Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:18]S(C(C)(C)C)=O)([C:12]1[N:16]=[C:15]([CH3:17])[O:14][N:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][CH2:9][C:10]([C:12]1[N:16]=[C:15]([CH3:17])[O:14][N:13]=1)([NH2:18])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(C)(COCc2ccccc2)NS(=O)C(C)(C)C)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(C(C)(N)COCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (example 112c, 1.2 g, 2.73 mmol) in methanol (15 ml) was added a 4.0M solution of hydrochloric acid in Dioxane (2.05 ml, 8.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 1.0M aqueous solution of sodium bicarbonate and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane\ethyl acetate gradient to yield the title compound (577 mg, 85%) as a light yellow oil. MS (ESI, m/z): 248.6 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10](OC)=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2ccoc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 1-benzofuran-6-carboxylate (J. Med. Chem. 1995, 38, 3094; 142 mg, 0.8 mmol) in THF (5 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (92 mg, 2.4 mmol) in THF (2 mL) at −10° C. The mixture was stirred at room temperature for 30 min, cooled to 0° C. and treated slowly with water (1 mL). The mix was brought to pH 1 with 2N HCl and extracted with ethyl acetate (3×). The combined extracts were washed with water, brine, dried (MgSO4) and concentrated to give the final product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.0 g, 23.2 mmol) in methanol (23 ml) was added 2N aqueous sodium hydroxide solution (23.2 ml, 46.4 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, and saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (7.4 g, 89%).
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[C:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[NH:22])[CH2:20][Cl:21])[CH2:14]1)(=[O:12])[NH2:11].Cl>O>[ClH:21].[C:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[NH:22])[CH2:20][SH:5])[CH2:14]1)(=[O:12])[NH2:11]
Reactant: [O-]P([O-])([O-])=S
Reactant: N=C(CCl)N1CCCC(C(N)=O)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
1.43 g of trisodium phosphorothioate were added to an ice-cooled solution of 2.04 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylchloride hydrochloride in 9.7 ml of water, and the mixture was stirred at room temperature for one hour. 7.9 ml of 1N hydrochloric acid were then added, and the mixture was heated at 50° C. for 30 minutes. The reaction mixture was then worked up in the same manner as in Example 3(2) to give 2.0 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[CH:15]([CH3:17])[CH3:16].CCO>[Pd].C(N(CC)CC)C>[ClH:1].[CH:15]([CH:8]1[C:9]2[C:4](=[CH:3][CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:5][CH2:6][NH:7]1)([CH3:17])[CH3:16]
Reactant: COc1ccc(Br)c2c1C(C(C)C)NCC2
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1C(C(C)C)NCC2
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To 5-bromo-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.0 g) were added EtOH (30 mL), triethylamine (1.3 mL), and 10% palladium-supported carbon (0.30 g), followed by stirring under a hydrogen atmosphere for 2 hours. The reaction liquid was filtered through celite and the solvent was evaporated. An aqueous 1 M NaOH solution was added to the reaction liquid, followed by extraction with EtOAc. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dissolved in EtOAc (30 mL). 4 M HCl/EtOAc (5 mL) was added to the mixture, and the precipitated solid was collected to obtain 1-isopropyl-8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2].C1COCC1.C1(O)C=CC=CC=1.[I:26]I>C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([I:26])[C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(O)c(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzoic acid ethyl ester (69.2 g, 282 mmol) in 2N aqueous potassium carbonate (423 mL) was added sufficient THF to completely dissolve the phenol and make the solution clear (˜300 to 500 mL). The solution was cooled to 0° C. and I2 (158 g, 621 mmol) was added portionwise at such a rate as not to accumulate a large amount of solid 12 on the bottom of the flask. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete in 2 h. Worked up by adding (slowly with caution) solid sodium bisulfite at a rate so excess foaming doesn't occur. Sodium bisulfite was added until nearly decolorized. The mixture was acidified with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layers combined, washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 90%) as a pale yellow solid. NMR indicated it was suitable for use in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ1.39 (t, J=6.8 Hz, 3H, —CO2CH2CH3), 4.32 (t, J=6.8 Hz, 2H, —CO2CH2CH3), 8.14 (d, 1H, arom), 8.32 (d, 1H, arom).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O1CCCC1.C(NC(C)C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Brc1ccsc1Br
Reactant: C#CCCCCC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC#Cc1sccc1Br
Temperature: 70 °C
Yield: 99.4 %

Procedure:
2 ml (18.0 mmol) of 2,3-dibromothiophene, commercially available from Aldrich under the Product No. D4,390-5, and 3.5 ml (27.0 mmol) of 1-heptyne, commercially available from Aldrich under the Product No. 24, 441-4, were mixed with a solvent of tetrahydrofuran/diisopropylamine (1:1), and 0.23 g (0.36 mmol) of palladium dichlorodiphosphine, 70 mg (0.36 mmol) of copper iodide and 0.1 g (0.36 mmol) of triphenylphosphine were sequentially added thereto. The reaction solution was heated at 70° C. for 8 hours, and washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over magnesium sulfate, dried under reduced pressure, and purified using silica gel column chromatography, thus obtaining 4.6 g of 2-heptynyl 3-bromothiophene. The compound thus obtained was added with 3.3 ml (23.2 mmol) of trimethylsilylacetylene, commercially available from Aldrich under the Product No. 21, 817-0 and then subjected to the above synthesis process, to prepare 2.7 g (9.84 mmol) of 2-heptynyl-3-trimethylsilylethynylthiophene, which was then mixed with 12.8 ml (12.8 mmol) of lithium diisopropylamide (1 M) at about −78° C. The reaction mixture was stirred at the same temperature for 30 minutes, then combined with 2.4 ml (11.8 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, commercially available from Aldrich under the Product No. 41,714-9, and allowed to react in a bath while the temperature was increased to room temperature. The resultant reaction solution was poured into an aqueous solution of 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate and distilled under reduced pressure, thus obtaining 4.1 g of a compound 1a in an oil phase. Analysis of the compound 1a produced the following NMR data: 1H NMR (300 MHz, CDCl3), δ(ppm) 0.24 (s, 9H), 0.92 (t, 3H, J=7.2 Hz), 1.24-1.64 (m, 18H), 2.49 (t, 2H, J=7.0 Hz), 7.47 (s, 1H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:66]1[CH:71]=[CH:70][C:69]([C:72]([N:74]2[CH2:79][CH2:78][O:77][CH2:76][CH2:75]2)=[O:73])=[CH:68][CH:67]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[N:1]1[CH:2]=[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:66]3[CH:67]=[CH:68][C:69]([C:72]([N:74]4[CH2:79][CH2:78][O:77][CH2:76][CH2:75]4)=[O:73])=[CH:70][CH:71]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)N1CCOCC1

Procedure:
4-Imidazo[1,2-α]pyridin-3-yl-pyrimidin-2-ylamine(Bioorganic & Medicinal Chemistry Letters 2004, 14(9), 2245-2248) (0.20 g, 0.95 mmol), palladium acetate (9 mg, 0.038 mmol), Xanthphos (33 mg, 0.057 mmol), caesium carbonate (0.46 g, 1.4 mmol) and (4-iodo-phenyl)-morpholin-4-yl-methanone (Method 16a in WO 05/044814) (330 mg, 1.05 mmol) were added to dioxane (7 ml) under a inert atmosphere and heated at reflux for 6 hours. Purification on silica using 0-10% MeOH in DCM as eluent gave the title compound as a colourless foam. Further purification was achieved using RPHPLC to give a colourless foam (239 mg, 63%); 1H NMR (400.132 MHz) 10.13 (d, 1H), 9.89 (s, 1H), 8.64 (s, 1H), 8.48 (d, 1H), 7.85 (d, 2H), 7.79 (d, 1H), 7.52 (t, 1H), 7.46 (d, 1H), 7.43 (d, 2H), 7.16 (t, 1H), 3.65-3.60 (m, 4H), 3.58-3.51 (m, 4H); MH+ 401.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18](F)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1>CS(C)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:18]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: OCC1CC1
Reactant: Fc1cccnc1-c1ccc(Cl)cc1
Solvent: CS(C)=O
Product: Clc1ccc(-c2ncccc2OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a mixture of 16.20 g cyclopropanmethanol in 150 ml dry DMSO 11 g sodium hydride (55%) was added and the mixture was stirred at room temperature for 30 minutes. A solution containing 37.30 g 2-(4-chloro-phenyl)-3-fluoro-pyridine in 50 mL dry DMSO was added dropwise. The reaction mixture was then stirred at room temperature for 3 h. The resulting suspension was partitioned between water and methylene chloride, the phases were separated. The organic phase was washed with brine; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethylacetate=2:1 to yield 34.95 g (74.90%) of the title compound as yellow oil, MS 260.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21](O)=[O:22])[C:10]=2[O:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(OCC)C>ClCCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]3[C:10]=2[O:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]([F:30])([F:32])[F:31])[C:21]3=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCCNCC(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2OCCN1CC(F)(F)F

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-[2-(2,2,2-trifluoroethylamino)-ethoxy]-1H-pyrazole-3-carboxylic acid, hydrochloride I-1h (45 mg, 0.1 mmol), triethylamine (0.05 ml) and 1-propanephosphoric acid cyclic anhydride (0.1 ml, 0.14 mmol) in 1,2-dichloroethane (0.6 ml) were stirred for 8 hours. The reaction was diluted into ethyl ether, washed 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (1A-1) as a white solid, 35 mg. 1H NMR in CDCl3 (ppm): δ7.52 (d, 1H), 7.38–7.34 (m, 2H), 7.23 (d, 2H), 7.15 (d, 2H), 4.47 (brs, 2H), 4.29 (br s, 2H), 3.91 (br s, 2H); ms (LCMS) m/z=456.3 (M+1).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([NH2:12])=[O:11].Cl.[C]=O>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([N:12]=[C:2]=[O:3])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(F)cccc1F
Agent: Cl
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=C=NC(=O)c1c(F)cccc1F

Procedure:
Twenty-eight grams (0.22 mol) of oxalyl chloride were added dropwise to a solution of 31.4 gm (0.20 mol) of 2,6-difluorobenzamide in 250 ml of toluene. The solution thus obtained was boiled under reflux for five hours, during which time hydrogen chloride and carbon monoxide were liberated. The solvent was then distilled off, in vacuo at the end. The product which remained was distilled in an oil pump vacuum.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:22][C:23]1[CH:24]=[C:25]([S:30][C:31]2[CH:32]=[C:33]3[C:39]([NH2:40])=[N:38][NH:37][C:34]3=[N:35][CH:36]=2)[CH:26]=[C:27]([F:29])[CH:28]=1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>O1CCCC1.ClCCl>[F:22][C:23]1[CH:24]=[C:25]([S:30][C:31]2[CH:32]=[C:33]3[C:39]([NH:40][CH2:52][C:51]4[CH:50]=[CH:49][C:48]([N:45]5[CH2:44][CH2:43][N:42]([CH3:41])[CH2:47][CH2:46]5)=[CH:55][CH:54]=4)=[N:38][NH:37][C:34]3=[N:35][CH:36]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(CNc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
41.5 μl of trifluoroacetic acid (0.539 mmol) and, in small fractions, 129 mg (0.611 mmol) of sodium triacetoxyborohydride are added to a solution of 100 mg (0.35 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine and 81 mg (0.395 mmol) of 4-(4-methylpiperazin-1-yl)benzaldehyde in 20 ml of a 1:1 mixture of dichloromethane and tetrahydrofuran. The reaction medium is stirred for 16 hours at room temperature. An additional fraction of 125 μl of trifluoroacetic acid and 388 mg of sodium triacetoxyborohydride are added and the reaction medium is stirred for an additional 24 hours. The solvent is then concentrated and the reaction medium extracted with ethyl acetate and washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield a yellow oil. A trituration of this oil in methanol leads to the isolation of 135 mg of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3C(OCC=C)=O)=[N:7][C:6]=2[CH:25]=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate (1.18 g, 3.248 mmol) and morpholine (2.8 mL, 32.48 mmol) in THF (30 mL) was added Pd(PPh3)4 (0.375 g, 0.32 mmol). The mixture was stirred at rt for 2 h. The solvent was removed in vacuo. The crude was purified via silica gel with 0˜100% EtOAc/DCM to obtain the title compound. ESI-MS (m/z): 280 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:30]3[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=3)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3cccnc32)c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4ccco4)c4ncccc34)CC2)cc1C(=O)O
Yield: 76 %

Procedure:
This compound was prepared following the procedure described in example 7, part G and H starting with 2.37 g (8.4 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 3 g (11 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification the overall yield was 76% (1.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:2].[O:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1>>[N+:12]([C:8]1[CH:7]=[C:6]([C:5](=[CH:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=CC1CCOCC1
Reactant: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Product: CCOC(=O)C(=CC1CCOCC1)c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl(3-nitrophenyl)acetate (11.60 g, 55.5 mmol) was condensed with tetrahydropyran-4-carboxaldehyde employing the procedure described in Preparation 30 to give ethyl 2-(3-nitrophenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=628.3 [2M+NH4]+. A solution of this compound (4.65 g, 15.2 mmol) in EtOH (80 mL) was treated with a slurry of Pd (10% on C, 49 mg, 0.46 mmol) in EtOH (10 mL) and H2O (1 mL). The mixture was stirred under a H2 atmosphere for 24 h, before being filtered through Celite. The Celite was washed with EtOAc (5×50 mL), then the combined filtrates were evaporated to give ethyl 2-(3-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. A solution of this compound (2.77 g, 10.0 mmol) in DME (10 mL) was added over 30 min to a stirred mixture of i-AmONO) (2.0 mL, 15.0 mmol) and MeSSMe (9.9 mL, 110.0 mmol). The temperature was raised to 45° C. for 0.5 h and then to 85° C. for 1.5 h. On cooling, the solvents were removed under reduced pressure, then the residue was dissolved in EtOAc (60 mL). The EtOAc solution was washed with 1M HCl (2×20 mL), H2O (20 mL), and brine (20 mL). Filtration, solvent evaporation, and column chromatography (CH2Cl2-Et2O, 1:0 to 99:1) afforded ethyl 2-(3-methylsulfanylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=309.2 [M+H]+. Saponification of this ester with LiOH.H2O, by the protocol outlined in Preparation 22, furnished the title compound: m/z (ES+)=561.3 [2M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][C:22]=4[CH3:23])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([NH:16][C:14]([C:11]2[C:7]3[N:8]=[CH:9][N:10]=[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)[C:6]=3[S:13][CH:12]=2)=[O:15])[CH:18]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylphenylcarbamate (7 g, 15.93 mmol) was dissolved in DCM (80 mL), TFA (12 mL, 159.3 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the organic solvent and the remaining TFA, and water (20 mL) was added thereto. The reaction mixture was neutralized with 2.0 N NaOH solution, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+]>>[Br:8][C:7]1[C:2](=[O:11])[NH:3][CH:4]=[C:5]([Br:9])[N:6]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1[nH]cc(Br)nc1Br
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A solution of 12.65 g of 2-amino-3,5-dibromo-pyrazine and 18.5 ml of 96% sulfuric acid is added dropwise to a solution of 3.45 g of sodium nitrite and 27.5 ml of 96% sulfuric acid at 0° to 5° C. The mixture is then allowed to warm to 20° C. in the course of 2 hours and is stirred at 20°-25° C. for a further 15 hours. The reaction mixture is poured into ice and the product is filtered off, washed with ice-water and dried to give 5.8 g of 3,5-dibromo-pyrazin-2-one.