Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([O:22][C:23]([O:26][CH3:27])([CH3:25])[CH3:24])C)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1)(=[O:49])=[O:48].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:27][O:26][C:23]([CH3:25])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:28]([C:53]2[CH:54]=[CH:55][C:50]([S:47]([CH3:46])(=[O:49])=[O:48])=[CH:51][CH:52]=2)=[CH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)OC(C)Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(Cc2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Yield: 43.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-{1-benzenesulfonyl-5-[2-(1-methyloxy-1-methyl-ethoxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-2-cyclopentyl-vinyl ester (1.12 g, 1.76 mmol), 4-(methanesulfonyl)phenylboronic acid (704 mg, 3.52 mmol), dichlorobis(triphenylphosphine)palladium (II) (124 mg, 0.17 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.2 mL). The resulting mixture was subjected to microwave irradiation for 1 h at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 44%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O6S2 [M+H]+ 621.79, observed 621.0.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)(=O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[N:1][C:2]2[N:3]([N:4]=[C:5]([SH:7])[N:6]=2)[C:11]=1[OH:10])=[O:14])[CH3:17]
Reactant: Nc1n[nH]c(S)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2nc(S)nn2c1O
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of 15 g 3-amino-5-mercapto-s-triazole, 28 g diethyl ethoxymethylenemalonate and 70 ml acetic acid was refluxed for 18 hours. After removing the solvent by distillation, the remaining brown oil was allowed to cool to room temperature, and the pH was adjusted to 10 with sodium hydroxide solution. After washing with 100 ml ethyl acetate, the brown aqueous solution was neutralized to pH 7.5 with 6N hydrochloric acid, and again washed with 100 ml ethyl acetate. The pH of the aqueous layer was lowered to 3.0 with 6N hydrochloric acid, and the separated crude product (12 g) was collected by filtration and recrystallized from 30 ml methanol, giving 9 g of the objective compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:20][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: N#CCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: Fc1cccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)c1

Procedure:
The title compound, light yellow solid (73 mg, 55%), MS (ISP) m/z=374.1 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: O[C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.CCN(S(F)(F)[F:28])CC.C(OCC)(=O)C>C(Cl)Cl>[F:28][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (MG Bursavich et al; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol) in 5 mL of DCM at −78° C. under nitrogen was added DAST (0.2 mL, 1.5 mmol). The mixture was allowed to warm up to rt with stirring over 3 h. To the mixture was added 100 mL of ethyl acetate and the organic layer was separated, washed with a saturated NaHCO3 solution, and then evaporated under vacuum. The residue was purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.11 (d, J=8.5 Hz, 2H), 6.93 (br. s., 1H), 6.89-6.82 (m, 2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.16 (d, J=7.2 Hz, 1H), 2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H), 1.76-1.65 (m, 1H), 1.53 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:11]([O:13]C)=[O:12])[C:7]([O:9]C)=[O:8])=[CH:2]1.[OH-].[Na+].CO>O>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]([OH:9])=[O:8])[C:11]([OH:13])=[O:12])=[CH:2]1
Reactant: COC(=O)C(C(=O)OC)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(C(=O)O)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Dimethyl 3-thienylmalonate, unpurified from the above reaction, (0.0385 kg, 0.18 mole) was added dropwise over 10 minutes to a stirred solution of sodium hydroxide (0.0157 kg, 0.39 mole) in water (0.065 dm3) maintaining the temperature between 10°-20°. The resulting solution was stirred at ambient temperature for 1 hour and the methanol (formed in the hydrolysis) distilled under reduced pressure (Buchi, to ≤50°). The concentrate was cooled to 10°, 4-methyl-2-pentanone (0.040 dm3) added and the pH adjusted to 5.0 with concentrated hydrochloric acid. The mixture was separated, the aqueous phase acidified to pH 3.0 (conc. HCl) and the solution extracted with dichloromethane (2×0.02 dm3). After separation the aqueous phase was acidified to pH 1.0 (conc. HCl) and the solution extracted with diethyl ether (2×0.05 dm3). The ethereal extract was treated with charcoal and dried over magnesium sulphate (0.01 kg). Filtration and evaporation of the filtrate gave a pale yellow gum that on trituration with dichloromethane (0.03 dm3) yielded 3-thienylmalonic acid as a white powder 0.025 kg (75%), m.p. 138°-139°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 10.0 g, 77.4 mmol) in N,N-dimethylformamide (130 mL) were added potassium carbonate (32.1 g, 0.23 mol) and benzyl bromide (21.2 mL, 0.18 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (52, 12.0 g, 50%). MS (ESI) [M+H+]+=310.2.
Reaction SMILES: [C:1](/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([NH2:6])=[O:5])#[N:2].Cl>C(O)C.[Pd]>[NH2:2][CH2:1][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: N#C/C(=C\c1ccccc1)C(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCC(Cc1ccccc1)C(N)=O
Reaction time: 24 h
Yield: 119.5 %

Procedure:
A solution of (E)-2cyano-3-phenyl-acrylamide (0.50 g, 2.91 mmol) was dissolved in ethanol (25 mL). Concentrated HCl (1 mL) was added, followed by 10% degussa palladium on carbon (1.0 g). The mixture was subjected to hydrogenation conditions (55 psi) for 24 hours. It was filtered through Celite and concentrated to give the product (0.62 g, 100%) as a white solid. [M+H]+ 179.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][CH:8]=[C:9]([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4][N:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[C:6]2[C:15](=[O:17])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][C:5]=2[S:4][N:3]=1
Reactant: CCOC(=O)C(=CNc1cc(C)ns1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2snc(C)c2c1=O
Temperature: 259 °C

Procedure:
Diethyl 2-((3-methylisothiazol-5-ylamino)methylene)malonate (10 g, 35.17 mmol) was added to refluxing diphenyl ether (40 mL) and the reaction was held at reflux (259° C.) for 3.5 h. After the starting material had been consumed, the reaction was allowed to cool to room temperature. The product was precipitated as a dark brown solid by adding diethyl ether (100 mL) to the cooled reaction mixture. The solid was filtered, washed with ether and allowed to air dry. The product ethyl 3-methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate was obtained as a brown powder (5.5 g, 66% yield). LC/MS m/z 239.0 [M+H]+, retention time 0.91 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:11][CH:12]([OH:22])[CH:13]([OH:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C(OCC)C>[CH2:14]([CH:13]1[CH:12]([CH2:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:22][C:1](=[O:2])[O:21]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(Cc1ccccc1)C(O)Cc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OC(Cc2ccccc2)C(Cc2ccccc2)O1
Reaction time: 0.25 h

Procedure:
Phosgene gas was slowly bubbled into a solution of 1,4-diphenyl-2,3-butanediol (Neher (1963) Hel. Chim. Acta. 46:1083) (96 mg, 0.4 mmole) and triethylamine (0.16 ml, 1 mmole) in anhydrous ethyl ether (75 ml). After 15 min, the phosgene addition was stopped, the solution filtered, and the solvent removed in vacuo (20° C./60 mm Hg) leaving a crystalline residue, which was flash chromatographed (CH2Cl2 eluent) affording 4,5-dibenzyl-1,3-dioxolan-2-one as a colorless, crystalline compound (98 mg, 94%): mp 155°-156° C.; IR (KBr) 3020, 1783, 1200, 1166, 1150, 1092, 1067, 1030, 765, 755, 703 cm-1 ; 'H NMR (CDCl3) 2.88(m, 4H), 4.55(t, J=3 Hz, 2H), 7.33(m, 10H); MS (70 eV) C17H16O3 calcd. 268.3235 obsd. 268.1096.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=1)C.C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH2:13]([CH:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][C:7]=1[N+:17]([O-:19])=[O:18])[CH2:15][CH3:16])[CH3:14]
Reactant: CCOC(=O)c1ccc(NC(CC)CC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
30.0 g of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid ethyl ester were dissolved in 100 ml ethanol and 10 ml THF and 107 ml of 2 M aqueous sodium hydroxide solution were added. After stirring at room temperature over night, the reaction mixture was brought to pH 1 by addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 27.0 g (100%) of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccnc(O)c2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NCC1CCN(c2ccnc(O)c2)CC1

Procedure:
To a solution of 500 mg (2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester in 5 ml CH2Cl2 3 ml TFA was added dropwise at 0° C. After 16 h 20 ml toluene were added and the solvent removed under reduced pressure to yield a brown foam.
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:3][C@@H:4]([CH2:16][N:17](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][Si:2]([CH3:36])([C:32]([CH3:34])([CH3:33])[CH3:35])[O:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1cccc2nc[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)COc1cccc2nc[nH]c12

Procedure:
(S)-4-(2-(Dimethyl-tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole (1.27 g. 2.5 mmol) was dissolved in methanol (140 mL) and treated with an excess of ammonium formate (1.64 g, 25.0 mmol) followed by 10% palladium on carbon (410 mg). The resulting suspension was stirred at reflux for 1 hour. After cooling, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to a brown oil (780 mg, 97%). NMR.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]([Cl:12])([Cl:11])[C:8](Cl)=[O:9]>CCOCC>[Cl:6][C:7]([Cl:12])([Cl:11])[C:8]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Yield: 85 %

Procedure:
The strategy for the synthesis of polymer 8 is outlined in SCHEME 1. Pyrrole was treated with trichloroacetyl chloride in ether to give compound 1 in 85% yield. The methyl ester of this compound (2) was formed by reacting compound 1 with sodium methoxide in refluxing methanol, achieving yields of 71%.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][O:23][C@H:24]2[C@@H:36]([OH:37])[C@@H:35](O)[C@H:34]([CH3:39])[O:33][C@@H:25]2[S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[S:7]([O:37][C@H:36]1[C@@H:35]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C@H:34]([CH3:39])[O:33][C@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:24]1[O:23][CH2:22][C:21]1[CH:40]=[CH:41][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:8])=[O:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@H]2[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Trifluoromethanesulfonic anhydride (1.8 mL, 10.8 mmol) is added at 0° C. to a solution of phenyl 6-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-14) (1.01 g, 2.69 mmol) and pyridine (2.2 mL, 26.9 mmol) in 30 mL of CH2Cl2. The solution is stirred at 0° C. for 1 h and allowed to warm at room temperature over 3 h. The reaction mixture is cooled to 0° C. before quenching with TEA (1.0 mL, 7.2 mmol). The reaction mixture is diluted with 30 mL of CH2Cl2, washed with saturated NaHCO3 (30 mL), 1N HCl (30 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (8% EtOAc/petroleum ether) to give 1.36 g (79%) of phenyl 6-deoxy-3,4-di-O-(trifluoromethanesulfonyl)-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-15): Rf 0.49 (20% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.48 (d, 2H, ArH), 7.33-7.21 (m, SH, ArH), 6.91 (d, 2H, ArH), 5.34 (t, J=2.0 Hz, 1H, H-3), 4.93 (d, J=9.2 Hz, 1H, H-1), 4.77 (d, J=11.2 Hz, 1H, CH2), 4.65 (d, J=11.2 Hz, 1H, CH2), 4.55 (dd, J=2.0, 8.8 Hz, 1H, H-4), 4.19-3.96 (m, 1H, H-5), 3.90 (s, 3H, OCH3), 3.47 (dd, J=2.0, 9.2 Hz, 1H, H-2), 1.36 (d, J=5.8 Hz, 3H, H-6).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:27]1[N:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: Cc1cnc(Br)nc1
Product: Cc1cnc(N2CCC([C@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.84 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[OH:13])=[O:5])[CH2:3][CH2:2]1.[IH:14]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:1][CH2:2][CH2:3][I:14])=[C:7]([OH:13])[CH:8]=1
Reactant: I
Reactant: O=C(c1ccc(F)cc1O)C1CC1
Product: O=C(CCCI)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
30.6 Parts of cyclopropyl (4-fluoro-2-hydroxyphenyl)-methanone were added portionwise to 450 parts of hydroiodic acid solution 50%. The whole was heated to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled to 0° C. The precipitated product was filtered off and dissolved in 300 parts of trichloromethane. The solution was dried, filtered and evaporated. The residue was dissolved in 210 parts of petroleumether while heating. The solution was treated twice with activated charcoal and the latter was filtered off each time. The filtrate was evaporated and the residue was suspended in 35 parts of petroleumether. After cooling to 0° C., the product was filtered off and dried, yielding 36.4 parts (70%) of 1-(4-fluoro-2-hydroxyphenyl)-4-iodo-1-butanone; mp. 41.4° C. (intermediate 89).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][OH:38]>CN(C)C=O>[OH:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (58 mg) and 3-bromo-1-propanol (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (44 mg, yield 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:13][CH:12]=[CH2:11])[CH:5]=[O:6]
Reactant: C=CCBr
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1Br

Procedure:
3-Bromo-4-hydroxybenzaldehyde (20.1 g, 0.100 mol) and allyl bromide (14.5 g, 0.120 mol) were heated under reflux together with potassium carbonate (20.7 g, 0.150 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. After complete concentration of the organic phase, there was obtained an oily residue that was used directly in the second step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10](O)([CH3:12])[CH3:11].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([CH3:12])([CH3:11])[CH3:9])=[C:4]([OH:8])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.5 g (170.3 mmol) of 3-bromophenol in 100 mL of carbon tetrachloride (under a blanket of argon) was added 16.4 g (221.3 mmol) of 2-methyl-2-propanol followed by 20 mL of conc. sulfuric acid. The reaction mixture was allowed to stir at ambient temperature for 3.5 days. The clear, colorless solution turned pink and eventually turned purple in color. The reaction mixture was neutralized with sat. NaHCO3 (aq.) solution and then extracted between water and dichloromethane. The layers were separated and the aqueous phase was washed with dichloromethane. The organic phases were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation (85-95° C., 2 mm Hg) gave the title compound as a clear, slightly yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]([CH3:11])[C:7](=[N:9][OH:10])[CH3:8])=[O:4].[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl.C(N(CC)CC)C>[CH3:20][NH:21][C:22]([O:10][N:9]=[C:7]([CH:6]([N:5]([C:12]1[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:11])[CH3:8])=[O:23]
Reactant: CC(=NO)C(C)N(C(=O)CCl)c1c(C)cccc1C
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Temperature: 25 °C
Yield: 96 %

Procedure:
3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone oxime (2.6 g) was dissolved in 75 ml methylene chloride and 5 drops of triethylamine were added. To this mixture was added 2.6 g methylisocyanate and the solution was stirred at room temperature. The solution was refluxed for 5 minutes and solvent was stripped. The oil was crystallized in ethanol-water to yield 3 g tan product. This product is tabulated as Compound No. 17 in Table I.