonate (13.5 g, 97.0 mmol) in DMF (75 mL) was vigorously stirred at rt for 24 h. The reaction mixture was diluted with water (100 mL) while stirring. The white precipitate was collected by vacuum filtration. The solid was rinsed with water (300 mL). The solid was dried under high vacuum to afford 1-(2-(allyloxy)-4-fluorophenyl)ethanone (7.92 g, 40.0 mmol, 82% yield) as a white solid. LCMS (M+Na)+=217.1. 1H NMR (500 MHz, chloroform-d) δ 7.82 (dd, J=8.7, 7.0 Hz, 1H), 6.71 (ddd, J=8.7, 7.6, 2.3 Hz, 1H), 6.66 (dd, J=10.8, 2.3 Hz, 1H), 6.08 (ddt, J=17.3, 10.6, 5.3 Hz, 1H), 5.55-5.41 (m, 1H), 5.41-5.29 (m, 1H), 4.63 (dt, J=5.4, 1.4 Hz, 2H), 2.62 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:29])[NH:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12])(=O)C.[Li+].[OH-]>CO>[OH:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([S:13]([NH:16][C:17](=[O:29])[NH:18][C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=2)(=[O:15])=[O:14])=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)OCCc1sc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2cc(C(F)(F)F)ccn2)sc1CCO

Procedure:
2-{3-Methyl-5-[({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)sulfonyl]-2-thienyl}ethyl acetate (310 mg, 0.55 mmol, 1 equiv.) was saponified by addition of 1 N LiOH (1.2 mL, 1 mmol, 2 equiv.) in MeOH (5 mL) for 60 min. The solution was purified by chromatography on a HPLC 75×30 mm RP18 5 μm column, with A=0.1% HCOOH and B=MeCN and with a gradient of 20% to 70% B in 10 min. The corresponding fractions were lyophilized to give the titled compound, 89 mg, mle 408.0 (MH−).
Reaction SMILES: [CH:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][NH2:12].Cl>>[CH3:11][NH:12][S:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: CN
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: Cl
Product: CNS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexanesulfonyl chloride (500 mg) was added to methylamine (12.3 mL, 2M solution in tetrahydrofuran) and the reaction mixture was stirred at room temperature for one hour. The solution was added to 1M aqueous HCl and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the product.