Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:22][CH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2oc(C)nc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc2oc(CBr)nc12
Yield: 20 %

Procedure:
453 mg (2.37 mmol) of methyl 2-methylbenzoxazole-4-carboxylate (prepared by the method in J. Heterocyclic Chem. 27, 335 (1990)) are dissolved in 40 ml of chlorobenzene, 421 mg (2.37 mmol) of NBS and 20 mg of benzoyl peroxide are added, and the resulting mixture is refluxed for 2 hours. It is concentrated, and the residue is taken up in ethyl acetate, extracted by shaking with saturated NaHCO3, 10 % strength Na2SO3 and saturated NaCl solution and dried over Na2SO4. Concentration and chromatography on SiO2 with n-heptane-ethyl acetate (2:1) yields 128 mg of the title compound.
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2OC)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[NH:12]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([B:24]([OH:29])[OH:25])=[CH:16][CH:15]=1)=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
n-Butyl lithium (1.6 M in hexane solution, 5.7 ml, 9.05 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.0 g, 3.62 mmol) in tetrahydrofuran (27 mL) at −78° C. After 30 minutes, triisopropyl borate (1.25 mL, 5.43 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 6 hours. Hydrochloric acid (2.5N, 27 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was re-crystallized from ethyl acetate/heptane to give 4-(anilinocarbonyl)phenylboronic acid (0.354 g, 40%). 1H NMR (DMSO-d6) δ 7.10 (m, 1H), 7.35 (m, 2H), 7.80 (m, 4H), 7.92 (m, 2H), 8.23 (s, 2H), 10.23 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-methoxy-phenyl)benzoic acid (440 mg, 0.9734 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.10 g, 2.0072 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (259 mg, 0.6137 mmol, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:12].C[Si](C)(C)N[Si](C)(C)C.[K].C[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=[O:24]
Reactant: COC(=O)c1cccc(C)n1
Reactant: Cc1ccnc2ccc(Br)cc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Cc2ccnc3ccc(Br)cc23)n1
Temperature: -70 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
Dissolve 6-bromo-4-methyl-quinoline (38.5 g, 153 mmol) in 600 mL dry THF. Cool to −70° C. and treat with the dropwise addition of 0.5 M potassium hexamethyldisilazane (KN(SiMe3)2 (400 mL, 200 mmol) over 2 hours while keeping the temperature below −65° C. Stir the resultant solution at −70° C. for 1 hour and add a solution of 6-methylpyridine-2-carboxylic acid methyl ester (27.2, 180 mmol) in 100 mL dry THF dropwise over 15 minutes. During the addition, the mixture will turn from dark red to pea-green and form a precipitate. Stir the mixture at −70° C. over 2 hours then allow it to warm to ambient temperature with stirring for 5 hours. Cool the mixture then quench with 12 N HCl to pH=1. Raise the pH to 9 with solid potassium carbonate. Decant the solution from the solids and extract twice with 200 mL ethyl acetate. Combine the organic extracts, wash with water and dry over potassium carbonate. Stir the solids in 200 mL water and 200 mL ethyl acetate and treat with additional potassium carbonate. Separate the organic portion and dry with the previous ethyl acetate extracts. Concentrate the solution in vacuo to a dark oil. Pass the oil through a 300 mL silica plug with methylene chloride then ethyl acetate. Combine the appropriate fractions and concentrate in vacuo to yield an amber oil. Rinse the oil down the sides of the flask with methylene chloride then dilute with hexane while swirling the flask to yield 38.5 g (73.8%) of the desired subtitled intermediate as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8](=[O:18])[C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:19][O:20][CH2:21][CH2:22]O>[Zn].C1(C)C=CC=CC=1>[CH3:19][O:20][CH2:21][CH2:22][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:18])=[C:7]([CH3:6])[CH:16]=1
Reactant: COCCO
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: COCCOc1cc(C)c(O)c2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) of 2-methyl-1,4-naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of 2-methoxyethanol and 15 mL of toluene, in an ice bath. After the addition was completed, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, then brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.87 g (76% yield) of the title compound. The resultant product had a melting point of 100-101° C. and an 1HNMR as follows: (300 Hz, DMSO-d6) δ 2.33 (s, 3H), 3.34 (s, 3H), 3.79 (t, 2H, J=4.5 Hz), 4.21 (t, 2H, J=4.5 Hz), 6.78(s, 1H), 7.47 (m, 2H), 8.08 (d, 1H, J=8.0 Hz), 8.14 (d, 1H, J=8.0 Hz), 8.54 (s, 1H). The mass spectrum showed a molecular ion at m/z 232.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:22])[C:20]=1[OH:21])[CH:16]=O>>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:16][C:15]2[CH:18]=[C:19]([CH3:22])[C:20]([OH:21])=[C:13]([CH3:12])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CSc1ccc(C(C)=O)cc1
Product: CSc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4-methylthioacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:8][CH:7]=1.O>C(O)(C(F)(F)F)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16](=[O:19])[NH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(Cc2ccc(F)cc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]cc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 90% HNO3 (57 mL, 1.22 mol) was added slowly to a stirred solution of 5-[(4-fluorophenyl)methyl]-2(1H)-pyridinone (249 g, 1.22 mol) in TFA (750 mL). The solution was heated at 75° C. for 2 h during which time additional 90% HNO3 (25 mL, 0.5 mol) was added. Water (1L) was added slowly and most of the TFA was removed by distillation. The mixture was allowed to cool to rt and the product was isolated by filtration as a yellow solid: 1H NMR (d6-DMSO) δ 12.76 (1H, br), 8.31 (1H, d, J=2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 7.30 (2H, dd, J=8.6, 5.7 Hz), 7.11 (2H, t, J=8.6 Hz), 3.76 (2H, s); ES+ MS: 249 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CO>[C:1]1([C:7]2[N:11]([CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCn1ccnc1-c1ccccc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
A mixture of 144 g of 2-phenylimidazole, 103 g of methyl acrylate and 500 g of methanol was heated and stirred at 60° C. for 20 hours. The solvent was distilled off in vacuo. Purification by column chromatography gave 193 g of methyl 3-(2-phenyl-1H-imidazol-1-yl)propionate (yield 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.C(=O)(O)[O-]>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(CCc1ccccc1)CC2)c1ccncc1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.33 mmol) was dissolved in acetonitrile (1 mL) and (2-Bromo-ethyl)-benzene (62 mg, 0.33 mmol) was added to the reaction mixture. The contents were heated to 80° C. for 2 h. The reaction mixture was cooled to RT after 2 h and diluted with saturated bicarbonate (20 mL). The desired compound was extracted with EtOAc (2×50 mL). The organic layer dried over sodium sulfate and concentrated under vacuum to obtain the crude product which was purified by reverse phase chromatography to obtain 8.7 mg of 8-Methyl-2-phenethyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, TFA salt) δ (ppm): 8.82 (d, 2H), 7.90 (d, 2H), 7.42 (s, 1H), 7.38-7.22 (m, 6H)7.16 (d, 1H), 7.02 (d, 1H), 4.90 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 3.60-3.40 (m, 4H), 3.24 (m, 2H), 2.95 (m, 1H), 2.44 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([CH2:12][CH3:13])[C:10]#[N:11].[CH2:14](N)[CH2:15][NH2:16]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([C:10]1[NH:16][CH2:15][CH2:14][N:11]=1)[CH2:12][CH3:13]
Reactant: CCC(C#N)c1cc(F)ccc1F
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cc(F)ccc1F

Procedure:
rac-2-[1-(2,5-Difluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,5-difluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 225.0 ((M+H)+.).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:9]1[CH2:13][C:12]2=[CH:14][C:15]3[C:16]([O:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH:11]2[C:10]1=[O:24])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:23][O:22][C:16]1[C:15]2[CH2:14][C:12]3[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:25])=[O:2])[C:10](=[O:24])[C:11]=3[O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=Cc3c(OC)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Yield: 72.3 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (0.75 g, 2.17 mmol) and lithium hydroxide monohydrate (0.12 g, 2.82 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (30 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (0.52 g, 72.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH:11]12[O:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2.[Cl-].[NH4+]>C(OCC)C>[F:10][C:4]1[CH:3]=[C:2]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[OH:17])[CH:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1CCCCC1c1cc(F)c(F)c(F)c1
Temperature: -58 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 1-bromo-3,4,5-trifluorobenzene (480 mg, 2.2 mmol) in diethyl ether (4.5 mL) was added drop wise at −76° C. under nitrogen butyl lithium (1.6 M in hexane, 1.31 mL, 2.1 mmol) keeping the temperature below −69° C. After 5 minutes cyclohexene oxide (216 uL, 2.1 mmol) was added dropwise keeping the temperature below −73° C. and then boron trifluoro etheroate (268 uL, 1.0 mmol) keeping the temperature below −66° C. The reaction was stirred for 30 minutes at −58° C. and then for 30 minutes at room temperature. Saturated aqueous ammonium chloride solution was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using heptane/ethyl acetate (7:3 v/v) as eluent to yield the title compound (221 mg, 43%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.83-6.91 (m, 2H), 3.57 (m, 1H), 2.37 (m, 1H), 2.10 (m, 1H), 1.75-1.86 (m, 3H), 1.26-1.56 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][C:6]#[CH:7].I[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][C:6]#[C:7][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCCC(=O)OC
Product: COC(=O)CCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], pent-4-ynoic acid methyl ester (W. D. Wulff, S. J. McCallum, F. A. Kunng, J. Am. Chem. Soc. 1988, 110, 7419-7434) was reacted with 1-iodo-4-trifluoromethoxy-benzene in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as brown oil.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:8]=[C:7]([Br:9])[S:6][C:5]=1[C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1.Cl>[Br:3][C:4]1[CH:8]=[C:7]([Br:9])[S:6][C:5]=1[CH:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=O)c1sc(Br)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1sc(Br)cc1Br
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.14 g, 3.7 mmol) was added portionwise to a solution of ethyl 2-(3,5-dibromothiophen-2-yl)-2-oxoacetate (10a) (0.42 g, 1.24 mmol) in anhydrous tetrahydrofuran (10 mL), previously cooled to −10° C. After 30 minutes stirring, a few drops of 1 M hydrochloric acid were added and the resulting precipitate was filtered. The filtrate was concentrated in vavuo. The residue was dissolved in brine, and extracted with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to provide the desired alcohol (10b) (0.32 g, 0.93 mmol, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(Br)cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(Br)c(N=C=O)cc1OC
Temperature: 90 °C

Procedure:
2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 245 mg), pyridine (1.3 eq, 0.22 ml) were added followed by phosgene (1.33 eq, 1.33 ml of a 20% solution in toluene). The mixture was heated to 90° C. for 4 hours. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (542 mg, quantitative) as a light brown oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:24]=[CH:23][C:22]=1[CH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([O:42][CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:22]2[CH:23]=[CH:24][C:25]([O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29])=[CH:26][C:21]=2[O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:40][CH2:39]1)(=[O:11])[CH2:9][CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCC1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 16 h

Procedure:
4-Dimethylaminopyridine (catalytic amount), triethylamine (68 μl) and propionyl chloride (42 μl) were added to a stirred solution of [4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol in anhydrous dichloromethane (3 ml) at room temperature under argon. After 16 hr, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:19 v/v) to give the title compound as a yellow oil and a mixture of diastereoisomers (114 mg, 92%); δH (CDCl3) −0.04 (6H, s), 0.02 (6H, s), 0.96 (9H, s), 1.00 (9H, s), 1.08-1.18 (3H, m), 1.20-2.10 (9H, m), 2.24-2.40 (2H, m), 2.76-2.92 (1H, m), 3.94 (0.6H, d), 4.18 (0.4H, d), 6.26 (1H, m), 6.40 (1H, dd), 6.94-6.98 (1H, m).
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C:14]2[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])=[CH:8][C:7]=1[Cl:25].C(OC([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:25][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:6]=1[O:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([C:41]2[CH:42]=[N:38][NH:39][CH:40]=2)[C:3]=1[C:29]#[N:30])[C:10]([NH:12][CH2:13][C:14]1[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])=[O:11]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Reactant: CC(C)(C)OC(=O)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4cn[nH]c4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a solution of 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (500 mg, 1.03 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (323 mg, 1.1 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the pure product 3-chloro-4-(2-cyano-3-(1H-pyrazol-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (331 mg, 68%). LRMS (M+H+) m/z: calcd 473.13. found 473. 1H NMR (300 MHz, d6-DMSO): δ 13.33 (s, 1H), 11.48 (s, 1H), 8.53 (t, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=6.9 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[N:8]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNCC1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCCCC1
Reaction time: 48 h

Procedure:
A solution of monochloroacetic acid (9.35 g.) in water (40 ml.) was adjusted to pH 8.0 with a solution of sodium hydroxide (4.0 g.) in water (30 ml.). Piperidine (8.0 ml.) was then added and the mixture was left at room temperature for 2 days and then heated on a steam bath for 2 hr. The solution was then evaporated and the residue was digested with hot ethanol, filtered and the filtrate was evaporated to give piperidinoacetic acid (12.55 g.) as a brown glass.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17](Cl)[N:16]=1>C1COCC1.O>[Cl:21][C:19]1[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=[CH:7][N:6]=2)[CH:18]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccnc(Nc2cc(Cl)cc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(trifluoromethyl)pyridin-2-amine (3.24 g, 20.0 mmol) and sodium hydride (1.2 g, 30 mmol) in THF (60 mL) was stirred at 0° C. under nitrogen for 1 hour, and then 2,4,6-trichloropyridine (3.62 g, 20.0 mmol) was added. The reaction was stirred at 25° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give 4,6-dichloro-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine. MS ESI calc'd. for C11H7Cl2F3N3 [M+H]+ 308. found 308. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H).