Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-(1,1-dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH--H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with IM HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 94 %

Procedure:
4-Bromo-benzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.66 g, 20.3 mmol, 94%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1

Procedure:
1.0 g (4.63 mmol) of 4-nitrobenzyl bromide (Fluka, Buchs, Switzerland), 799 mg (11.6 mmol) of 1,2,4-triazole and 0.692 mL (4.63 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene (Fluka, Buchs, Switzerland) in 10 ml of CH2Cl2 are stirred at rt for 1.5 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography (CH2Cl2-MeOH 49:1 to 19:1) to provide the title compound as a pale yellow solid. ES-MS: 205 (M+H)+; analytical HPLC: tret=2.54 minutes (Grad 1).
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c2c1OCCO2
Temperature: 40 °C
Yield: 62 %

Procedure:
29.3 g of 8-amino-1,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and then cooled to 5° C. and a solution of 10.5 g of sodium nitrate in 20 ml of water was added in portions with the temperature being maintained at from 5°-10° C. The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (d=1.18) with the temperature being maintained below 30° C. The precipitate was dried off, washed in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid. The precipitate was dried off, washed with water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 195° C.; yield 62%).
Reaction SMILES: [Na].[CH3:2][CH:3]([OH:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:5][CH:3]([CH3:4])[CH3:2])[N:8]=1
Reactant: CC(C)O
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Product: CC(C)Oc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
Sodium pieces (200 mg) was added portion wise to 2-propanol (0.521 g, 6.35 mmol) and the reaction was stirred for 12 h at RT. To the above thick solution, 2,6-dibromo pyridine (1 g, 4.23 mmol, Aldrich) was added and the reaction was heated to 90° C. for 2 h. The mixture was cooled to RT and the solvent was removed. The crude residue was treated with ice water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (Eluent: 0.5% EtOAc in petroleum ether) to give 2-bromo-6-isopropoxypyridine (600 mg, 66.5%) as a colorless liquid. MS (ESI, pos. ion) m/z: 216.0 (M+1); 1H-NMR (400 MHz, CDCl3): δ 7.38-7.34 (m, 1H), 6.99 (dd, J=7.2 Hz, J=4 Hz 1H), 6.60 (dd, J=8.0 Hz, J=4 Hz 1H). 5.28-5.25 (m, 1H), 1.32 (d, J=4.4 Hz, 6H). A solution of 2-bromo-6-isopropoxypyridine (1 g, 4.67 mmol) in dry THF (10 mL) was treated with n-BuLi (1.6M in hexane) (3.2 mL, 5.14 mmol) dropwise at −78° C. and the reaction was stirred at the same temperature for 30 min. Tributyl tin chloride (1.8 mL, 5.60 mmol, Aldrich) was added to the reaction at −78° C. and the reaction was stirred at the same temperature for 30 min. The mixture was treated with saturated NH4Cl solution (10 mL) and extracted with EtOAc (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified with silica gel column chromatography using (eluent: 100% petroleum ether) to give 2-isopropoxy-6-(tributylstannyl)pyridine (1 g, 50%) as a colorless liquid. 1H-NMR (300 MHz, CDCl3): δ 7.40-7.35 (m, 1H), 6.99 (dd, J=5.4, 4.5 Hz, 1H), 6.65 (dd, J=7.2, 0.6 Hz, 1H). 5.32-5.24 (m, 1H), 1.34-1.32 (m, 10H), 1.31-1.25 (m, 13H), 0.87-0.84 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:45]=[CH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(N(CC)CC)C>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[CH:45]=[CH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:16]
Reactant: C=Cc1ccccc1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCC1(CCO)OCCc2c1[nH]c1c(C=Cc3ccccc3)cc(C(C)C)cc21
Temperature: 90 °C

Procedure:
The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(debenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90° C. (oil bath) overnight. It is quenched with water and extracted with ethyl acetate. Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title-compound.
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].O.[CH3:17]O>>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH3:17])=[O:14]
Reactant: O=C(O)c1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1O
Yield: 98 %

Procedure:
H2SO4 (4.0 mL, 74.63 mmol) was added to a solution of salicylic acid (5.0 g, 36.20 mmol) in MeOH (60 mL). The reaction mixture was refluxed for 20 h, allowed to reach r.t., poured into H2O (100 mL) and extracted with CH2Cl2 (120 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 5.44 g of methyl 2-hydroxybenzoate (colourless oil, yield: 98%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH:5]=[CH2:6])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:19])[S-:18])=[N:14][CH:15]=1.C([NH+](CC)CC)C>C(#N)C.C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:18])[S:19][CH2:6][CH2:5][C:4](=[O:7])[C:2]([CH3:8])([CH3:3])[CH3:1])=[N:14][CH:15]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC(=O)C(C)(C)C
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A solution of 2,2-dimethylpent-4-en-3-one (30.0 g) in anhydrous acetonitrile (60 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (82.0 g) in anhydrous acetonitrile (400 cc). The reaction is allowed to proceed for 3 hours at between 5° and 20° C. The crystals which appear are filtered off; the filtrate is evaporated under reduced pressure (20 mmHg) at 45° C. The residue obtained and the crystals separated off beforehand are dissolved in methylene chloride (750 cc). The organic solution is washed four times with distilled water (total 600 cc), dried over sodium sulphate and evaporated. The product obtained (98.0 g) is dissolved in chloroform (400 cc). The solution is chromatographed on a column of diameter 6.8 cm, containing silica (0.063-0.2 mm; 800 g). Elution is carried out with chloroform (2.6 liters), this eluate being discarded, and then with chloroform (7.2 liters), this eluate being collected and evaporated to dryness. The product obtained (85.0 g) is purified by recrystallisation from acetonitrile (350 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (70.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 111° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[CH:7][C:6]=1[F:13].[C:14](=[O:17])(O)[O-:15].[Na+]>O.S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:14]([OH:15])=[O:17])=[CH:7][C:6]=1[F:13]
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(OCCBr)c(F)c1
Yield: 65 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and concentrated sulfuric acid (18 mL) was heated at 110° C. for 12 hours. The solution was then cooled to room temperature and neutralized with solid sodium bicarbonate. Acidification with glacial acetic acid leads to a white solid precipitate, which was collected by filtration and dissolved in dichloromethane. The resulting solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product as a beige-colored solid (2.65 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.69 (d, J=12.0 Hz, 1H), 7.29 (dd, J=8.8 Hz, 8.4 Hz, 1H), 4.48 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.2 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)Oc1ccccc1C(=O)O
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2OS(C)(=O)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methanesulfonyloxybenzoic acid (0.30 g, 1.4 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (10 mL) was heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.49 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.47 mmol) and triethylarmine (98 μL, 0.72 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (55%) of the title compound as white crystals: mp 144-145° C.; [α]21D −7.1° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (10, M+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Ag+:13].N>CO.O>[Ag:13].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: Oc1ccc(Br)cn1
Solvent: O
Solvent: CO
Product: [Ag]

Procedure:
5-Bromo-2-hydroxypyridine (1.795 g) was dissolved in methanol (60 mL), a solution of silver nitrate (1.752 g) in water (40 mL) was added and the mixture was stirred. Aqueous ammonia was added, and the precipitate was collected by filtration to give 5-bromo-2-hydroxypyridine silver salt (2.68 g). The salt (2.37 g) and 2-{[4-(chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.364 g) obtained in Example 1 were dissolved in ethanol (50 mL), and the mixture was stirred for 46 hr with heating under reflux. The reaction mixture was filtered through celite and the solvent was evaporated. The residue was dissolved again in ethyl acetate (100 mL), and the mixture was washed successively with 0.5 mol/L aqueous hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate=9/1-6/4) to give the title compound (247 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:19])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([F:15])[C:8]([F:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
To 36.0 g (0.15 mole) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid were added 45 ml of toluene, 15 ml of thionyl chloride and 0.2 ml of N,N-dimethylformamide, and the mixture was refluxed by heating for 4 hours. After the reaction, toluene and excess thionyl chloride were removed under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 54 ml of ethyl acetate and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 25°-30° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvent was distilled off. Toluene (100 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 66.0 g of the title compound were obtained as a brown oil (yield: 95.2%, GLC purity: 95.1%, α-tocopheryl acetate content: 2.0, ethyl acethyl acetate recovery rate: 50%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:15]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of resorcinol (10 g, 90.8 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (12.6 g, 90.8 mmol) and benzyl bromide (10.8 mL, 90.8 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 3-benzyloxy-phenol (6.0 g, 33%) was obtained as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.CC(C)([O-])C.[K+].O>CN1C(=O)N(C)CCC1>[CH3:16][C:12]1[CH:11]=[C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 10.7 %

Procedure:
To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100° C. with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3×150 mL). The combined extracts were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (50% EtOAc/50% hexane) to afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H)+). A14c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
Reaction SMILES: C(OC(=O)C)(=O)C.C(O)(=O)C.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>CO>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:31]3[C:27](=[CH:26][C:25]([N:24]([CH3:34])[CH3:23])=[CH:33][CH:32]=3)[C:28](=[O:29])[O:19]2)=[CH:16][CH:15]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Temperature: 55 °C
Yield: 76.6 %

Procedure:
A stirred mixture of 306.0 g of acetic anhydride, 200.0 ml of glacial acetic acid, 298.0 g p-dimethylaminobenzaldehyde and 386.0 g of m-dimethylaminobenzoic acid was heated at reflux for a period of approximately four hours. The resulting mixture was cooled to 55° C., diluted with 700 ml of methanol and heated at reflux for approximately thirty minutes. The mixture was then cooled to approximately 15° C. and the solid which separated was collected by filtration and washed with 700.0 ml of fresh methanol chilled to 10°-15° C. The methanolwet solid was reslurried in 400 ml of fresh methanol at 10°-15° C. for approximately twenty minutes, separated by filtration and washed with 150 ml of chilled methanol. The solid was dried at 70° C. in vacuo to yield 453.2 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=4-(CH3)2N-C6H4 which after recrystallization from toluene was obtained as an ivory-colored solid melting at 184.5°-185.5° C.
Reaction SMILES: [F:1][C:2](=[C:5]([F:7])[F:6])[CH2:3]Br.[P:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>>[F:6][C:5]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[C:2]([F:1])=[CH2:3].[F:1][C:2](=[C:5]([F:7])[F:6])[CH2:3][P:8](=[O:9])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)=C(F)CBr
Product: C=C(F)C(F)(F)P(=O)(OCC)OCC
Product: CCOP(=O)(CC(F)=C(F)F)OCC
Yield: 14 %
Yield: 11 %

Procedure:
A solution of 2,3,3-trifluoro-2-propenyl bromide (5.25 g, 30 mmol) and triethyl phosphite (4.15 g, 25 mmol) in acetonltrile (15 mL) was heated at reflux for overnight. The residue obtained after evaporation of the solvent was chromatographed over silica gel (hexanes/ethyl acetate/ethanol, 80/20/1) to give diethyl (1,1,2-trifluro-2-propenyl)phosphonate (0.8 g, 11%) and diethyl (2,3,3-trifluro-2-propenyl)phosphonate (1.0 g, 14%).