Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].O1CCCC1>C1(C)C=CC=C(C)C=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: Nc1cccc(Cl)n1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1cccc(C)c1
Solvent: C1CCOC1
Product: Nc1cccc(N2CCNCC2)n1
Yield: 5.3 %

Procedure:
To a solution of 6-chloro-2-pyridinylamine (406 mg, 3.16 mmol) and piperazine (381 mg, 4.42 mmol) in m-xylene (10 ml), were added sodium tert-butoxide (425 mg, 4.42 mmol) and bis-(tri-o-tolylphosphine)palladium(II) dichloride (124 mg, 0.158 mmol). The mixture was heated at reflux under N2 for 24 h. The reaction was cooled down and tetrahydrofuran (THF, 10 ml) added, and the mixture was filtered on a celite pad. The filtrate was evaporated and purified via flash chromatography (CH2Cl2/MeOH/NH4OH) affording 30 mg of 2-amino-6-(piperazin-1-yl)pyridine (intermediate “Ia”) as a tan solid (5% yield). H-NMR (CD3OD): 2.95 (m, 4H), 3.47 (m, 4H), 5.93 (m, 1H), 6.01 (m, 1H), 7.24 (m, 1H). M+=179.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][N+:17]([O-])=O)=[CH:11][C:10]=1[F:20].CO>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][C:10]=1[F:20]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
Lithium borohydride (2.16 g, 99 mmol) was suspended in THF (50 ml). Trimethylchlorosilane (21.6 g, 198 mmol) was added dropwise. A solution of 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (5.0 g, 24.8 mmol) in THF (20 ml) was added dropwise. Strong gas evolution and foam formation was observed. The white suspension was stirred at RT for 3 days. Carefully MeOH (80 ml) was added. The solvents were removed in vacuo and the residue was purified by flash column chromatography (CH2Cl2/MeOH+5% aq. NH4OH 4:1) to yield 2-(4-chloro-3-fluoro-phenyl)-ethylamine (3.1 g, 73%) as a white solid. MS (ISP) 174.1 (M+H)+. 1HNMR (DMSO-d6, 300 MHz): δ2.92 (t, J=4.8 Hz, 2H), 3.02 (t, J=6.3 Hz, 2H), 7.15 (dd, J=6.0 and 1.2 Hz, 1H), 7.38 (dd, J=1.2 and 7.8 Hz), 7.53 (t, J=6.3 Hz, 1H), 7.93 (br, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([I:9])=[CH:4][C:3]=1[Cl:10].[OH:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:16]2[CH:17]=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=2)=[C:5]([I:9])[CH:4]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Clc1cc(I)c(I)cc1Cl
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: Oc1cccc(-c2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 1,2-dichloro-4,5-diiodobenzene (1.5 g, 3.76 mmol), 3-hydroxyphenylboronic acid (0.52 g, 3.76 mmol), Na2CO3 (1.99 g, 18.8 mmol) and Pd(PPh3)4 (0.35 g, 0.30 mmol), in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (300 mg, 22% yield). ESI-MS m/z: 362.9 [M−H]−.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:5]1.S(C1C=CC(C)=CC=1)(O[CH2:23][C@@H:24]1[O:26][CH2:25]1)(=O)=O.[Cl-].[NH4+]>O.CN(C)C=O>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:23][C@H:24]3[CH2:25][O:26]3)[CH:13]=2)=[N:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Cn1nc(-c2cccc(O)c2)c2sccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cccc(OC[C@H]3CO3)c2)c2sccc21
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
Add sodium hydride (0.14 g, 0.0059 mol) at 0° C. under nitrogen to a stirred solution of 3-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)phenol (example 3) (1.13 g, 0.0049 mol) and dimethylformamide (50 mL). Stir 15 min. and add (R)-(−)-glycidyl tosylate (1.12 g, 0.0049 mol, Aldrich Chemical Company), and then stir overnight at room temperature. Pour into water (400 mL), add a little ammonium chloride and extract with ethyl acetate. Dry (Na2SO4), filter and evaporate the extract, and purify the residue by flash chromatography (silica gel, elute with dichloromethane and then with 2% methanol in dichloromethane). Concentrate the desired fractions to afford the title compound as a white solid (0.85 g, 60% yield).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br-].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Zn+])=[CH:13][CH:12]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
To a stirred mixture of ethyl 2-chloro-2-oxoacetate (35 g, 256.35 mmol, 1.00 equiv) and Pd(PPh3)2Cl2 (9 g, 12.82 mmol, 0.05 equiv) in tetrahydrofuran (200 mL) maintained under nitrogen at 0° C. was added dropwise a solution of (4-fluorobenzyl)zinc(II) bromide (65 g, 255.47 mmol, 1.00 equiv) in tetrahydrofuran (500 mL). The reaction mixture was refluxed for 12 h then cooled to 0° C. and quenched by dropwise addition of 500 mL of saturated NH4Cl solution. The resulting mixture was extracted with 2×500 mL of ethyl acetate. The combined organic layers was washed with 1×1 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-5% of ethyl acetate in petroleum ether to give 18 g (34%) of ethyl 3-(4-fluorophenyl)-2-oxopropanoate as a yellow oil. 1H-NMR (300 MHz, DMSO): δ 7.36-7.33 (m, 2H), 7.18-7.12 (m, 2H), 4.50 (s, 1H), 4.26 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:14][O:13][C@@H:12]([CH3:25])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:26])=[O:23])[CH2:14][O:13][C@@H:12]([CH3:25])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A solution of (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (4.75 g) in N,N-dimethylformamide (50 ml) were added potassium carbonate (1.76 g) and methyl iodide (1.62 ml) and the mixture was stirred at room temperature for 5 hours. The solution was poured into water and the resulting aqueous solution was extracted with ether. The organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (75 g) with a mixture of n-hexane and ethyl acetate (20:1) as an eluent to give (2R,4R,5S) -4-t-butyldimethylsiloxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (4.17 g) as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.CC(C)=O>O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 94 %

Procedure:
A mixture of sodium azide (9.5 g, 0.14 mol), 3-bromomethyl-3-hydroxymethyloxetane (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1H NMR 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); NMR 44.283, 53,852, 64,073, 76.227.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16].[NH:17]1[CH2:20][CH2:19][C:18]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:15][CH3:16])=[C:2]([N:17]2[CH2:20][CH2:19][C:18]2=[O:21])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1c(Br)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=C1CCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1c(N2CCC2=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 106.6 %

Procedure:
An oven-dried Schlenk tube was charged with the above nitroanisole (500 mg, 1.74 mmol), 2-azetidinone (150 mg, 2.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol) and cesium carbonate (795 mg, 2.44 mmol). The tube was capped with a rubber septum, purged with argon and 1,4-dioxane (7 mL) was then added through the septum via a syringe. The tube was sealed with a teflon screwcap and the reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the crude product was purified by column chromatography (2:1 hexane-EtOAc) to give 1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-azetidin-2-one (516 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][OH:12])[C:9]#[N:10].[C:13](OCC)(=[O:15])[CH3:14]>CCCCCC>[C:13]([O:12][CH2:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]#[N:10])(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: N#CC(CO)c1ccccc1Cl
Solvent: CCCCCC
Product: CC(=O)OCC(C#N)c1ccccc1Cl

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2-chlorophenyl)-3-hydroxypropanenitrile was used in place of 2-2-chloro-5-(difluoromethoxy)phenyl-3-hydroxypropanenitrile. The preparation of 2-(2-chlorophenyl)-3-hydroxypropanenitrile is described in Example 13. The recovered ester product was a colorless oil (70% yield), Rf 0.3 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@H:12](Br)[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]>CN(C)C=O.O>[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([N:1]=[N+:2]=[N-:3])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 72.5 °C
Yield: 100 %

Procedure:
Add sodium azide (157 g, 2.39 mol) to (2R,4S)-4-bromo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (370 g, 1.20 mol) in N,N-dimethylformamide (2.5 L) and heat at 70-75° C. for 16 h under nitrogen. Cool to room temperature, dilute with water (5 L), and extract with ethyl acetate (3 L). Wash with brine (2 L). Extract the brine layer with ethyl acetate (3 L), combine the organic layers, dry over sodium sulfate, filter and concentrate to obtain an oil (324.5 g). Dissolve the material in ether (2 L), wash with water (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain 261.2 g of a dark yellow oil. Back-extract the aqueous layer with ether (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain an additional 7.3 g of product. Overall yield 268.5 g (83%). [α]D20+39.5 (c=1.0 in methanol). 1H NMR (400 MHz, CDCl3) δ 1.40-1.41 (s, 9H), 2.09-2.13 (m, 1H), 2.40-2.44 (m, 1H), 3.37-3.45 (m, 1H), 3.61-3.65 (m, 1H), 3.67-3.69 (s, 3H), 4.09-4.15 (m, 1H), 4.25-4.38 (m, 1H).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCCCCCCCc1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: CCCCCCCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 95 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (0.30 g, 0.26 mmol) and p-n-octylphenylboronic acid (1.0 g, 4.3 mmol) were sequentially added to a stirred solution of 4-nitroiodobenzene (0.87 g, 3.5 mmol) in 1,2-dimethoxyethane (13 mL) and aqueous sodium carbonate (2 M, 13 mL) under dry nitrogen. The stirred mixture was heated under reflux overnight and cooled. Water was added and the product was extracted into ether (30 3 mL) and the combined ethereal extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by chromatography using a short silica gel column (hexane:ethyl acetate—5:1 to 2:1] to provide 4′-nitro-4-n-octyl-biphenyl as a yellow oil, which solidified upon standing (1.04 g, 95% yield). The solid was used without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38].CCN(CC)CC>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38]
Reactant: C=C(c1cc(Cl)c(C)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)C(C)(C)OB4O)=NO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
The mixture of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (62 mg, 0.3 mmol) and NCS (48 mg, 0.36 mmol) in DMF (2 mL) was stirred at rt overnight. To the mixture was added 1,3-dichloro-2-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (75 mg, 0.3 mmol) and Et3N (0.1 mL) and the mixture was stirred at rt for 4 h. It was partitioned between EA and H2O. The organic layer was washed with H2O, brine, dried over Na2SO4, concentrated under vacuum. The residue was purified to give the desired product (30 mg, 21.8% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]([S:34]([CH3:33])(=[O:36])=[O:35])[S:34]([CH3:33])(=[O:36])=[O:35])=[CH:17][CH:16]=2)=[O:20])=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)N(c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1)S(C)(=O)=O

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and methanesulfonyl chloride by using the same method as in Example 107.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=[C:31]=[N:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:37][N:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:12]([C:11]2[CH:10]=[C:9]([C:7]3[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)[CH:17]=[CH:16][CH:15]=2)=[O:14])[CH2:31][CH2:38]1
Reactant: CC(=O)c1ccc(-c2cccc(C(=O)O)c2)o1
Reactant: CCN=C=NCCCN(C)C
Agent: CN1CCCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(-c2cccc(C(=O)N3CCCN(C)CC3)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109 %

Procedure:
To a solution of 3-(5-acetylfuran-2-yl)benzoic acid (1.10 g, 4.78 mmol) and HOBt (1.29 g, 9.56 mmol) in DMF (10 mL) was added EDCI (1.83 g, 9.56 mmol). The reaction was stirred at rt for 10 min and then added 1-methylhomopiperazine (2.38 mL, 19.12 mmol) followed by DIEA (3.35 mL, 19.12 mmol). The reaction mixture was stirred at rt for 1 h and diluted with H2O (50 mL). The mixture was extracted with DCM (3×50 mL), dried over Na2SO4 and concentrated to give brown oil (1.70 g). LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH2:11][C@H:10]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(Cc2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(Cc2ccccc2)C1
Yield: 33.6 %

Procedure:
To a solution of 1.8 g (5.6 mmol) (3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50 ml THF were consecutively added 0.75 g (6.2 mmol) benzoic acid, 1.1 g (6.2 mmol) diethyl azodicarboxylate and 1.6 g (6.2 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 0.80 g (3S,5R)-benzoic acid 1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-yl ester as a light brown oil. The ester was dissolved in a mixture of 50 ml dioxane and 18 ml 1N aqueous sodium hydroxide solution. The reaction mixture was heated at 70° C. for 5 h. After cooling to room temperature the mixture was extracted with tert-butyl methyl ether. The organic extract was washed with a 2N aqueous solution of sodium carbonate. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.10 g (17%) of the title compound as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O.O>[Br:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCBr)no1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.5 g, 24 mmol) in N,N-dimethylformamide (20 mL) was treated with potassium carbonate (6.8 g, 49 mmol) and 1,3-dibromopropane (2.5 mL, 24 mmol) was added and the mixture was stirred at 40° C. for 1 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (0-70% ethyl acetate/hexanes) to give the desired product (1.6 g, 25%). MF=C8H11BrNO4; LCMS calculated for C8H11BrNO4 (M+H)+: m/z=264.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.CC1(C)[C@@]23C4(ON4S(=O)(=[O:34])C2)C[C@@H]1CC3.[Cl-].[NH4+]>C1COCC1.O.C(#N)C>[F:6][C:7]1[C:12]([OH:34])=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:15][C:8]=12
Reactant: CC1(C)[C@H]2CC[C@]13CS(=O)(=O)N1OC13C2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
sec-Butyllithium (27 mL, 38 mmol; 1.4M in cyclohexane) was added dropwise to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17 mmol; Example 1, Step D) in THF (200 mL) at −78° C., and the reaction was stirred for 30 minutes. (1S)-(+)-(10-Camphorsulfonyl)oxaziridine (9.4 g, 41 mmol) in THF (40 mL) was added rapidly, and the reaction was stirred at −78° C. for 30 minutes. A solution of saturated ammonium chloride (50 mL) was added, and the reaction mixture was allowed to reach room temperature. After one hour, the aqueous phase was extracted with AcOEt, dried over MgSO4 and concentrated to a solid, which was triturated in ether. The solid (most of the camphor side product) was filtered off, and the filtrate was concentrated and purified by reverse phase chromatography (Biotage SP4, C-18 40M+, water/ACN 40/60→0/100, 12 CV) to yield 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g, 49% yield) as a paste.