Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:23](=[O:25])[CH3:24]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:23]([OH:25])[CH3:24])[CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: Brc1cccc(CN2CCOCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C(c1cccc(Br)n1)N1CCOCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-[(6-Bromopyridin-2-yl)methyl]morpholine (Example 45, step 1) (200 mg, 0.78 mmol) was placed under argon and then taken up in tetrahydrofuran (8 mL). The solution was cooled to −78° C. followed by the addition of LDA (0.65 mL of 1.8 M, 1.17 mmol) over 30 minutes. The reaction was maintained at −78° C. for one hour. Acetaldehyde (0.1 mL, 7.8 mmol) was then added and the reaction was then stirred at −78° C. for 2 hours. An additional portion of acetaldehyde (0.1 mL, 7.8 mmol) was then added and the reaction was then stirred an additional 2 hrs at −78° C. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the crude mixture via flash chromatography (silica, 0-5% methanol/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:8]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1F
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of 2,3-difluoro-6-nitroaniline (200 mg, 1.15 mmol) in DMF (10 ml) was added phenol (108 mg, 1.15 mmol) and potassium carbonate (317 mg, 2.30 mmol). The reaction was heated (120° C.) overnight and then cooled to rt. The reaction was diluted with ethyl acetate (200 mL) and then washed with water (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-50% ethylacetate/hexane to afford the desired product (267 mg, 94%) 1H NMR (300 MHz, DMSO-d6) 7.85 (dd, J=9.8, 2.2 Hz, 1H), 7.34-7.49 (m, 4H), 7.19-7.27 (m, 1H), 7.08-7.16 (m, 2H), 6.21 (dd, J=9.7, 7.8 Hz, 1H); HPLC RT (Method A) 3.48 min.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[C:34]([O:39][CH3:40])[N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:35]=[C:34]([O:39][CH3:40])[N:33]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: COc1cc(Cl)nc(OC)n1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(OC)nc(OC)n2)C3)cc1

Procedure:
Compound ea was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2,6-dimethoxy-4-chloropyrimidine. LC-MS: m/z=+535 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]2[C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13](I)=[C:9]2[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH3:19][S:20][C:21]1[N:26]=[C:25]([Sn](C)(C)C)[CH:24]=[CH:23][N:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Li+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[C:1]([NH:4][C:5]1[N:10]2[C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]([C:23]3[CH:24]=[CH:25][N:26]=[C:21]([S:20][CH3:19])[N:22]=3)=[C:9]2[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc2c(I)c3cccnc3n12
Reactant: CSc1nccc([Sn](C)(C)C)n1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1nccc(-c2c3cccnc3n3c(NC(C)=O)nccc23)n1
Yield: 16.2 %

Procedure:
A solution of 20a (130 mg, 0.37 mmol), 2-methanesulfenyl-4-trimethylstannylpyrimidine (93 mg, 1.10 mmol), Pd2(dba)3 (76 mg, 0.07 mmol), PPh3 (39 mg, 0.15 mmol), LiCl (47 mg, 1.10 mmol) and CuI (14 mg, 0.07 mmol) in dioxane (10 ml) was refluxed for 1.5 hours. The organic solvent was removed and the oil dissolved in CH2Cl2. The organic solution was extracted four times with 4N HCl and the aqueous solution basified with solid Na2CO3. The aqueous solution was extracted with CH2Cl2. The organic layer was evaporated and purified by flash column chromatography. Elution with CH2Cl2/MeOH (99/1) gave 9-Acetylamino-5-(2-methanesulfenylpyrimidin-4-yl)pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (21 mg, 16%) as a yellow solid and with CH2Cl2/MeOH (95/5) gave 21 (30 mg, 26%) as a yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[N:16][CH:17]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].COCCOCCO.[H-].[Na+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C.COCCO>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:35][C:36](=[O:37])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[C:15]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[N:16][CH:17]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCO
Solvent: COCCO
Solvent: CN(C)C=O
Product: COCCOCc1ncc(C(=O)NC2CCN(C(C)C)CC2)n1CC(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 49 mg of 2-(2-Methoxy-ethoxymethyl)-3H-imidazole-4-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide [prepared by following the procedure from example 66 replacing 2-(2-methoxy-ethoxy)-ethanol by 2-methoxy-ethanol in step (i)] in DMF (3 mL) was added 17 mg of sodium hydride (60% in mineral oil). The mixture was stirred at 50° C. for 1 h and cooled to 30° C. 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide (41 mg) was added and stirring was continued for 1.5 h. Another portion of 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (10 mg) was added. The mixture was stirred for 30 min at 30° C., carefully quenched by dropwise addition of water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(OCC)C.O>[C:9]1([C:14]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCS
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCSC(=O)c1cccs1

Procedure:
A mixture of 26.5 g (0.25 mol) of 3-mercaptopropionic acid, 150 mls of ethyl ether and 250 mls of 1-normal NaOH has been treated dropwise, the temperature being maintained between 0° C. and 5° C., with vigorous stirring, with 40.3 g of 2-thenoyl chloride (0.275 mol) in 80 mls of ethyl ether, while concurrently adding, so as to keep the pH of the reaction environment constantly alkaline, 31.5 g (0.36 mol) of NaHCO3 in 800 mls of water. On completion of dripping, stirring has been continued for 16 additional hours at room temperature. Upon separation of the organic phase, the waters have been extracted with ethyl ether again, and then made acidic with 4-normal hydrochloric acid. The as-formed precipitate has been recrystallized from 70% ethanol.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.CCCCCC.[Pd]>[C:22]([O:21][C:19](=[O:20])[NH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4.00 g, 11.0 mmol) in MeOH (40 mL) was added 5% Pd/C (400 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1 hr, filtered through a pad of celite, and concentrated to give a white solid. A suspension of the above solid in hexane (15 mL) was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, dried under reduced pressure to give trans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester (2.52 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:19]=[CH:18][C:11]3[N:12]=[C:13](S(C)=O)[S:14][C:10]=3[CH:9]=2)[CH:6]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:19]=[CH:18][C:11]3[N:12]=[C:13]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[OH:27])[S:14][C:10]=3[CH:9]=2)[CH:6]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc(Br)c3)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 110 °C
Yield: 66.4 %

Procedure:
To a suspension of 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg, 0.37 mmol) from Step 6 of this Example and (1R,2R)-2-aminocyclohexanol (126 mg, 1 mmol) in anhydrous DMA (1.0 mL) was added DIEA (320 μL, 1.8 mmol). The mixture was heated in a sealed tube at 110° C. for 7 h. The mixture was cooled to rt and water was slowly added while stirring to give a precipitate. The mixture stirred for 10 min and the solid was collected by filtration to afford (1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 68%) as a tan solid. The material was used in the next step without further purification. LCMS (ESI) m/z 407 and 409 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([N+:13]([O-])=O)[CH:7]=[CH:6][C:5]=2[CH3:16].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([CH3:16])=[C:4]2[C:9]=1[C:10](=[O:12])[CH:11]=[C:2]([CH3:1])[O:3]2
Reactant: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C)c2o1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(=O)c2c(N)ccc(C)c2o1
Temperature: 25 °C

Procedure:
1.78 g (8.12 mmol) of 2,8-dimethyl-5-nitro-4H-chromen-4-one are heated with 9.16 g (40.6 mmol) of tin(II) chloride dihydrate in 70 ml of ethyl acetate at 70° C. overnight. After cooling to room temperature, the reaction mixture is brought to pH 9-10 with saturated sodium bicarbonate solution. After filtration through kieselguhr, the organic phase is separated off, and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed in vacuo. 1.5 g (99% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[N:21][C:13]=4[N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([NH2:27])=[O:24])[CH:20]=[N:21][C:13]=4[N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(=O)O)cnc1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(N)=O)cnc1-2
Reaction time: 0.17 h

Procedure:
A mixture of 17 mg (0.05 mmol) of 9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylic acid, 30 mg, (0.061 mmol) of HATU and 0.022 ml (0.155 mmol) of triethylamine in 2 ml of DMF was stirred for 10 min. Ammonia (gas) was bubbled through the mixture for 5 min. The mixture was stirred for 1 hour, concentrated in vacuum and partitioned between ethyl acetate and 0.01 N aqueous HCl. The organic layer was concentrated and the residue purified on 4 g silica column eluting with 7-8% Methanol in DCM to give 114. Yield 2.4 mg. MS(ESI+) 339.2. 1H NMR (400 MHz, CH3OH+D2O) δ 8.70 (d, J=1.8, 1H), 8.33 (s, 1H), 8.05 (d, J=1.8, 1H), 7.52 (s, 1H), 6.48 (d, J=1.6, 1H), 5.16 (dd, J=13.2, 6.6, 1H), 4.56 (t, J=5.1, 2H), 3.52-3.45 (m, 2H), 1.49 (d, J=6.6, 6H).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)([CH3:28])[CH3:27]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 90.3 %

Procedure:
Dissolve dehydroisoandrosterone (10.0 g, 34.67 mmol) in dimethylformamide (DMF, 150 mL) under an atmosphere of nitrogen. Add t-butyldimethylsilyl chloride (5.23 g, 34.67 mmol), triethylamine (5.32 mL, 38.14 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.21 g, 1.73 mmol) with stirring at room temperature. After two days pour the reaction into rapidly stirring water (1.5 L). Filter the white solid and wash with water (2×50 mL). Dissolve the solid in ethyl acetate (350 mL) and wash with 0.5N hydrochloric acid (2×150 mL), half-saturated sodium bicarbonate (2×150 mL) and brine (100 mL). Dry the organic layer over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (ethyl acetate/hexane, 15:85, silica gel) to provide (3β)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-androst-5-en-17-one (12.60 g) as a white solid, Rf =0.78 (ethyl acetate/hexane, 1:1, silica gel), mp 146°-148° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22]>C(#N)C>[CH2:21]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:22]
Reactant: CCI
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCCC1c1cccc(O)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.5 g) in dry acetonitrile (60 ml) was added milled potassium carbonate (4.1 g), followed by iodoethane (1.3 ml) at ambient temperature, under nitrogen, with stirring for 7 hrs. The reaction mixture was filtered through a pad of celite and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and the residue was diluted with 48% hydrobromic acid (30 ml) and warmed at 100° C. for 3.5 hrs. Upon cooling to ambient temperature, the reaction mixture was neutralized with saturated sodium bicarbonate solution and the filtrate was extracted with dichloromethane (2 times). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane/0-10% methanol). The appropriate fractions were collected and concentrated to give 0.8 g (26%) of 3-[1-ethyl-2-pyrrolidinyl]phenol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([F:36])[C@@:30]([OH:35])([CH3:34])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[C@:30]([OH:35])([CH3:34])[C:29]([F:37])([F:36])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)[C@@](C)(O)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=419.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].Br[CH2:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:23])=[CH:20][CH:19]=1>CO.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:34][CH:35]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C(=O)c2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 2-butyl-4-chloro-5-(hydroxymethyl)imidazole (11.12 g, 54 mmol, 1 eq) in 200 mL methanol was added dropwise a freshly prepared sodium methoxide solution (1.36 g Na, 59 mmol, 1.1 eq in 50 mL MeOH). After stirring for 0.5 hours, the methanol was removed in vacuo and the resultant glass was dissolved in 200 mL DMF. To this mixture was added a solution of methyl 2-[4-(bromomethyl)benzoyl]benzoate (18.00 g, 59 mmol, 1.1 eq) in DMF and the entire contents was stirred overnight under N2 at room temperature. The solvent was then removed in vacuo and the residue dissolved in 500 mL ethyl acetate and 500 mL H2O. The layers were separated and the aqueous layer was extracted twice with 500 mL portions of ethyl acetate. The organic layers were dried and concentrated and the crude product flash chromatographed to separate the two regioisomers in 60:40 hexane/ethyl acetate over silica gel. The faster moving isomer was isolated to yield 14.72 g of a glassy solid. NMR (200 MHz, CDCl3) δ8.03 (d, 1H, J=7 Hz); 7.67 (m, 4H); 7.36 (d, 1H, J=7 Hz); 7.05 (d, 2H, J=7 Hz); 5.28 (s, 2H); 4.43 (s, 2H); 3.63 (s, 3H); 2.53 (t, 2H, J=7 Hz); 1.60 (t of t, 2H, J=7,7 Hz); 1.30 (t of q, 2H, J=7,7 Hz); 0.87 (t, 3H, J=7 Hz). Mass Calcd. for C25H26ClF3N4O5S: 586.1264. Found: 586.1285.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)(C(C)(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH2:24]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=1)[CH:35]=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.N>C1COCC1.O>[CH2:41]([O:40][C:38]1[CH:37]=[C:34]([CH:35]([OH:36])[CH2:15][C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:33]=[C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:39]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(CC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl pyridine (1.20 g) in anhydrous THF (15 ml) under nitrogen and at −78° C. was added LDA (3.22 ml), and the solution stirred at −78° C. for 1 hour. 3,5 dibenzyloxy-benzaldehyde (2.05 g) was then added dropwise as a solution in THF, and the reaction mixture allowed to warm to ambient temperature over 1 hour. Water (20 ml) was added and the resulting mixture extracted with ethyl acetate (3×30 ml). The extracts were combined, washed with brine (20 ml), dried (MgSO4) and evaporated to give a gum. This was dissolved in THF (10 ml) and concentrated hydrochloric acid (10 ml) added. The mixture was stirred at ambient temperature for 3 hours, cooled to 0° C. and taken to pH 8.5 with concentrated ammonia solution. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined, dried (MgSO4) and evaporated to leave an oil which was purified by MPLC on silica, eluting with 60–100% ethyl acetate in hexane to give 6-{2-[3,5-bis(benzyloxy)phenyl]-2-hydroxyethyl}pyridin-3-ol (2.25 g) as a glass, m/z 428 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][NH+:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Reactant: BrCCc1cccc[nH+]1
Agent: [Br-]
Product: Cc1cc(-c2nc(SCCc3ccccn3)n[nH]2)oc1C
Yield: 55 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(2-bromoethyl)pyridinium bromide (example 8a). Yield 55%. 1H NMR (500 MHz, CDCl3): δ 1.96 (s, 3H), 2.24 (s, 3H), 3.28 (t, 2H), 3.49 (t, 2H), 6.77 (s, 1H), 7.13-7.23 (m, 2H), 7.65 (t, 1H) 8.58 (s, 1H). MS (M+H, 301).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].BrBr.[Br:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13](=[O:25])[C:12]=2[CH:11]=1>C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:25])[C:12]=2[CH:11]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc(Br)cc12
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2oc2ccc(Br)cc12
Temperature: 100 °C
Yield: 41 %

Procedure:
The reaction solution was refluxed for 5 hours at 100° C. under heating and stirring in a nitrogen atmosphere. Upon completion of the reaction, chloroform and a saturated aqueous sodium sulfite solution were added to the reaction solution and stirring was continued until the color of bromine was lost. The organic layer was separated, washed with a saturated aqueous sodium carbonate solution, dried with magnesium sulfate, and filtered. The solvent in the filtrate was distilled away at a reduced pressure. The precipitated solid was purified with a silica gel column (toluene: 100%). As a result, 2.9 g (yield: 41%) of 2-bromoxanthone and 2.2 (yield: 25%) g of 2,7-dibromoxanthone were obtained.