Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (7.2 g, 180 mmol) in anhydrous N,N-dimethylformamide (200 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (30.24 g, 150 mmol) so as to keep the pot temperature below 20° C. After one hour at 40° C., the mixture was treated with 3-chlorobenzyl bromide (37.0 g, 180 mmol) and heated to 100°±5° C. for one hour, then cooled to room temperature and added to water (600 mL). A solid precipitate soon formed, which was collected, washed with water, partially air dried, and dissolved in methylene chloride. The solution was filtered through alumina (eluted with methylene chloride) and the filtrate was concentrated in vacuo. The residue was taken up in a mixture of 50% sodium hydroxide (50 mL), water (50 mL), and ethanol (100 mL), and refluxed for one hour. Most of the ethanol was removed in vacuo and water (400 mL) was added to dissolve all solid. The aqueous solution was extracted with ether (100 mL), then with petroleum ethers (30°-60° C., 100 mL), cooled (0° C.), and acidified to pH 3 with concentrated hydrochloric acid (about 90 mL). The resultant precipitate was collected and the solid was washed with water, dried, and recrystallized (2 crops) from ethanol to afford 28.36 g (61%) of pale tan solid; mp 182.5°-184.0° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1>>[CH3:19][C:14]1[CH:13]=[CH:12][C:17]2[O:18][C:9](=[O:10])[CH2:8][CH:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:16]=2[CH:15]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2

Procedure:
retention times are: t-cinnamic acid=3.3 min., p-cresol=4.2 min. and the title compound=20.3 min.) or TLC (acetone/cyclohexane (20/80), acetic acid (0.5%); wavelength=254 nm) usually 6 hours. When the reaction is complete the mixture is cooled to 100° and added to a prewarmed separatory funnel (500 mL). The bottom layer containing the sulfuric acid is removed and toluene (280 mL), water (50 mL) and potassium carbonate (47%, 10 mL) are added to the separatory funnel containing the crude product. If necessary the pH of the aqueous layer is adjusted to between 5-8 with additional 47% potassium carbonate. The layers are separated and the organic layer is then washed once with water (50 mL). The organic layer is concentrated to a final volume of approximately 150 mL under reduced pressure. Isopropanol (350 mL) is then added, and distillation is continued to a volume of 350 mL. Isopropanol (150 mL) is again added and again distilled to 350 mL. Isopropanol (150 mL) is again added and again distilled to 350 mL. The mixture is then cooled to 30-40° with rapid stirring until the product crystallizes. The rapid stirring is continued after crystallization. The product is cooled to 0-5° and held at this temperature for approximately 1 hour, filtered and washed with isopropanol (200 mL) cooled to 0-5°. If the last portion of the wash is colored the wash is continued until no more color is removed. The solids are then dried at 60° under reduced pressure to give the title compound, mp (uncorrected)=83°-85°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Br:8])=[N:5][CH:4]=1.[CH3:9][NH:10][C:11](=[N:14][N+:15]([O-:17])=[O:16])SC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:8][C:6]1[S:7][C:3]([CH2:2][NH:1][C:11]([NH:10][CH3:9])=[N:14][N+:15]([O-:17])=[O:16])=[CH:4][N:5]=1
Reactant: NCc1cnc(Br)s1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Br)s1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A mixture of 0.39 g of 5-(aminomethyl)-2-bromothiazole, 0.30 g of 1,2-dimethyl-3-nitroisothiourea, 0.58 g of cuprous bromide, 0.55 g of anhydrous potassium carbonate and 4 ml of dry acetonitrile was stirred in an oil bath of 60° C. for 45 minutes. The reaction mixture was purified by a column chromatography [developing solvent: dichloromethane-methanol (10:1)] to obtain 1-(2-bromo-5-thiazolylmethyl)-3-methyl-2-nitroguanidine (Compound No. 39), as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)C.[CH3:13][O-:14].[Na+]>CO>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:14][CH3:13]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccnc1OC
Yield: 70.9 %

Procedure:
A mixture of quinoxaline-6-carboxylic acid (2 g, 11.49 mmol) and thionyl chloride (30 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness using a rotary evaporator to afford quinoxaline-6-carboxylic acid chloride (crude quantitative). A solution of the above acid chloride (11.49 mmol) in DCM (50 mL) and pyridine (20 mL) was mixed with N,O-dimethyl hydroxylamine HCl salt (2.24 g, 23 mmol) and stirred at room temperature for 12 hours. The reaction was quenched by adding aqueous HCl (50 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield quinoxaline-6-carboxylic acid methoxy-methyl-amide (2 g, 80%). To a solution of the above Weinreb amide (2.0 g, 9.2 mmol) in THF (30 mL) at 0° C. was added methyl magnesium bromide (3.9 mL, 11.6 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then 1 hour at room temperature, quenched by adding aqueous HCl (20 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield 6-acetylquinoxaline (1.17 g, 74%). A solution of 2-chloronicotinic acid ethyl ester (5.0 g, 27 mmol) in MeOH (25 mL) was mixed with sodium methoxide (25.6 mL, 112.5 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding water (100 mL), extracted with DCM (3×100 mL), concentrated using a rotary evaporator to afford 2-methoxynicotinic acid methyl ester (3.2 g, 71%). A solution of 6-acetylquinoxaline (0.62 g, 3.6 mmol), 2-methoxynicotinic acid methyl ester (0.64 g, 3.8 mmol), and sodium hydride (0.46 g, 11.4 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL) and AcOH (20 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was re-dissolved in DCM (5 mL) and MeOH (3 mL) and was diluted with Hexanes (50 mL). The solid was removed by filtration and the filtrate was concentrated to afford the diketo compound (0.7 g, 60%). A solution of the above diketone (0.4 g, 1.3 mmol) in AcOH (50 mL) and sulfuric acid (conc., 15 drops) was stirred at reflux for 1 hour. Most of the solvent was removed using a rotary evaporator. The residue was re-dissolved in MeOH and neutralized with potassium carbonate to pH=8. The solid residue was removed by filtration, washed with MeOH and DCM. The filtrate was extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator. The solid residue was purified by column (SiO2, Hexanes/EtOAc/MeOH=2:2:1) to afford 2-(quinoxalin-6-yl)-4H-pyrano[2,3-b]pyridin-4-one (90 mg, 24%); MS (ES) m/z: 276 (M+1); MP 272.3-274.8° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[N:14]O)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[ClH:17]>CO>[ClH:17].[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH2:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)C(=NO)C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
A solution of oxime 5 (18.0 g, 80.0 mmol) in MeOH (220 mL) was mixed with 1.25 M HCl solution in MeOH (130 mL) at rt. The solution was flushed with N2 and then charged with 5% Pd—C (3.1 g). A hydrogen balloon was attached to the flask and the resulting mixture was stirred at rt for 2.5 h. More 5% Pd-C (˜1.8 g every 2 h) was added as the reaction was carefully monitored by LCMS. Eventually, the reaction was completed in 8 h with totally 9.4 g of 5% Pd—C added. After Pd catalyst was removed by filtering through a Celite pad, the clear solution was concentrated under reduced pressure to afford hydrochloride salt of pure product 6 (20.0 g, 100%) as a white solid. ESI MS m/z 212.2 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[N:10]2)=[C:5]([F:16])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)=O.Cl[CH:27]([F:29])[F:28]>COCCOCCOC.O>[F:28][CH:27]([F:29])[N:12]1[C:13](=[O:14])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=2[F:16])[N:10]=[C:11]1[CH3:15]
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Temperature: 190 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a one liter stainless steel autoclave equipped with a mechanical stirrer, thermometer, and a gas inlet tube were placed 50.0 grams (0.20 mole--1.0 equiv.) of the sodium salt of 4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole and 13.8 grams (0.10 mole--0.5 equiv.) of solid potassium carbonate in 500 mL (% wt/vol. triazole to solvent--10.0%) of diglyme. The autoclave was sealed, and the reaction mixture was warmed to 190° C. Upon reaching 190° C. the reaction vessel was vented to expel water and carbon dioxide. The reaction vessel was resealed, and 34.6 grams (0.40 mole 2.0 equiv.) of chlorodifluoromethane was bubbled in below the surface of the reaction mixture. The pressure in the autoclave following the addition of chlorodifluoromethane was about 64 psi. Upon completion of the addition the reaction mixture was maintained at 190° C. for about 30 minutes, after which the reaction mixture was cooled to ambient temperature, the autoclave was opened, and the reaction mixture was then poured into 1500 mL of water. The autoclave was rinsed with N,N-dimethylformamide, and the rinse was also added to the 1500 mL of water. The mixture was stirred vigorously for two hours, and the solid product was collected by filtration. The filter cake was washed with five 300 mL portions of water and air-dried to a constant weight, yielding 52.3 grams of 95.0% pure 4-difluoromethyl-4,5-dihydro-1-(4-chloro-2-fluorophenyl)-3-methyl-5-oxo-1H-1,2,4-triazole (89.4% yield). GC analysis of the product indicated the presence of <0.5% 0-isomer by-product.
Reaction SMILES: [NH:1]1C=CC=N1.ClC1C(C(NC2C=CC=CC=2[C:22]2[CH:27]=[C:26]([F:28])[C:25]([N:29]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]3)=[C:24]([F:38])[CH:23]=2)=O)=CC=CN=1.O.O.[Sn](Cl)Cl>C(O)C>[F:38][C:24]1[CH:23]=[C:22]([NH2:1])[CH:27]=[C:26]([F:28])[C:25]=1[N:29]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]1
Reactant: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1

Procedure:
A mixture of 1-(2,6-difluoro-4-nitrophenyl)-3-trifluoromethyl)-1H-pyrazole (i.e. the product of Step A; 2.39 g, 8.15 mmol) and tin(II) chloride dihydrate (9.33 g, 41.3 mmol) in ethanol (173 mL) was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with 1 N aqueous sodium hydroxide, and then water. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to provide the title compound (2.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Agent: Cl
Solvent: CCO
Product: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
tert-butyl 3-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)pyrrolidine-1-carboxylate (3.0 g, 5.63 mmol) from the above was added to a solution of hydrogen chloride in ethanol (2.0 M, 20 mL) and ethanol (30 mL), and the resulting mixture was stirred at ambient temperature for 4 hours. After this time, the mixture was concentrated, washed with dry ether and dried in vacuo overnight to afford the title product as a white solid (2.2 g, 91% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.86 (1H, d), 8.78 (1H, m), 8.50 (1H, s), 4.20 (1H, m), 2.94 (2H, m), 2.79 (1H, m), 2.67 (1H, m), 1.93 (1H, m), 1.67 (1H, m). MS m/z: 419.20, 421.20 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:36])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(-c3cccc4ccccc34)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(Nc1nc(CCO)cs1)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 5B-b, 60 mg, 0.117 mmol) in diethyl ether (1 mL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride powder (6.7 mg, 0.176 mmol). The reaction mixture was stirred at 0° C. for 30 min, at which time, thin layer chromatography showed the absence of starting material. The reaction mixture was slowly quenched by the dropwise addition of a saturated aqueous sodium bicarbonate solution (2 mL). The resulting reaction mixture was treated with ethyl acetate (2 mL) and allowed to stir at 25° C. for 15 h. The two-phase reaction mixture was then partitioned between water (20 mL) and ethyl acetate (20 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-naphthalen-1-yl-phenyl)-propionamide (19 mg, 34%) as a yellow foam: mp 84-87° C.; EI-HRMS m/e calcd for C29H30N2O2S (M+) 470.2028, found 470.2020.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:17]1([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCCC1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed overnight in 250 ml of toluene that contained pyrrolidine (7.10 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was washed with an aqueous K2CO3 solution and then the organic phase was concentrated. The residue obtained in this manner was purified by flash chromatography (5% Et3N, toluene) to give, after recrystallization from benzene/pentane, 2.91 g, m.p. 201°-203°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([NH2:37])[CH3:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][NH:37][CH2:35][CH3:36])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CNCC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A3) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[F:11][C:12]1[C:16]([F:17])=[CH:15][NH:14][CH:13]=1.CC([O-])=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[C:16]([F:17])=[CH:15][NH:14][C:13]=1[CH:4]=[O:5]
Reactant: Fc1c[nH]cc1F
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (4.3 ml) was cooled in ice-water bath under N2 and POCl3 (5.2 ml) was added dropwise. The mixture was stirred at room temperature for 10 min. The ice-water bath was replaced, and the mixture was diluted with DCM (45 ml). A solution of 3,4-difluoro-1H-pyrrole (Intermediate 18; 4.57 g) in DCM (45 ml) was added dropwise. The mixture was refluxed for 30 min, cooled to room temperature and a solution of NaOAc (23 g) in water (60 ml) was added slowly. The resulting mixture was refluxed for 30 min, organic phase was separated and aqueous phase was extracted with DCM. The combined organic phase was washed with NaHCO3, dried over Na2SO4, and concentrated in vacuo. The crude solid was triturated with DCM (20 ml)/pentane (100 ml), and then cooled to −20° C. to give the title compound as pale brown needles (4.73 g). NMR (CDCl3): 6.87 (m, 1H), 9.6 (m, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[C:25](=[NH:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25](=[N:38][C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N=C(c3ccccc3)c3ccccc3)nc12
Temperature: 90 °C
Reaction time: 64 h
Yield: 93.3 %

Procedure:
A mixture of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.576 g, 1.40 mmol), benzophenone imine (0.26 mL, 1.54 mmol), cesium carbonate (0.912 g, 2.80 mmol), palladium acetate (0.031 g, 0.14 mmol) and BINAP (0.087 g, 0.14 mmol) in 14 mL of tetrahydrofuran was stirred at 90° C. in a sealed tube for 64 h then concentrated. The resulting residue was taken up in 30 mL of ethyl acetate and sequentially washed with 30 mL of water and 30 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to a residue. Column chromatography (10→25% EtOAc/hexanes) afforded 0.670 g (93%) of 1-[2-(benzhydrylidene-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:27]=[CH:28][CH:29]=1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1)Oc1ccccc1

Procedure:
This compound was prepared according to the procedure in Example 1, part D, using 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (551.5 mg, 1.84 mmol) and toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (1.04 g, 2.39 mmol): Rf=0.54 in 1:4 EtOAc:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H) 7.30 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.98-6.95 (m, 1H), 6.82 (d, J=8.4 Hz, 2H) 6.83-6.81 (m, 2H), 4.23 (t, J=6.8 Hz, 2H), 4.20 (q, J=7.6 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.09 (d, J=14.0 Hz, 1H), 2.97 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.6 Hz, 3H); MS (EI)=564.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: OCCCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 332 (M{37Cl}+H+, 50), 330 (M{35C,}+H+, 100).