Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][SH:5].[OH-].[K+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CO.C(O)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Reactant: CC(C)=CCC/C(C)=C/CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 54.6 %

Procedure:
To a stirred solution of (E)-3,7-dimethylocta-2,6-dienylmercaptan (1.00 g=5.9 mmol) in methanol (40 ml) was added potassium hydroxide (0.33 g=5.8 mmol) and 1-chloro-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethane (1.62 g=5.9 mmol) in ethanol at room temperature, and then the reaction mixture was refluxed for 90 minutes. After cooling, the methanol was evaporated, and then the residue was diluted with chloroform. The chloroform layer was washed with water, followed by drying over anhydrous sodium sulfate. Concentration followed by column chromatography on silica gel (ethyl acetate:hexane=2:3) gave 1.32 g of Compound 10 as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:19][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])([CH2:10][CH2:9]2)[CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C=C1CCC(O)(c2ccc(Br)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 50 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
To a solution of methyl 2-(4-(4-bromophenyl)-4-hydroxycyclohexylidene)acetate (190 mg, 0.58 mmol) in acetonitrile (7 mL) was added Cs2CO3 (381 mg, 1.17 mmol) and the reaction was let stir in a 50° C. oil bath for 24 h. The resulting reaction mixture was diluted with ethyl acetate and washed with water, followed by a saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 188 mg of crude orange film. The crude material was purified by column chromatography (24 g silica gel, 0-40% EtOAc:Hept, monitor 230 nm) to afford 64 mg (34%) of the title compound as a colorless film that solidified upon standing. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.56-1.81 (m, 4H), 1.85-1.97 (m, 2H), 2.14 (td, J=9.9, 3.9 Hz, 2H), 2.92 (s, 2H), 3.63 (s, 3H), 7.32 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ ppm 170.3, 142.0, 130.9, 127.1, 119.8, 86.0, 83.2, 51.3, 37.6, 35.4 (additional signal likely hidden under DMSO solvent signal). ESI-MS m/z: 327.0 [M+H]+, retention time 1.55 min (condition E).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:21]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[CH2:3][OH:2])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1

Procedure:
To a solution of (R)-2-Dibenzylamino-3-(2-fluoro-phenyl)-propionic acid methyl ester (4.6 g, 12 mmol) in 100 mL of THF at −10° C. is slowly added a 1M solution of lithium aluminum hydride in THF (19 mL, 18 mmol). After 10 minutes the reaction is quenched by slow addition of 1.2 mL of water and 1.2 mL of 1N sodium hydroxide. The mixture is then filtered through a pad of celite and the filtrate is concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1
Reactant: [H][H]
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Agent: [Ni]
Solvent: CO
Product: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Yield: 95.6 %

Procedure:
200 mg (0.46 mmol) of the compound obtained in Example 1 was dissolved in 10 ml of methanol, to which 100 mg of Raney-Ni was added. Reaction was continued for 14 hours at room temperature with 3 atmospheric pressure of hydrogen gas. The reaction solution was filtered to eliminate Ni, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 177 mg (yield: 96%) of the target compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH2:29]=[CH:30]CCCC.CC(CCC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(=CC(=O)CC2)CC3)CC1)C)C.C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CCC(C[C@@H]4CC[C@H]3[C@@H]2CC1)=O)CCCC(C)C.CC(C(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(CCCC2)CC3)CC1)C)C>C(C(C)=O)C>[CH3:29][CH2:30][C@@H:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([OH:19])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH3:8]
Reactant: C=CCCCC
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCC(C)=O
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reaction time: 4 h

Procedure:
Cholesterol (20 g), methyl ethyl ketone (150 ml), and Girdler G65-S-RS catalyst (10.0 g) and 1-hexene (13 g) were heated and rocked at 250° C. for 4 hours. An analysis by gas chromatography indicated conversion to a mixture of 4-cholesten-3-one (78 parts), cholesterol (4 parts), coprostanone (8 parts), and cholestanone (6 parts). Similar results are obtained when sitosterol is used in place of cholesterol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[C:21]([OH:26])(=[O:25])[CH2:22][CH2:23][CH3:24].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.O>[CH2:27]([CH:22]([CH2:23][CH3:24])[C:21]([OH:26])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC(=O)O
Reactant: ClCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Diisopropylamine (3.2 ml) was dissolved in 20 ml of tetrahydrofuran, cooled to 0° C. and treated with 14.2 ml of 1.6M n-butyllithium. After 30 minutes, the lithium diisopropylamide was added to 1 g of n-butyric acid in 75 ml of tetrahydrofuran at -78° C. After 10 minutes the reaction was warmed to -20° C. After 10 more minutes the reaction was warmed slowly to room temperature. The solution was then heated to approximately 35° C. for 30 minutes and then cooled back to room temperature and 1.3 ml of benzyl chloride was added. After 1.5 hours the reaction mixture was heated to 35° C. for 2.5 hours. The solution was then cooled, diluted with 300 ml of water, rinsed with diethyl ether (2×200 ml), and the aqueous phase was acidified with 1 M hydrochloric acid and extracted with diethyl ether (3×200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by radial chromatography (50% ethyl acetate in hexane, 2 mm plate) to yield 1.56 g of 2-benzylbutyric acid (77% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:10]([OH:26])[C:11]([NH:13][O:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[CH:10]([OH:26])[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCC(=O)O

Procedure:
A solution of Example 117A (0.99 g, 2.1 mmol), and 10% Palladium on charcoal (0.21 g) in THF (10 mL) at room temperature was stirred for 4 hours under an atmosphere of hydrogen gas, filtered, and concentrated to provide the desired product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]4[CH2:29][NH:30]C(=O)OC(C)(C)C)[C:20]([F:38])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[NH2:30][CH2:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[C:21]1[C:20]([F:38])=[CH:19][N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[N:22]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCCCC4CNC(=O)OC(C)(C)C)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCCCC4CN)n3)cc2)CC1
Yield: 74.4 %

Procedure:
A solution of tert-butyl (1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-2-yl)methylcarbamate (56 mg, 0.11 mmol) in TFA (3 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (35 mg) MS 428.4 (M+H); UV 213.8, 258.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:30][CH:29]=[CH2:28])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (0.60 gm; 2.2 mmoles), potassium carbonate (0.83 gm; 6.0 mmoles) and allyl bromide (0.73 gm; 6.0 mmoles) in acetone (25 mL) was refluxed for a period of 22 hours. The reaction mixture was cooled, filtered through Celite, and concentrated in vacuo. The residue was chromatographed on silica gel using 15% ethylacetate in hexane as eluent to yield 2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Sc2ccc(NS(C)(=O)=O)cc2)s1
Yield: 96.6 %

Procedure:
A solution of 2-acetamido-5-(4-aminophenylthio)thiazole (3.2 g) in pyridine (64 ml) was added methanesulfonyl chloride (1.52 g) at 5° C. with stirring. The reaction mixture was stirred for 3 hours at 5° C. and concentrated in vacuo to give solid. The solid was subject to column chromatography on silica gel (silica gel, 70-230 mesh; Merck: 200 g) and eluted with a mixture of chloroform and methanol (50:1) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-acetamido-5-(4-methanesulfonylaminophenylthio)thiazole (4.0 g, yield: 96.6%). mp: 236°-239° C.
Reaction SMILES: [OH2:1].O.P([O-])(O)(O)=O.[Na+].OO.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[C:17]([C:21]2[C:25]([F:26])=[C:24]([O:27][CH:28]([F:30])[F:29])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[Na+].Cl>O.C(#N)C>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[C:17]([C:21]2[C:25]([F:26])=[C:24]([O:27][CH:28]([F:29])[F:30])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:13]=1[C:14]([OH:1])=[O:15]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(F)c1OC(F)F
Reactant: O
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: CC#N
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(F)c1OC(F)F
Reaction time: 1 h

Procedure:
First, a solution of 0.85 g (5.5 mmol) of sodium dihydrogen phosphate dihydrate in 10 ml of water and then 2.7 ml of a 30% strength aqueous hydrogen peroxide solution were added dropwise to a solution of 7.4 g (22 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzaldehyde in 200 ml of acetonitrile. A solution of 2.9 g (33 mmol) of sodium chloride in 25 ml of water was then added dropwise to the reaction mixture in the course of 20 minutes. After the solution had been stirred for one hour, the resulting mixture was acidified with dilute hydrochloric acid. Finally, the solid product of value which had formed was filtered off and dried. Yield: 6.3 g.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(OCC)(=O)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CCOC(C)=O
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
A mixture of the above described 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (800 mg, 2.248 mmol) and 1-methylpiperazine (5 ml, 45 mmol) was stirred at 23° C. for 18 h. Diluted with ethyl acetate, washed with sat. sodium hydrogen carbonate-solution, dried the organic layer over sodium sulfate. Filtration and removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with ethyl acetate to ethyl acetate +10% methanol-ammonium hydroxide (10:1) and trituration with diethyl ether to give the title compound as a white foam (320 mg, 34%), MS (ISP) m/e=420.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].N1C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(Nc2ccc3cc(Cl)ccc3n2)cc1
Solvent: c1ccc2ncccc2c1
Product: COC(=O)C(C)Oc1ccc(Nc2ccc3cc(Cl)ccc3n2)cc1

Procedure:
Methyl 2-{4-[N-(6-chloro-2-quinolinyl)amino]-phenoxy}propionate was prepared from 4-[N-(6-chloro-2-quinolinyl)amino]phenol and methyl 2-bromopropionate essentially as described in Example 19, Part b). It was isolated as a sticky brown syrup. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 7.9-6.7 (10H, m, NH, quinoline and phenoxy protons); 4.8 (1H, q, --CHCH3); 3.8 (3H, s, OCH3); 1.6 (3H, t, CH--CH3).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:12][N:11]=[C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:10]3[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[O:12][N:11]=3)[CH2:17]2)[CH:23]=[C:24]([Cl:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)no1
Yield: 96.2 %

Procedure:
Similarly to example 14.2, the 5′-(3,5-Dichloro-phenyl)-5′-trifluoromethyl-4′,5′-dihydro-[3,3′]biisoxazolyl-5-carboxylic acid tert-butyl ester (393 mg) was deprotected with trifluoroacetic acid to give the 5′-(3,5-Dichloro-phenyl)-5′-trifluoromethyl-4′,5′-dihydro-[3,3′]biisoxazolyl-5-carboxylic acid (331 mg) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.65 (bs, 1H) 7.46 (m, 2H), 7.44-7.42 (m, 2H), 4.17 (d, 1H), 3.81 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21]2.Cl.[N:33]([O-])=O.[Na+].O>C(O)(=O)C>[CH2:11]([O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[N:1]=[N:33][C:19]3[C:18]([C:3]=2[CH:4]=1)=[CH:27][CH:26]=[C:25]1[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21][C:20]=31)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=N[O-]
Reactant: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3N)cc2cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc3c4cc(OCc5ccccc5)c(OC)cc4nnc3c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
6-(2-Amino-5-benzyloxy-4-methoxyphenyl)-2,3-dimethoxy-naphthalene 41 (35 mg, 0.084 mmol) was dissolved in acetic acid (0.65 mL) and concentrated hydrochloric acid (0.13 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.052 g in 0.52 mL water). The reaction mixture was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution containing some precipitate was added 50 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried using anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 20:80 hexanes:ethyl acetate to give the pure 42 (24 mg) in 67% yield; mp 244-246° C.; IR (KBr) 2935, 1621, 1507, 1466, 1307, 1269, 1234, 1206, 1168 cm−1; 1H NMR (CDCl3) δ4.07 (3H, s), 4.14 (3H, s), 4.21 (3H, s), 5.40 (2H, s), 7.25 (1H, s), 7.37-7.60 (5H, m), 7.91 (1H, d, J=9.0), 7.97 (1H, s), 8.01 (1H, d, J=9.0), 9.11 (1H, s); 13C NMR δ56.48, 56.86, 56.91, 71.64, 101.69, 104.43, 107.82, 109.58, 116.84, 118.19, 118.81, 126.95, 127.97, 128.34, 128.90, 129.34, 131.51, 136.31, 141.61, 144.52, 151.00, 151.14, 152.31, 152.93; HRMS (EI) calcd for C26H22N2O4 m/z: 426.1580; found: 426.1577.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].Br[CH2:31][CH:32]=[CH2:33]>COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:11]([O:13][CH3:14])=[O:12])([CH2:33][CH:32]=[CH2:31])[C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCC(Cc1ccc(OC)c(OCCc2ccccc2)c1)(C(=O)OC)C(=O)OC
Yield: 94 %

Procedure:
To a solution of the crude methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylpropionate (7.45 g) in 75 ml of 1,2-dimethoxyethane, 0.80 g of 60% sodium hydride (oily) was added little by little at room temperature under stirring. The resultant solution was stirred further at 40° C. for 1.5 hours. To this solution, 2.66 g of 3-bromo-1-propene was added and stirred at room temperature for 1.5 days. The reaction solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to obtain 7.76 g of methyl 3-[4-methoxy-3-(2-phenylethoxy) phenyl]-2-methoxycarbonyl-2-(2-propen-1-yl)propionate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.I[C:22]1C(C)=CC(C)=C(C=1)C(OC)=O.IC1C=C(C=CC=1C)C(OC)=O>>[CH3:22][C:10]1[CH:11]=[C:2]([CH3:1])[C:3]([B:12]2[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]2)=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cc(I)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(I)c1
Product: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.4, except methyl 5-iodo-2,4-dimethylbenzoate (compound 31.1) was used in place of methyl 3-iodo-4-methylbenzoate (compound 5.3). m/z (ES+) 291(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[O:10][C:11](C)(C)[CH3:12].CSCC(OCC)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:11](=[O:10])[CH2:12]2
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OCl
Agent: CCOC(=O)CSC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane, at -60° to -65° C., was added, dropwise, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60° to -65° C., and then was added, dropwise, a solution of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in 25 ml of dichloromethane. Stirring was continued at -60° C. for 1 hour and then was added, dropwise, at -60° to -65° C., a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed, and when the reaction mixture had warmed to room temperature, 100 ml of water was added. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which was added 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed