Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5]([OH:7])=O.[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:54]([O:53][C:51]([NH:50][CH2:49][CH2:48][CH2:47][C@H:39]([NH:38][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:37])[C:10]([CH2:11][S:12][C:13]2[N:14]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:15]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=3)([CH3:20])[CH3:19])=[CH:16][N:17]=2)=[C:2]([Cl:1])[CH:3]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:52])([CH3:56])([CH3:57])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 0° C. solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluoro-phenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.94 g, 0.17 mmol), (S)-tert-butyl 2-amino-5-(tert-butoxycarbonylamino)pentanoate (0.050 g, 0.18 mmol) and HATU (0.067 g, 0.18 mmol) in DMF (4 mL) was added DIPEA (0.058 mL, 0.33 mmol). The ice bath was removed and the reaction was stirred for 2 h at room temperature. The reaction was quenched with satd NaHCO3 and diluted with EtOAc. The organic layer was washed with H2O (2×5 mL), brine, and dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography to afford 114 mg of (S)-tert-butyl 5-(tert-butoxycarbonylamino)-2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)pentanoate. The compound was then dissolved in 4N solution of HCl in dioxane and stirred for 2 h, when the reaction was determined to be complete by LCMS. Ether was added to the reaction mixture. Then the solids were collected by filtration and dried under vacuum to afford the title compound (75 mg). 1H-NMR (DMSO6, 400 MHz) δ 9.00 (d, J=8.3 Hz, 1H), 8.01 (s, 3H), 7.93 (s, 1H), 7.82-7.75 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.67-6.64 (m, 1H), 6.61-6.57 (m, 1H), 6.53-6.52 (m, 1H), 6.50-6.47 (m, 1H), 4.43-4.38 (m, 1H), 4.19 (s, 2H), 3.70 (s, 3H), 2.84-2.80 (m, 2H), 1.97-1.80 (m, 2H), 1.75-1.66 (m, 2H), 1.51 (m, 6H); MS (ES): 677 [M]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccccc1I
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Brc1ccccc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C

Procedure:
1.672 g of carbazole, 1.6 mL of 1-bromo-2-iodobenzene, 2.7646 g of potassium carbonate, 95 mg of copper iodide and 25 mL of xylene were refluxed in a nitrogen atmosphere. The mixture was cooled to room temperature, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate to remove moisture, and the solvent was removed under reduced pressure. Silica gel column separation using a hexane solvent was conducted, thus obtaining a compound from which the solvent was then removed under reduced pressure, followed by vacuum drying, yielding 9-(2-bromophenyl)-9H-carbazole as a desired white solid intermediate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[CH2:10]1C[O:13][CH2:12][CH2:11]1>O.C(O)(=O)C.C=O>[OH:13][CH:12]1[CH2:11][CH2:10][N:4]([CH2:5][C:6]2[C:2]([CH3:1])=[C:3]([CH:8]=[O:9])[NH:4][C:5]=2[CH3:7])[CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: C1CCOC1
Agent: C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C=O)c(C)c1CN1CCC(O)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (2.5 g, 20 mmol) in THF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde (37% wt. % solution in water, 5 mL) and the appropriate amine (30 mL) was heated to reflux (oil bath 90-100° C.) for 6 hours and then stirred at rt for overnight. The reaction was concentrated to a volume of 30 mL, basified with 2N NaOH and extracted with ethyl acetate (2×150 mL) and DCM (4×100 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to give 2.3 g (49%) of 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde as a solid.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(Cl)C(=O)Cl
Product: CC(Cl)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 63.5g (0.5 mole) of 2-chloropropionyl chloride with 67g (0.5 mole) of tert-butylbenzene. Obtained after high vacuum concentration was 100g of a clear, yellow liquid product: ir (film) 3.4 (s), 5.9 (s), 6.3 (s), 8.0 (s), 10.5 (s), 11.8 (s) microns: nmr (CDCl3) 7.67 (4H, d of d), 5.21 (1H, q), 1.67 (3H, d), 1.28 (9H, s) ppm. A VPC analysis indicated one pure product.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:3]([CH3:4])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH:11][CH:3]([CH3:4])[CH2:2][C:1]([OH:5])=[O:6]
Reactant: CC1CC(=O)O1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCOCC
Product: CC(CC(=O)O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
86 g (1.00 mole) of β-butyrolactone was added to 146 g (1.00 mole) of 3-chloro-4-fluoroaniline, and this mixture was stirred at 80°-90° C. for 30 minutes and then allowed to cool to room temperature. To the resulting reaction solution was added 1000 ml of ether. This mixture was filtered to remove any insoluble matter, and the filtrate thus obtained was extracted with 750 ml of a 2N aqueous solution of sodium hydroxide. This extract was acidified with 130 ml of concentrated hydrochloric acid and then extracted with 1000 ml of ether. The ether layer was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. Thus, there was obtained 111 g (47.9% yield) of 3-(3-chloro-4-fluoro-anilino) butyric acid in the form of pale-yellow oily matter.
Reaction SMILES: [ClH:1].C([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][O:15]/[N:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:8]1)=[O:6])C.O>C(O)C.[OH-].[Na+]>[ClH:1].[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1/[CH:17]=[N:16]/[O:15][CH2:14][CH2:13][N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[CH2:8]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/N=C/c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1/C=N/OCCN1CCC[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above ester (2.22 g, 6.3 mmol) was dissolved in a mixture of ethanol (65 ml) and 12N sodium hydroxide (4.9 ml) and stirred at ambient temperature for 1 h. Water (20 ml) was added and the mixture extracted with diethyl ether (3×30 ml). The phases were separated and pH in the aqueous phase was adjusted to 5 with 2N hydrochloric acid. The aqueous phase was extracted with dichloromethane (2×40 ml) and the solvent was evaporated from the combined organic phases in vacuo. The residue was dissolved in toluene (25 ml), then methanol (0.17 ml) and chlorotrimethylsilane (0.52 ml) were added and the mixture left for crystallisation. This afforded 0.51 g of the title compound as a solid. M.p. 108.5°-109.9° C.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH:6]([NH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C.[NH3:27]>CO>[NH2:25][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([NH2:27])=[O:4]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCCCC(N)C(=O)OCC
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC(N)C(N)=O
Temperature: 60 °C
Reaction time: 65 h
Yield: 93 %

Procedure:
A slurry of ethy-2-aminoeicosanoate hydrochloride prepared as in Example 28B (74.2 g, 0.189 mol) in anhydrous methanol (500 ml) was saturated with anhydrous ammonia at 0° C. The resulting mixture was sealed in a pressure bottle and heated to 60° C., resulting in a pressure of 40 psi. After 65 h at 60° C., the crystalline mixture was cooled to -20° C. and the solid was filtered to give 57.6 g (93%) of the product as off-white plates: mp 103°-4° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.5 Hz, 3 H), 1.37 (m, 35 H), 1.82 (m, 1 H), 3.67 (m, 1 H), 5.30 (br s, 1 H), 7.09 (br s, 1 H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[N:1]1([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCCC1CC(=O)N(CCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CC(=O)N(CN2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline x158 (400 mg, 3 mmol, 1 eq) in DMF (7 ml) maintained under argon is added NaH (60% in mineral oil; 120 mg, 3 mmol, 1 eq). The reaction mixture is stirred for three hour at room temperature, then a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol, 1 eq) is added. The reaction mixture is stirred for 20 hours at the same temperature. Water (70 ml) is added and the resulting mixture is extracted with ethyl acetate (30 ml). The organic phase is washed twice with water and dried over Na2SO4. After filtration and evaporation, the crude product is purified by two consecutive chromatographies on silicagel (CH2Cl2/MeOH gradient, then CH2Cl2). Pure 1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295 is obtained as syrup (231 mg).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]([N:9]([CH2:13][CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:12])[CH3:11])([CH3:8])[CH3:7].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][CH2:14][CH2:13][N:9]([CH:6]([CH3:8])[CH3:7])[C:10](=[O:12])[CH3:11])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(=O)N(CCCC(=O)c1ccccc1)C(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)N(CCCC(=NNC(N)=S)c1ccccc1)C(C)C
Yield: 100.2 %

Procedure:
Thiosemicarbazide (6.1901 g, 67.9 mmol) was added to a solution of N-isopropyl-N-(4-oxo-4-phenyl-butyl)-acetamide (11.20 g, 45.3 mmol), prepared in the previous step, in 160 ml of methanol plus 12.2 ml of 1 N HCl, plus 12.2 ml of water and the reaction stirred at room temperature for 22 hours (overnight). The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 14.54 g of a yellow foam. The foam was crystallized from ethyl acetate to give 10.28 g (71%) of the title compound as a white solid, mp 141-147° C.
Reaction SMILES: [OH-].[K+].CI.[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].N1C=C[CH:29]=N1>CC(C)=O>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:24])[F:25])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([O:10][CH3:29])=[O:9]
Reactant: c1cn[nH]c1
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Yield: 48 %

Procedure:
A KOH powder (0.1 g, 1.8 mmoles) and methyl iodide (0.26 g, 1.8 mmols) were added to a solution of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid (0.30 g, 0.8 moles) in 20 ml acetone and reacted with this pyrazole derivative under reflux 3 hours. Then the extraction with ethylacetate, washing with water, dehydration, and concentration of the extract solution, and purification of the residue by column chromatography gave the title compound (0.15 g), yield 48%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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.O1CCOCC1>[OH:17][CH2:16][C@:11]([CH3:15])([CH2:10][C@H:9]([NH:18][C:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[CH:3][CH:4]=1)[C:12]([OH:14])=[O:13]
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1ccc(C[C@H](C[C@@](C)(CO)C(=O)O)NC(=O)c2c[nH]nn2)cc1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 2-methylphenylboronic acid (25.1 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (13.3 mg). MS m/z [M+H]+ calc'd for C23H26N4O4, 423.20. found 423.2.
Reaction SMILES: [CH3:1][N:2]([N:15]=[O:16])[C:3]([NH:5][C@@H:6]1[O:14][CH2:13][C@@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[OH:8])=[O:4].C(O[C:21](=[O:23])[CH3:22])(=O)C>N1C=CC=CC=1>[CH3:1][N:2]([N:15]=[O:16])[C:3]([NH:5][C@@H:6]1[O:14][CH2:13][C@@H:11]([O:12][C:21](=[O:23])[CH3:22])[C@H:9]([O:10][C:9](=[O:10])[CH3:11])[C@H:7]1[O:8][C:7](=[O:8])[CH3:6])=[O:4]
Reactant: CN(N=O)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1NC(=O)N(C)N=O
Yield: 87 %

Procedure:
1-methyl-1-nitroso-3-(β-D-xylopyranosyl)urea (110 mg) was dissolved in a mixture of pyridine (1 ml) and acetic anhydride (1 ml) and the resulting mixture was allowed to stand at room temperature for effecting the acetylation. The reaction mixture was then concentrated under a reduced pressure to give a crystalline residue which was then crystallized from ethanol, yielding the titled compound (147 mg). Yield 87.0%. mp. 127°-127.5° C (with decomposition). [α]D20 -25.4° (c 0.7, chloroform).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.[CH2:25]([O:27][CH:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29])[CH3:26].O.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:33]3[CH:32]=[N:31][N:30]([CH:28]([O:27][CH2:25][CH3:26])[CH3:29])[CH:34]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a 250 mL round bottom flask equipped with a stir bar, condenser and 3-way valve was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 30 g, 0.112 mol), 1,4-dioxane (300 mL, 4.0 mol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 35.8 g, 0.134 mol, 1.2 equiv), water (150 mL, 8.3 mol) and potassium carbonate (K2CO3, 61.9 g, 0.448 mol, 4.0 equiv) at room temperature. The resulting mixture was degassed four times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (5.0 g, 0.00433 mol, 0.039 equiv). The reaction mixture was then degassed four times back filling with nitrogen each time before being warmed to 85° C. The reaction mixture was stirred at 85° C. for 2-5 h. When the reaction was deemed complete, the reaction mixture was allowed to cool to room temperature before being diluted with 20% aqueous brine (250 mL) and ethyl acetate (250 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic fractions was washed with water and brine, dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 25% to 40% ethyl acetate/hexane gradient elution) to afford {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18) as a orange oil, which was directly used in the subsequent reaction assuming the theoretical yield. For 18: C19H25N5O3 (MW, 371.43), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[O:1]1[C:2]([C:10]([Cl:16])=[O:12])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2o1
Reaction time: 15 h

Procedure:
A suspension of 2-benzofurancarboxylic acid (0.746 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 15 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of benzo[b]furan-2-carbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1>>[F:7][C:8]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Ic1cccs1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2cccs2)c1

Procedure:
2-Iodothiophene and 3-fluorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-fluorophenyl)thiophene as oil.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:31][C@H:30]1[CH2:42][C@H:43]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:45]([CH2:55][OH:56])[CH2:44]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OCC)(=[O:59])C>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:37])[CH3:36])[CH2:31][C@H:30]1[CH2:42][C@H:43]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:45]([C:55]([OH:59])=[O:56])[CH2:44]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](C[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)C[C@H]1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
Pyridinium dichromate was added to a solution of (2R, 4R)-N-tert-butoxycarbonyl-2-[(2S, 4R)-N-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidin-4-ylmethyl]-4 -(tert-butyldimethylsiloxy)pyrrolidine (3.00 g, 5.84 mmol, compound of Reference Example 2-6) in N,N-dimethylformamide (30 ml) and stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution and washed sequentially with water and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 80 ml, n-hexane-ethyl acetate (1:1)) to obtain (2R, 4R)-N-tert-butoxycarbonyl-2-[(2S, 4R)-N-tert-butoxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-(tert-butyldimethylsiloxy)pyrrolidine (1.77 g, yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(F)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(c2ccc(F)cc2)CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of ethyl 4-(4-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylate (7.1 g, 28 mmol) and KOH (3.2 g, 56 mmol) in 100 mL EtOH/H2O (4:1) was refluxed for 4 hours, M−1=223. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 4.9 g of the product as a white solid. MS (m/z)=223 (M−1)−.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Methyl salicylate (149 g) was dissolved in acetic acid (900 mL), and bromine (50 mL) was added thereto. The mixture was stirred at room temperature for 21 hr. Water (10 L) was added to the reaction mixture, and the precipitated solid was collected by filtration, which was then recrystallized from methanol to give methyl 5-bromosalicylate (175 g) as white crystals.