Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[C:11]#[CH:12])=[CH:6][CH:5]=1.C([Mg]Cl)#C.C(C1C=CC(C=O)=CC=1)(O)=O.Br[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:41]/[C:42]1[NH:43][CH:44]=[CH:45][C:46]=1[O:47][CH3:48])/[C:34](=[O:40])[NH:35]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[C:11]#[C:12][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2/[C:33](=[CH:41]/[C:42]2[NH:43][CH:44]=[CH:45][C:46]=2[O:47][CH3:48])/[C:34](=[O:40])[NH:35]3)=[CH:6][CH:5]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1

Procedure:
Using Method D above, 4-(1-hydroxy-2-propynyl)-benzoic acid methyl ester (137 mg, 0.72 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-carboxybenzaldehyde (Aldrich) using Method B above to give the acid which was converted to its methyl ester by Method E above), was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (221 mg, 0.69 mmol) using (Ph3P)2PdCl2 (37 mg) (Aldrich) and CuI (18 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]benzoic acid methyl ester. (Yield 52 mg, 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:33])([CH3:34])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-4-nitro-benzamide was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-4-nitro-benzamide and 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. The product was isolated as an orange-yellow solid. 88% HPLC purity, LCMS 510.21, MP 247-248, 1H-NMR (CDCl3, 400 MHz) δ: 11.19 (s, 1H), 9.57 (s, 1H), 8.20 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.37 (s, 1H), 7.06 (s, 1H), 6.97 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.30 (m, 1H), 3.10 (d, J=4.8 Hz, 3H), 2.41 (t, J=6.8 Hz, 2H), 2.10 (t, J=7.1 Hz, 2H), 1.40 (s, 6H).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5]CC)=[O:4].[CH:11]1([C:16](=[S:18])[NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:16]2[S:18][C:8]([CH3:10])=[C:2]([C:3]([OH:5])=[O:4])[N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=S)C1CCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Product: Cc1sc(C2CCCC2)nc1C(=O)O

Procedure:
Ethyl 2-chloroacetoacetate and 1-cyclopentane carbothioamide were treated as the starting materials by the same method as in Production Example 203, to give 2-cyclopentyl-5-methyl-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22]([CH3:25])(=[O:24])=[O:23])[NH:11][C:10]=2[CH:9]=1.[OH-].[K+]>C(C(C)=O)C>[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22]([CH3:25])(=[O:24])=[O:23])[N:11]([CH2:2][CH2:3][CH2:4][Cl:5])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Yield: 75.5 %

Procedure:
2-Methoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (m.p. 122°-124°C.; 15.0 g.) is prepared by reacting 1-bromo-3-chloropropane (30.4 g.) with 2-methoxy-6-methylsulphonylphenothiazine (15.9 g.) in the presence of 85% pure ground potassium hydroxide (5.6 g.) dissolved in methyl ethyl ketone (75 cc.).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1.O.O.Cl[Sn]Cl.CCO.[OH-].[K+]>O>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)co1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(N)cc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-methyl-4-(4-nitrophenyl)oxazole (J. Heteocyclic Chemistry, 1981, 885)(1.12 g, 5.48 mmol) was added to a refluxing solution of SnCl2.2H2O (6.33 g, 28.1 mmol), conc HCL (10 mL) and EtOH (20 mL). The reaction is stirred for 30 min then cooled to room temperature and poured into a solution of 24 g of KOH in 100 mL of water. The resulting mixture was cooled in an ice bath and stirred for an additional 30 min. The product was collected by filtration as a yellow solid (1.35 g, 83%). LC-MS (M+H): 191
Reaction SMILES: Br[C:2]1[C:3]([OH:15])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:8]=[CH:7]2.[N:16]([O-:18])=[O:17].[Na+].O>O1CCCC1.C(O)(=O)C>[OH:14][C@H:12]([CH3:13])[CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([OH:15])[C:2]=2[N+:16]([O-:18])=[O:17])[CH:7]=[N:8]1
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(Br)c21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)Cn1ncc2ccc(O)c([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of the product from Step A (6.99 g, 24.8 mmol) in a mixture of tetrahydrofuran (20 mL) and acetic acid (20 mL) was cooled in an ice bath. Sodium nitrite (5.13 g, 74.4 mol) was added and the mixture was stirred for one hour, warmed to room temperature and stirring continued for one hour. Water (200 mL) was added to the reaction mixture, which was extracted with ethyl acetate (200 mL). The organic layer was washed with aqueous saturated sodium bicarbonate (100 mL, to pH 7), dried (magnesium sulfate), filtered and saturated sodium bicarbonate (100 mL, to pH 7), dried (magnesium sulfate), filtered and evaporated to an oil (4.75 g). Purification by chromatography gave a bright yellow solid (2.96 g, 50%): mp 70–74° C.; LC/MS m/z 238.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21](=[O:23])=[O:22]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:21]([OH:23])=[O:22]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) in THF (120 mL) was added LiHMDS (2.0 M solution, 21 mL, 42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixture was added to a solution of CO2 in THF (1 L). The dry-ice bath was removed and the reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous HCl (835 mL), concentrated, and washed with ether (250 mL). The combined organics were washed with 5% aqueous NaOH (300 mL) and water (100 mL). The aqueous layer was acidified (pH 0) with concentrated HCl. The resulting suspension was extracted with ether (2×300 mL), dried over MgSO4, filtered, concentrated under reduced pressure to afford 7.70 g (72% yield) of the desired product (2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.FC(F)(F)C(O)=O.[NH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C1COCC1>[CH3:23][C:18]([NH:17][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])([CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)NC(=O)c1cnccn1
Temperature: 22 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (0.202 g, 1.6 mmol) in THF (6 mL) at 0° C. were added methyl 2-amino-2-methylpropanoate trifluoroacetate (0.25 g, 1.6 mmol), HOBt (0.22 g, 1.6 mmol), DIEA (0.21 g, 1.6 mmol) and EDCI (0.343 g, 1.8 mmol). The reaction mixture was allowed to stir at 22° C. After 12 h, the reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (0.36 g, 99%). LC/MS: Rt=1.24 min, ES+224 (Formic Acid method).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[Na+].[Na+].[CH:10]12[CH2:17][CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[C:18](Cl)=[O:19]>>[CH:10]12[CH2:17][CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[C:18]([CH:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])=[O:19]
Reactant: O=C(Cl)C1CC2C=CC1CC2
Reactant: O=C([O-])CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)C(C(=O)O)C(=O)C1CC2C=CC1CC2
Yield: 88 %

Procedure:
To a solution containing sodium malonate (17.1 g) which was prepared according to the same procedure as in Example 7, bicyclo[2,2,2]oct-5-ene-2-carbonyl chloride (17.1 g) obtained in Preparation Example 2 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 60° C. for 9 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 21 g of the pure title compound (purity: 99%, yield: 88%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:28])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.B(OC(C)C)(OC(C)C)[O:30]C(C)C.[Cl-].[NH4+]>CCCCCC.O1CCCC1.CCOCC>[F:28][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=[C:7]([OH:30])[CH:8]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
15 ml (24.00 mmol) of 1.6 molar n-butyllithium solution in hexane are added dropwise to a solution, cooled to -70° C., of 7.61 g (20.00 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine in 400 ml of tetrahydrofuran, and the mixture is stirred at -70° C. for 15 minutes. 7.5 g (40.00 mmol) of triisopropyl borate are subsequently added dropwise, the mixture is stirred at -70° C. for 1.5 hours and warmed to room temperature, 500 ml of ammonium chloride solution and 500 ml of ether are added, and the organic phase is separated off and washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The resultant 3-fluoro-2-(4-octyloxyphenyl)pyridine-5-boronic acid is refluxed for 2 hours in 100 ml of tetrahydrofuran with 30 ml of 17.5% strength by weight aqueous hydrogen peroxide solution and subsequently cooled to 0° C., and 200 ml of aqueous sodium sulfite solution are added dropwise. The organic phase is separated off, washed twice with aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Recrystallization from 1,2-dichloroethane gives 5.08 g of 3-fluoro-5-hydroxy-2-(4-octyloxyphenyl)pyridine. ##STR17##
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([OH:7])=O.C(Cl)CCl.[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:13][N:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)=[O:7]
Reactant: Nc1ccc2cnccc2c1
Reactant: CN(C)CC(C(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN(C)CC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% MeOH/CH2Cl2) gave pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide. The pure compound was taken up in CH2Cl2 and HCl was added. The solvents were evaporated to give pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44).
Reaction SMILES: Cl.[OH:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]2[CH2:12][CH2:11][O:10][C:9](=[O:13])[C:8]=12.I[CH3:21].S([O-])([O-])(=O)=O.[Ca+2]>[Ag]=O>[CH3:21][O:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:7]2[CH2:12][CH2:11][O:10][C:9](=[O:13])[C:8]=12
Reactant: CI
Reactant: O=C1OCCc2cc(-c3ccccc3)nc(O)c21
Agent: O=[Ag]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Product: COc1nc(-c2ccccc2)cc2c1C(=O)OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
8-hydroxy-6-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on HCl salt (300 mg, 1.080 mmol), iodo methane (3.68 g, 25.92 mmol), silver oxide (936 mg, 4.04 mmol) and calcium sulfate (239.7 mg, 1.76 mmol) were dissolved in 20 mL of anhydrous and then stirred overnight at room temperature. The mixture was evaporated under reduced pressure. A silica gel column chromatography (30% EtOAc/Hexane) was performed on the resulting residue and 193 mg (70%) of 8-methoxy-6-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[N:3][C:2]1=[S:6].[H-].[Na+].[N:9]12[CH2:12][CH:11]1[CH2:10]2>O1CCCC1>[NH:9]1[CH2:12][CH:11]([S:6][CH:2]2[NH:3][CH2:4][CH2:5][S:1]2)[CH2:10]1
Reactant: C1C2CN12
Reactant: S=C1N=CCS1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1CSC(SC2CNC2)N1
Reaction time: 1 h

Procedure:
To a 5 ml solution of dried tetrahydrofuran containing 550 mg (4.61 mmol) of 1,3-thiazoline-2-thione which was being cooled with ice, on the other hand, there was added 181 mg (55%) of sodium hydride, and the resulting mixture was stirred for one hour. To the obtained solution, there was added dropwise the above solution of 1-azabicyclo[1.1.0]butane dissolved in tetrahydrofuran at -78° C., and the resulting solution was stirred at a room temperature for 20 hours, and, then, the reaction liquid was subjected to high performance liquid chromatography, and, thus, there was obtained 2-(azetidin-3-ylthio)-1,3-thiazolidine (9).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([OH:36])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[CH2:14]([O:36][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]
Reactant: COCCOCCOCCOCCOCCOCCOCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
6.7 g (60 mmol) of TEA are dropwise added, in 10 min, to a solution of 13.3 g (60 mmol) of 4-nitrobenzenesulfonyl chloride (marketed product) and of 20.4 g (60 mmol) of 3,6,9,12,15,18,21-heptaoxadocosan-1-ol (according to Liebigs Ann. Chem. 1980, 858-862) in 60 mL of AcOEt. After 2 h at the temperature of 20° C., the precipitated TEA hydrochloride is filtered off, washing with 10 mL of AcOEt for three times. The filtrates are collected, washed with 30 mL of H2O, 20 mL of 2N HCl and then with H2O to reach a neutral pH. The organic phase is evaporated to dryness, to give a thick oil which is directly used in the successive step without a further purification. 25 g (47 mmol) of the desired product are obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[CH:19][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[N:35][O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])=[CH:19][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=O)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=NOCc2ccccc2)cc1
Yield: 82.6 %

Procedure:
5.3 g (0.016 mol) of methyl 2-(4-acetylphenoxymethyl)phenylglyoxylate O-methyloxime and 3.0 g (0.019 mol) of benzyloxyamine hydrochloride in 60 ml of methanol are stirred at room temperature for 24 hours. The mixture is then hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.9 g (83%) of the title compound are obtained in the form of colorless crystals (melting point 104°-106° C., compound no. 590).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15]>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
We have studied the method of the U.S. Pat. No. 2,439,237 to determine whether or not it can be applied to 3,4,5,6-tetrafluorophthalic acid which is the starting material for the present invention. As indicated in a comparative experiment (control), 3,4,5,6-tetrafluorophthalic acid was simply heated in an alkaline aqueous solution in accordance with the method of the U.S. Patent for the purpose of decarbonating the acid. The reaction which ensued mainly gave rise to trifluorophenol having fluorine atoms substituted by hydroxyl groups and failed to produce 2,3,4,5-tetrafluorobenzoic acid selectively. It may be safely concluded that the fluorine atom at the para position of a benzene ring posessing such an electron-attracting group as the --COOH group is more susceptible to the nucleophilic substitution reaction than the chlorine atom at the same position. By the method of the U.S. Pat. No. 2,439,237, therefore, the alkaline substance is believed to form a phenol by substitution of the fluorine atom. It is, accordingly, proper to conclude that the method, when applied to 3,4,5,6-tetrafluorophthalic acid, is liable to induce secondary reactions and is not useful for the decarboxylation aimed at by the present invention. Methods for the decarboxylation of 3,4,5,6-tetrafluorophthalic acid are described in G. G. Yacobson et al, Journal of General Chemistry, 36, No. 1,144 (1966) and British Pat. No. 2,122,190. The former method causes this acid to react in dimethylformamide as a solvent at a temperature of 145° C. This method, however, dose not deserve commercialization because it produce 2,3,4,5-tetrafluorobenzoic acid in low a yield of 44.0 mol %. The latter method causes the acid to react in an organic solvent, and that at a temperature of 200° C. It does not produce any 2,3,4,5-tetrafluorobenzoic acid but barely gives rise to 1,2,3,4,-tetrafluorobenzene in a yield of 0.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:13]=1.[OH-].[Li+]>CO.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:13]=1
Reactant: COC(=O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Reaction time: 24 h
Yield: 90 %

Procedure:
To a stirred solution of (E)-methyl 3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylate (6.3 g, 20 mmol) in MeOH (100 mL) and H2O (20 mL) was added lithium hydroxide (1.5 g, 61 mmol). The resulting mixture was stirred for 24 hours and then partially concentrated under reduced pressure. The pH of the residual aqueous mixture was adjusted to 5 by addition of 2N HCl and extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 0-20% gradient of MeOH in DCM to give the desired product as a white solid (5.4 g, 94% yield). LCMS (ESI) m/z: 300.0 [M+H+].
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][C:12](=O)[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[BH4-].[Na+]>O1CCOCC1>[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCNCC2

Procedure:
A solution of glacial acetic acid (1.8 g) in dioxan (10 ml) is added to a suspension of 7,8-dimethoxy-1,3,4,5-tetrahydro-2-H-3-benzazepin-2-one (1.3 g, 6 mmol) and sodium borohydride (1.1 g, 3 mmol) in dioxan (20 ml). The resulting mixture is refluxed for 3 hours, evaporated and mixed with water. The mixture is extracted twice with methylene chloride, the extract is concentrated by evaporation and the residue is taken up in ether. After filtering, the ether is eliminated in vacuo. Yield: 1.1 g. Mp: 86°-89° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9].[CH:26](OB(O)O)=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([C:11]1[N:10]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[N:6][C:7]([CH2:8][OH:9])=[C:2]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=[C:4]2[N:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Reactant: OB(O)OC=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCc1nc2cc(C=Cc3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
5.08 g(0.0127 mole) of the compound obtained in step 7 of Example 1 was dissolved in 12 ml of dimethylformamide(DMF) and to the resulting solution were added 5.64 g(0.0381 mole) of styrylboric acid, 0.29 g(0.00127 mole) of palladium acetate, 0.67 g(0.00254 mole) of triphenylphosphine and 13 ml(0.0889 mole) of triethylamine. The resultant was stirred for 1 hour at 120° C., cooled, extracted with 300 ml of ethyl acetate and washed with 300 ml of water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified with column chromatography (methanol/methylene chloride=1:9) to obtain 4.58 g of the title compound(yield 85%).