Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43](=[NH:45])[NH2:44])=[CH:39][CH:38]=2)[C:16]([NH:18][C@@H:19]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:20](=[O:29])[NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:17])[CH:12]=[CH:13][CH:14]=1.Cl.[C:47](=[NH:52])(OCC)[CH3:48].C(N(CC)CC)C.C(#N)C.O>CO.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43](=[NH:44])[NH2:45])=[CH:39][CH:38]=2)[C:16]([NH:18][C@@H:19]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:20](=[O:29])[NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:47](=[NH:52])[CH3:48])[CH2:25][CH2:24]2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)NCC2CCNCC2)C2CCCCC2)c2cccc(Br)c2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=N)N1CCC(CNC(=O)[C@@H](NC(=O)C(Cc2ccc(C(=N)N)cc2)c2cccc(Br)c2)C2CCCCC2)CC1
Yield: 63 %

Procedure:
A solution of 2-(3-bromo-phenyl)-3-(4-carbamimidoyl-phenyl)-N-{(S)-cyclohexyl-[(piperidin-4-ylmethyl)-carbamoyl]-methyl}-propionamide trifluoracetic acid salt (100 mg, 0.13 mmol, less polar diastereomer), ethyl acetimidate hydrochloride (32 mg, 0.26 mmol), and triethylamine (138 μl, 1.04 mmol) in methanol (40 ml) was stirred for 5 days. During the five days the same amount of triethylamine and ethyl acetimidate hydrochloride was added twice. The reaction mixture was evaporated in vacuo and purified by prep. HPLC (HPLC conditions: Purospher(R)Star HP-18e (10 μM), acetonitrile/water+1% TFA, 10% to 100% acetonitrile) to give 70 mg of the desired product (63% yield). MS m/z: 623.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NC(C)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(±)-Cis-N-[1-(4-acetylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (100 mg, 0.24 mmol) in 2.5 ml tetrahydrofuran was added acetyl chloride (44 μL, 0.63 mmol) followed by triethylamine (88 μL ,0.63 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (3:1) to give the title compound (51 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[O:17]CC([O-])=O)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([OH:17])[CH:22]=[CH:23][CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])COc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the acetate from Step 2 (550 mg) in THF (5 mL) and methanol (5 mL) was added milled potassium carbonate (414 mg) and the mixture stirred at room temperature for 2.5 hours. The mixture was poured into pH 7 buffer solution and extracted with ethyl acetate. The organic layer was dried, filtered and filtrate evaporated to afford the title product as yellow-solid: m.p. 197°-199° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Reactant: Cc1cc(-c2ccn(C[C@@H](C)N)n2)ccc1C#N
Product: Cc1cc(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 66.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (13 mg, 0.069 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (17 mg, 0.071 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 19 mg (67%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.48 (s, 3H), 4.31 (m, 2H), 4.47 (m, 1H), 6.82 (d, 1H), 7.31 (s, 1H), 7.75 (m, 4H), 7.81 (d, 1H), 7.85 (s, 1H), 8.40 (d, 1H), 8.63 (m, 2H), 13.92 (br s, 1H).
Reaction SMILES: B(Br)(Br)Br.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)=[CH:15][CH:16]=2)[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:10][C:9]1([CH3:37])[CH3:36])(=[O:7])[CH3:6].O>ClCCl>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[CH:15][CH:16]=2)[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:10][C:9]1([CH3:37])[CH3:36])(=[O:7])[CH3:6]
Reactant: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 4 h

Procedure:
BBr3 (0.69 ml) was added dropwise to a solution of 1-acetyl-6-(2-methoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.64 g) in dichloromethane (40 mL). After stirring for 4 h, TLC indicated complete conversion. Water was added to the reaction mixture and stirring was continued for 15 min. The mixture was washed with 5% aq. NaHCO3 and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].[Se]=[O:16]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](=[O:16])[C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13]
Reactant: O=[Se]
Reactant: CC=CC(=O)C1=C(C)C=CCC1(C)C
Solvent: C1COCCO1
Product: CC=CC(=O)C1=C(C)C=CC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
2.5 g (13 mMole) of 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohexa-1,3-dien [prepared according to the method given in Helv. Chim. Acta 54, 1899 (1971)] dissolved in 50 ml of dioxane were heated, under nitrogen atmosphere, during 45 min. at 60°, in the presence of 1.8 g (16 mMole) of selenium oxide. The reaction mixture was then cooled, concentrated under reduced pressure, and the obtained residue, diluted with 50 ml of acetic acid, was finally stirred at room temperature for 2 hours in the presence of 6 g of Raney nickel. The reaction mixture was then filtered, evaporated to dryness and the obtained residue was distilled (b.p. 100°-110°/o.2 Torr) to afford 2.4 g of a material containing 80 % of the desired keto compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (5.0 g, 20.55 mmol) in methanol (60 mL) and toluene (100 mL) was added a 2M solution of trimethylsilyldiazomethane (20 mL) in hexanes (the addition was accompanied by effervescence and a small exotherm). The resulting pale yellow solution was allowed to stir at ambient temperature for 1 hr. The solvent was removed under reduce pressure to give the title compound as a pale yellow oil (5.28 g 20.55 mmol, 100%); 1H NMR (CDCl3) δ 1.20 (s, 3H), 1.34-1.39 (m, 2H), 1.44 (s, 9H), 2.03-2.07 (m, 2H), 2.96-3.03 (m, 2H), 3.70 (s, 3H), 3.72-3.77 (m, 2H); MS m/e MH+. 257
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1Br.C([O-])([O-])=O.[Cs+].[Cs+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1OCC(Br)=C1Br
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCC(N2CCOCC2)=C1Br
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a stirred solution of 3,4-dibromofuran-2(5H)-one (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) at room temperature under a N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 3-bromo-4-morpholinofuran-2(5H)-one (0.87 g, 85%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)N.N([O-])=O.[Na+].[BrH:16]>[Cu]Br>[Br:16][C:8]1([O:10][CH3:11])[CH:7]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH2:9]1
Reactant: Br
Reactant: COc1cc(N)cc(OC)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: COC1=CC=CC(Br)(OC)C1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
100 mmol of 3,5-dimethoxyaniline were mixed with 75 ml of 48% hydrobromic acid. 150 mmol of sodium nitrite powder were added portionally over 20 minutes with rigorous stirring. The reaction was monitored by iodine-starch test paper until the paper turned blue. The resulting diazonium salt solution was added to a pre-prepared boiling solution of 50 mmol copper (I) bromide in 7 ml of 48% hydrobromic acid. The addition was complete after 20 minutes. The reaction mixture was then heated for 30 minutes with rigorous stirring. Steam distillation of the reaction mixture provided a white solid product with a yield of 40%.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:25]([NH:26][C:27](=[O:47])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42](=[O:45])[NH:43][CH3:44])[CH:37]=4)=[CH:31][C:30]=3[F:46])=[CH:24][C:23]([C:48]([CH3:51])([CH3:50])[CH3:49])=[N:22]2)[CH:16]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].[ClH:52].O1CCOCC1>O1CCOCC1.CCOCC>[ClH:52].[ClH:52].[P:1]([OH:8])([OH:3])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:25]([NH:26][C:27](=[O:47])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42](=[O:45])[NH:43][CH3:44])[CH:37]=4)=[CH:31][C:30]=3[F:46])=[CH:24][C:23]([C:48]([CH3:49])([CH3:51])[CH3:50])=[N:22]2)[CH:16]=1)=[O:2]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c3)c(F)c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COP(=O)(O)O)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a room temperature solution of example 12, di-tert-butyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]amino}-1H-pyrazol-1-yl)benzyl phosphate, (0.45 g, 0.62 mmol) in dioxane (12 mL) was slowly added HCl/dioxane (4M, 4 mL, 16 mmol). A white precipitate formed and the suspension was stirred at room temperature for 3 h. The reaction mixture was diluted with ether (20 mL) and the solids were collected. The resulting solids were washed with ether followed by hexanes to afford 0.40 g (94%) of the desired product as a white powder. MS m/z 612.9 (M+H)+; Retention time (LC-MS): 3.05 min.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(CO)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc(C=O)c2)cc1
Yield: 50.7 %

Procedure:
Manganese dioxide (100 g) was added to the solution of 11 (14.3 g, 0.057 mol) in 250 mL chloroform and the mixture was refluxed for 12 h. The mixture was then filtered and the filtrate was concentrated under vacuum to afford a yellow oil which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 12 as a white solid (7.2 g, 51%). 1H NMR (CDCl3, δ/ppm), 9.97 (s, 1H), 7.81 (m, 2H), 7.63 (m, 1H), 7.34 (d, 2H), 7.16 (m, 1H), 6.40 (t, 1H), 2.42 (s, 3H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=C[C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([Cl:19])=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6].IC.[H-].[Na+].C(OCC)(=O)C.[CH3:33][N:34]([CH:36]=O)[CH3:35]>O>[CH3:33][N:34]([CH3:35])[C:36]1[CH:7]=[C:4]([CH:3]=[CH:2][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([Cl:19])=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2N)c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)c1nn(-c2ccc(C#N)cc2N(C)C)c2nccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
Compound (107a) (0.08 g) and iodomethane (0.16 mL) were dissolved in DMF, and sodium hydride (0.028 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring at room temperature for 1 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-(dimethylamino)-4-(4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzonitrile, which was used in the subsequent reaction without being purified. According to Example 107(2), compound (108) (0.014 g, the third stage yield: 12%) was prepared using 3-(dimethylamino)-4-(4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzonitrile instead of compound (107a).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1I>O1CCOCC1>[Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:31]3[CH:30]=[CH:29][C:28]([N:33]4[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]4=[O:43])=[CH:27][C:26]=3[F:25])=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO[Si](C)(C)C(C)(C)C)C4)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]4,5-dihydroisoxazole (427 mg, 0.94 mmol), N-{[(5S)-3-{3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (355 mg, 0.96 mmol) and 2-trifurylphosphine (22 mg, 0.094 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture placed under an atmosphere of argon. Tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (49 mg, 0.05 mmol) was added and the reaction mixture stirred for 16 hours at 90° C. A second portion of 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazole (427 mg, 0.94 mmol), 2-trifurylphosphine (22 mg, 0.094 mmol) and tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (49 mg, 0.05 mmol) were added and the reaction mixture stirred for another 20 hours at 90° C. Silica gel (2 g) was added and the mixture concentrated in vacuo. Purification by column chromatography (20 g silica gel bond elut: 30% to 100% ethyl acetate/hexanes) yielded 170 mg (33%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:18]2
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: C#Cc1ccccc1
Product: Fc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Yield: 92 %

Procedure:
The general procedure was used to convert 4-Chloro-2-fluoro-6-iodo-phenylamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 92% yield. 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 7.98-7.95 (d, J=7.72, 2H), 7.51-7.46 (t, J=7.53, 2H), 7.44 (s, 1H), 7.40-7.35 (t, J=7.72, 1H), 7.11-7.07 (d, J=10.92, 1H), 6.96 (s, 1H). 13C NMR (75 MHz, DMSO) δ 150.98, 147.70, 141.53, 133.51, 132.04, 129.73, 129.04, 126.54, 124.59, 124.10, 116.44, 108.27, 100.39. Anal. Calcd. for C14H9ClFN: C, 68.44; H, 3.69; Cl, 14.43; F, 7.73; N, 5.70. Found C, 68.26; H, 3.76; Cl, 14.70; F, 7.5; N, 5.72. m.p.: 153-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)ccc1F
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(F)ccc1F

Procedure:
Following General Procedure BI above, and using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-Butyl Ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:17]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated except that 2,6-di-t-butylhydroquinone and docosanoyl chloride were employed to yield the above named product. It has a melting point of 59°-61°C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccs1
Product: CCOC(=O)n1c(C(=O)c2cccs2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-(bromoacetyl)thiophene (Steinkopt, Justus Liebig Ann. Chem., 1923, 430, 103).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16]CC)=[O:15])[O:3]1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23].[OH-].[Li+].Cl>CN(C=O)C.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH:22]([CH3:24])[CH3:23])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1
Reactant: CC(C)I
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2 mmol) in 5 mL DMF was added 60% NaH (400 mg, 10 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, followed by addition of 2-iodopropane (374 mg, 2.2 mmol). The reaction mixture was stirred at 0° C. for 7 h and quenched by ice water. The resulting mixture was extracted with EtOAc (2×15 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in 2 mL MeCN and treated with lithium hydroxide (96 mg, 4 mmol) in 5 mL H2O for 30 min. The reaction mixture was acidified by 1N HCl to pH=5 and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as a white powder (170 mg, Yield 32.2%, two steps). 1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 9.09 (d, J=2.8 Hz, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.44 (d, J=9.2 Hz, 1H), 4.58-4.55 (m, 1H), 3.15-3.00 (m, 1H), 2.24 (s, 3H), 2.08-2.02 (m, 1H), 1.27 (d, J=5.6 Hz, 6H). MS (ESI) m/z=529 [2M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1(I)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:17]([O:16][C:14]([C:11]1([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: IC1CCCC1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2CCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A solution of 5 g ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate in 50 mL THF was added at −75° C. drop wise over 50 min. The yellow solution was stirred at −75° C. for 2 h. A solution of 4.5 g cyclopentyliodide in 20 mL THF was added drop wise over 45 min. The reaction was stirred at −75° C. for 1 h. The reaction was allowed to warm to room temperature over the weekend. The reaction was cooled to 0° C., quenched with 150 mL 10% citric acid solution. The aqueous layer was separated and extracted once with 150 mL ethyl acetate. The organic layers were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude product (yellow viscous oil, 7.75 g) was purified over silica chromatography eluting with a gradient formed from heptane and TBME to yield after evaporation of the product containing fractions 5.54 g (88%) of the title compound as colourless viscous oil. MS ISP (m/e): 326.3 [(M+H)+].