Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([CH:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)(C)[C@@H]1COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4C(C)(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 0.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-4-tert-butyloxazolidin-2-one (286 mg), the title compound (9 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:39][CH2:38]2)=[O:34])[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]([C:25]2[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:41][CH2:42]3)=[O:34])[CH:28]=[CH:29][CH:30]=2)=[O:24])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C2OCCO2)cc1
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Nc2ccc(C3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4-(1,3-dioxolan-2-yl)phenylamine (0.0826 g, 0.500 mmol) and N,N-diisopropylethylamine (348 μL, 2.00 mmol) in DCM (2.0 mL) at room temperature was added a solution of biphenyl-2-ylcarbamic acid 1-{2-[(3-chlorocarbonylphenyl)methylcarbamoyl]ethyl}piperidin-4-yl ester (0.260 g, 0.500 mmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. LC-MS (Method 10-90) showed product was present (Rt 3.41 min; m/z 649.4 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the title compound (345 mg containing some solvent residue, ca. 100% yield) as a brown oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)=[CH:27][CH:28]=1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Reactant: OB(O)c1ccc(Cl)nc1
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1-c1ccc(Cl)nc1

Procedure:
The product from Example 140A and 2-chloropyridine-5-boronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48-10.92 (bs, 1H), 9.13 (dd, J=7.0, 1.7 Hz, 1H), 8.72 (d, J=1.9 Hz, 1H), 8.65 (dd, J=4.2, 1.7 Hz, 1H), 8.05 (dd, J=8.5, 2.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.32-7.36 (m, 2H), 7.13-7.19 (m, 3H), 3.69 (s, 2H); MS (APCI) m/z 382 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][C:16]([CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:18]
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 2.0 g of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (1.0 g, 4.01 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH:14]=[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1C=C1CCNCC1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A mixture of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (80 mg; 0.15 mmol; 1 eq.) and TFA (1 mL) in DCM (1 mL) was stirred at room temperature for 30 min then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organics were dried over magnesium sulfate and concentrated in vacuo to afford the title compound (40 mg, 62%) as a white solid. 1H NMR (CDCl3) δ 7.41-7.25 (m, 4H), 6.33 (s, 1H), 5.01-5.00 (m, 2H), 4.47-4.45 (m, 2H), 2.90 (s, 2H), 2.85-2.78 (m, 5H), 2.69 (s, 1H), 2.61 (s, 2H), 2.41-2.38 (m, 2H), 2.26-2.23 (m, 2H). HPLC (max plot) 96%, Rt 2.63 min. UPLC/MS: (MS+) 422.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=1>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[N:6]=[C:2]2[CH3:1])[N:23]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=316.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloro-4-methoxypyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CS(C)=O>[F:26][C:25]([F:28])([F:27])[CH2:24][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Yield: 63.3 %

Procedure:
5-Fluoro-2-nitrophenol (3.07 g, 19.5 mmol) was dissolved in 50 mL of DMSO with cesium carbonate (7.62 g, 23.4 mmol) and stirred. 2,2,2-Trifluorethyl trifluoromethanesulfonate (5.00 g, 21.5 mmol) was added with 5 mL of DMSO. The reaction was stirred overnight and quenched with 50 mL of H2O. The mixture was poured into 1:1 diethyl ether/hexanes and H2O. The layers were separated, and the organic layer was washed with 10% K2CO3 (aqueous) (2×), H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 2.95 g (63%) of the title compound of step A. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J=9.0, 6.0 Hz, 1H), 7.45 (dd, J=10.7, 2.5 Hz, 1H), 7.08 (ddd, J=9.0, 7.9, 2.6 Hz, 1H), 4.97 (q, J=8.6 Hz, 2H).
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]([CH3:48])([CH3:47])[CH2:8][C:9]([O:11][C@H:12]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@:17]3([CH3:44])[C@@H:26]2[CH2:25][CH2:24][C@H:23]2[C@@:18]3([CH3:43])[CH2:19][CH2:20][C@@:21]3(/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])[CH2:33][C:32](=[O:34])[C:31]([CH:35]([CH3:37])[CH3:36])=[C:22]32)[C:13]1([CH3:46])[CH3:45])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:40](/[CH:39]=[CH:38]/[C@:21]12[CH2:33][C:32](=[O:34])[C:31]([CH:35]([CH3:37])[CH3:36])=[C:22]1[C@@H:23]1[C@@:18]([CH3:43])([CH2:19][CH2:20]2)[C@@:17]2([CH3:44])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:46])([CH3:45])[C@@H:12]([O:11][C:9](=[O:10])[CH2:8][C:7]([CH3:47])([CH3:48])[C:6]([OH:49])=[O:5])[CH2:29][CH2:28]3)[CH2:25][CH2:24]1)([OH:42])=[O:41]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a solution of (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylic acid (200 mg, 0.294 mmol) in dichloromethane (6 mL) stirred at room temp was added trifluoroacetic acid (TFA) (3 mL). The reaction mixture was stirred at 20° C. for 1 h. The product was extracted with DCM (15 mL*3) and the residue was purified by preparative-HPLC to give the title compound (85 mg, 39%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.05 (d, J=16.1 Hz, 1H), 5.75 (d, J=16.3 Hz, 1H), 4.52 (dd, J=4.8, 11.3 Hz, 1H), 3.32-3.11 (m, 1H), 2.78-2.61 (m, 3H), 2.34-2.12 (m, 3H), 2.06-0.61 (m, 44H); LC/MS: m/z calculated 624.4. Found 625.3 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][CH2:11][C@H:12]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][CH2:11][C@H:12]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:13](=[O:26])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[N:23]([OH:24])[C:36](=[O:38])[CH3:37])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C(=N)NO)cc1
Solvent: CC(=O)O
Product: CC(=O)N(O)C(=N)c1ccc(CNC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
A solution of compound II (14.8 g, 20.0 mmol) and acetic anhydride (5.7 ml, 60.0 mmol) in acetic acid (100 ml) was stirred at room temperature for 45 min, and then solvent was evaporated in vacuo. The resultant residue was dissolved in EtOAc (300 ml) and extracted with water (2×75 ml) and brine (75 ml). The organic layer was then dried over MgSO4, evaporated and dried in vacuo to provide compound JJ (9.58 g, 18.2 mmol) as yellowish solid. LC-MS [M+H] 527.6 (C27H34N4O7+H, calc: 527.9). Compound JJ was used without further purification.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.51 g, 35.6 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (7.60 g, 42.7 mmol) and 2,2′-azobis(isobutyronitrile) (290 mg, 1.78 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(6-fluoropyridin-2-yl)-3-oxopropionate (7.51 g, 35.6 mmol) in 1,2-dimethoxyethane (70 ml) was added sodium hydride (60% in oil, 1.42 g, 35.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (7.74 g, 52%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([CH3:37])[CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[C:32]([CH3:37])[CH:31]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 49%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[CH2:21]([O:20][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C:16]([F:17])([F:18])[F:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOC(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCOC(c1ccc(O)cc1)C(F)(F)F
Reaction time: 8 h
Yield: 98.9 %

Procedure:
1.1 g (3 mmol) of the product (9-1) of Preparation Example 2 was dissolved in a mixture of 80 ml of tetrahydrofuran and 20 ml of methanol, and the solution was added with 0.2 g of 10% Pd/C and stirred vigorously under hydrogen pressure of 1-1.2 atm. for 8 hours. After the reaction, Pd/C was filtered out and the filtrate was concentrated to obtain 0.82 g of (+)-4-(1-hexyloxy-2,2,2-trifluoroethyl)phenol (3-1). Yield: 99%; [α]D20 =+44.0° (c=1, CHCl3).
Reaction SMILES: BrC[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18][C:19]1[CH:24]=[C:23]([NH2:25])[C:22]([CH3:26])=[CH:21][C:20]=1[NH2:27]>O1CCCC1>[NH2:25][C:23]1[C:22]([CH3:26])=[CH:21][C:20]([NH:27][C:8]2[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])=[C:6]([OH:13])[C:5]([C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:4][CH:3]=2)=[C:19]([CH3:18])[CH:24]=1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: Cc1cc(N)c(C)cc1N
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc(C(C)(C)C)c(O)c2C(C)(C)C)c(C)cc1N

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask 2,5-dimethyl-benzene-1,4-diamine (2.17 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. 2,5-dimethyl-para-phenylene diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 4-[(4-Amino-2,5-dimethyl-phenylamino)-2,6di-tert-butyl-phenol is 1.86 g (65%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:1]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2cccc(Cl)n2)cc1
Reaction time: 0.33 h

Procedure:
A stream of phosgene was passed into 120 ml. of dry toluene maintained at a temperature of about 0° to about 5°C. until a weight of 13.4 grams (0.135 mole) had been absorbed. 4-((6-Chloro-2-pyridinyl)oxy)benzenamine (10.0 grams; 0.045 mole) in 100 ml. of dry toluene was then added to the stirred phosgene solution over a period of about 15 minutes while maintaining the reaction temperature within a range of about 2° to about 5°C. Following the completion of the addition, the reaction mixture was stirred for about 20 minutes and the reaction temperature then gradually raised as excess phosgene was purged with a stream of nitrogen. When a reaction temperature of about 85°C. was attained, the reaction mixture became clear. The toluene solvent was then substantially removed under reduced pressure and hexane added to the residue to give the desired 4-((6-chloro-2-pyridinyl)oxy)phenyl isocyanate product as a white crystalline product having a melting point of 96°-97° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (1 equiv) in DMF (0.47 M) was added sodium hydride (3 equiv, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at 0° C. for 15 min, (2-(chloromethoxy)-ethyl)trimethylsilane (1.1 equiv) was added. Then the mixture was stirred at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to afford the title compound (80% yield). MS (ESI) m/z 354.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB(/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)O1.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.O>[C:40]1(/[CH:39]=[CH:38]/[C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(Br)cc2)N1C(=O)OC(C)(C)C
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
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: COC(=O)[C@@H]1CC[C@H](c2ccc(/C=C/c3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407.
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19]([C:23]#[N:24])=[N:20][O:21][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](=[N:20][O:21][CH3:22])[C:23]([NH2:24])=[O:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON=C(C#N)c1ccccc1Oc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 90275.7 %

Procedure:
85% Potassium hydroxide (1.19 g, 0,018 mol) and toluene (30 ml) were added to 2-phenoxy-α-methoxyiminobenzyl cyanide (E/Z=7/93)(3.78 g, 0.015 mmol). The mixture was stirred at 80° C. for 2.5 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with conc. hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (3.66 g, Yield: 90.3%, E/Z=6/94).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1cccc(Cl)c1
Product: ClCCCOc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and 1-bromo-3-chloropropane.