Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N)CC>CCOCC.[Cu](I)I>[Si:6]([C:5]#[C:4]/[CH:3]=[CH:2]\[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)C#C/C=C\Cl
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCCN
Product: CC(C)(C)[Si](C)(C)C#C/C=C\C#C[Si](C)(C)C
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
Tetrakistriphenylphosphine (4.75 g, 4.10 mmol, 0.48 equiv) was added to a solution of (Z)-1-chloro-4-(tert-butyldimethylsilyl)-1-buten-3-yne (17.2 g, 85.7 mmol, 1 equiv) in ether (160 mL) at -78° C. The resulting suspension was deoxygenated by alternately evacuating the reaction vessel and flushing with argon (5×), then was warmed to 23° C. In another flask, copper iodide (2.45 g, 12.8 mmol, 0.15 equiv) was added to a solution of trimethylsilylacetylene (17.0 mL, 120 mmol, 1.40 equiv) and n-propyl amine (27.5 mL, 334 mmol, 3.90 equiv) in ether (100 mL) at -78° C. The solution was deoxygenated (as above, 5×), then was stirred in an ice bath for 10 min causing the light green solution to turn reddish brown. The reddish brown solution was cooled to -78° C. and the palladium-containing suspension prepared above was added over 5 min via a wide-bore cannula. The mixture was deoxygenated (as above, 5×), then was stirred in an ice bath for 3 h and at 23° C. for 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (200 mL) and hexanes (300 mL). The aqueous layer was separated and extracted further with hexanes (2×300 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was filtered, then was purified by distillation under reduced pressure (bp 70°-80° C., 0.5 mmHg) to provide (Z)-1-(tert-butyl-dimethylsilyl)-6-trimethylsilyl-3-hexen-1,5-diyne as a light brown oil (20.4 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.Cl[CH2:21][C:22](=[O:24])[CH3:23].O.ClCCl>N1C=CC=CC=1>[CH2:21]([S:17][CH:16]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:18])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:19])[C:22]([CH3:23])=[O:24]
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: CC(=O)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)CSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 72.9 %

Procedure:
In 10 ml pyridine was dissolved 1.5 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 0.6 g of chloroacetone was added dropwise to the mixture with stirring with cooling at 5° to 10° C. over a period of 10 minutes. After cooling was continued at room temperature for 2 hours, water was added to the mixture for extraction with dichloromethane. The dichloromethane layer was separated out, washed with dilute hydrochloric acid and water, successively, and dried over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with a mixed solvent of ether and hexane and dried, thereby producing 1.3 g (yield of 73%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 131°-132° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O1C=CC[CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:13]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH3:14]
Reactant: O=C([O-])Cc1cccc(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccccc1
Reaction time: 3 h

Procedure:
To a 0° C. solution of 116 g (0.644 mol) of the above 3hydroxyphenylacetate in 645 ml dichloromethane and 64.6 ml (0.71 mol) dihydropyran was added a few crystals of 4-toluenesulfonic acid monohydrate. The reaction was stirred for 3 hours at 0° and then added to 200 ml saturated sodium bicarbonate. The organic extract was dried over magnesium sulfate and evaporated to give 161 g (95%) of 3-(tetrahydro-2H-pyran-2-yl)oxy]-phenylacetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-benzyloxy-4-fluoro-1-nitrobenzene (2.4 g, 10 mmol) in EtOH (20 mL) is added SnCl2 (9.45 g, 50 mmol) and the suspension is stirred at RT overnight. The solvent is removed under reduced pressure and the residue is adjusted to pH >8. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with water and brine, then dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give the product as a red oil.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[Na+].O>[CH3:22][O:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C(=CO)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=C(C(=O)OC)c1cccc(C(F)(F)F)c1
Reaction time: 40 h

Procedure:
(ba) 26 g of methyl 3-hydroxy-2-(α,α,α-trifluoro-m-tolyl)acrylate were dissolved in 1N sodium hydroxide solution while cooling in an ice-bath and treated with 10.6 ml of dimethyl sulfate. The mixture was stirred at about 0° for about 40 hours and an additional 40 ml of 1N sodium hydroxide solution and 3.8 ml of dimethyl sulfate were added. After the reaction was completed, the mixture was diluted with water and extracted with methylene chloride. After drying with sodium sulfate, the extract was distilled, whereby methyl 3-methoxy-2-(α,α,α-trifluoro-m-tolyl)-acrylate was obtained as a colorless oil of b.p. 75°-90°/0.2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:14][C:15]#[N:16].[I-].[CH3:18][S+](C)(C)=O.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C@@H:13]1[CH2:18][C@H:14]1[C:15]#[N:16]
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc2ccccc2c1C=CC#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2ccccc2c1[C@@H]1C[C@H]1C#N

Procedure:
5 g (23.9 mmol) of the compound obtained in Step A dissolved in 50 ml of DMSO are added dropwise to the ylid formed starting from 7.9 g (1.5 eq) of trimethylsulphoxonium iodide and 1.15 g (1.2 eq) of NaH (60% suspension in oil) in 20 ml of DMSO. The title compound is obtained in the form of an oil and is purified by chromatography over silica gel (eluant: CH2Cl2/i-PrOH 98/2).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38]>CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=4[F:38])[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1ccc(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccc(F)c(F)c1F

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 82 mg of 1-(bromomethyl)-2,3,4-trifluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 76 mg of (8S)-2-(morpholin-4-yl)-9-(2,3,4-trifluorobenzyl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH:20]([O:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26])([CH2:22][CH3:23])[CH3:21]>ClCCl>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH:27][C:25]([O:24][CH:20]([CH2:22][CH3:23])[CH3:21])=[O:26])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCC(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: CCC(C)OC(=O)C=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 4(p-trifluoromethylphenoxy)benzaldehyde (30 g) and sec butyloxycarbonyl methylene triphenylphosphorane (50 g) dissolved in dichloromethane was allowed to stand for 1 hour at room temperature. After evaporation of the solvent the white solid was tritiated with petroleum ether to give a solution which on evaporation yielded sec butyl 4-(p-trifluoromethylphenoxy)cinnamate (40 g) b.p. 150°/0.007 mm.
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C@@H:11]([NH:13][C:14]2[C:15]3[C:22]([C:23]4[CH:31]=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)=[CH:21][N:20](COCC[Si](C)(C)C)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:12])[N:3]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.FC(F)(F)C(O)=O.N>>[O:1]=[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C@@H:11]([NH:13][C:14]2[C:15]3[C:22]([C:23]4[CH:31]=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:12])[N:3]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C[C@H](Nc1ncnc2c1c(-c1cc(NS(C)(=O)=O)cc3[nH]ccc13)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ncnc2[nH]cc(-c3cc(NS(C)(=O)=O)cc4[nH]ccc34)c12)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 18.9 %

Procedure:
(S)—N-(4-(4-((1-(4-Oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl)methanesulfonamide (152 mg, 0.21 mmol) was treated with trifluoroacetic acid (1 ml, 12.9 mmol) and a solution of ammonia (7N in methanol, 5 mL, 35 mmol) according to the method described in Example 27 to give 23 mg (18% yield) of the title compound. Purity 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH2:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH:17][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1cc(F)ccc1-c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A stirred solution of 1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethylamine (0.26 g, 1.12 mmol) in dichloromethane (10 mL) was treated with 4-methoxybenzenesulfonyl chloride (0.23 g, 1.12 mmol), and pyridine (0.09 g, 1.12 mmol). The reaction was stirred at room temperature for twelve hours, diluted with dichloromethane, washed sequentially with a 1 N hydrochloric acid solution (2×) and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and evaporated to a residue which, after crystallization from ethyl acetate-hexane, afforded the title compound (0.22 g, 0.53 mmol, 48%) as a racemic, homogeneous, colorless, crystalline solid, m.p. 182-184° C.;
Reaction SMILES: [I-:1].[CH:2]1([O:7][N:8]=[C:9]([C:46]2[N:47]=[C:48]([NH:51][CH:52]=[O:53])[S:49][CH:50]=2)[C:10]([NH:12][C@@H:13]2[C:44](=[O:45])[N:15]3[C:16]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:17]([CH2:21][N+:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[CH2:18][S:19](=O)[C@H:14]23)=[O:11])[CH2:6][CH2:5][CH:4]=[CH:3]1.CN(C)C=O.P(Cl)(Cl)Cl>O>[I-:1].[CH:2]1([O:7][N:8]=[C:9]([C:46]2[N:47]=[C:48]([NH:51][CH:52]=[O:53])[S:49][CH:50]=2)[C:10]([NH:12][C@@H:13]2[C:44](=[O:45])[N:15]3[C:16]([C:28]([O:30][CH:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:29])=[C:17]([CH2:21][N+:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2S(=O)C1
Agent: [I-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Temperature: -33 °C
Yield: 95.2 %

Procedure:
A mixture of benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer, 5.3g) and N,N-dimethylformamide (50 ml) was stirred at -33° C. and phosphorus trichloride (1.68 g) was added thereto with stirring. The reaction mixture was stirred for 10 minutes at the same temperature, and poured into water (400 ml). Precipitates were collected by filtration and washed with water to give benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (syn isomer, 4.95 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C:5]2=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][NH:9][CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(n1)CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 2-chloro-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Light brown solid. MS (m/e): 154.9 ([M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cc2nc(-c3cccnc3Cl)[nH]c2cc1F
Reactant: BrCc1ccccc1
Product: Fc1cc2nc(-c3cccnc3Cl)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, intermediate a, from 2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-benzene (CAS Reg. No. 100-39-0). Colorless solid (52%). MS (Turbo Spray): m/z=356.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(OO)(=[O:21])C>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:21])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccc(F)c1
Reactant: CC(=O)OO
Product: COC(=O)c1cc(Cl)c[n+]([O-])c1-c1cccc(F)c1
Yield: 60.6 %

Procedure:
A solution of methyl 5-chloro-2-(3-fluorophenyl)nicotinate (11 g, 41 mmol) in ethaneperoxoic acid (30 mL, 100 mmol) was heated at 90° C. for 1 hour. Evaporation and purification by flash column chromatography with ethyl acetate in hexanes (0-50%) gave the desired compound (7.0 g, 68%). LCMS calculated for C13H10ClFNO3 (M+H)+: m/z=282.0. found: 281.8. 1H NMR (300 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.85 (s, 1H), 7.49 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:14])[C:5]([F:13])=[C:6]2C(=O)[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][O-:17].[Na+].[OH-].[Na+].Cl.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>C1(C)C(C)=CC=CC=1.CO>[CH3:16][O:17][C:3]1[C:2]([F:1])=[C:7]([CH:6]=[C:5]([F:13])[C:4]=1[F:14])[C:8]([OH:10])=[O:9]
Reactant: C[O-]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1c(F)c(F)cc(C(=O)O)c1F
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 10 g (0.0397 mol) of the tetrafluorophthalic anhydride prepared in Example 3 and 20 ml of methanol were charged, and the mixture was stirred for 2 hours under reflux. After cooling, 42.8 g (0.079 mol) of a 10% methanol solution of sodium methoxide was dropwise added thereto. Then, under reflux, the mixture was stirred for one hour. Then, 15.9 g of a 10% sodium hydroxide aqueous solution was added thereto and the mixture was stirred for 12 hors under reflux. After cooling, 8 g of a 20 % hydrochloric acid aqueous solution was added. Further, 21.1 g (0.0596 mol) of trioctylamine and 40 g of xylene were added thereto, and the mixture was stirred. The organic layer was separated and stirred at 140° C. for 2 hours. After completion of the reaction, 30 ml of a 20% sodium hydroxide aqueous solution was added thereto and stirred. The aqueous phase was separated and neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. The solvent was distilled off to obtain 6.7 g of 3-methoxy-2,4,5-trifluorobenzoic acid. The yield was 81.5%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:5]([NH:6][CH3:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C1CCCCC=1.C(=O)([O-])[O-].[Na+].[Na+].[N:28]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>C(O)C.[Pd]>[NH2:10][C:8]1[C:5]([NH:6][CH3:7])=[C:4]([NH:13][C:29]([NH:28][C:31]2[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=2[CH3:37])=[S:30])[CH:3]=[C:2]([F:1])[CH:9]=1
Reactant: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CNc1c(N)cc(F)cc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 32.4 %

Procedure:
In 75 mL of ethanol was mixed 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline, 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol %) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 h and filtered into a flask containing 0.77 g (7.3 mmol) of sodium carbonate and 1.07 g (6.04 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The resulting slurry was refluxed for 4 h, concentrated and slurried in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexanes/ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].CCOC(C)=O.CCCCCC>C(N(CC)CC)C.[Cu]I.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>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:15])[CH3:14]
Reactant: Clc1ccc2ccccc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Chloroquinoline (1.02 g, 6.17 mmol), CuI (12.1 mg, 0.622 mmol), and PdCl2(PPh3)2 (22.7 mg, 0.0317 mmol) were dissolved in triethylamine (20.6 mL), followed by stirring for 5 min. To the resulting mixture, trimethylsilyl acetylene (1.34 mL, 9.44 mmol) was added dropwise at 60° C., followed by heating. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:10). When the reaction was completed, the reactant was cooled down to room temperature and extracted with a saturated aqueous solution of NaCl and ethyl acetate, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:10, R.f: 0.4), to thereby obtain 2-((trimethylsilyl)ethynyl)quinoline (1.289 g, 93%) as brown oil.
Reaction SMILES: [F:1][C:2]([F:23])([O:9][CH:10]([F:22])[C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:3]([F:8])([F:7])[CH:4]([F:6])[F:5].[CH3:24][N:25]1[C:32](=[O:33])[CH:31]([C:34](OCC)=[O:35])[C:29](=[O:30])[N:28]([CH3:39])[C:26]1=[O:27]>C1(C)C=CC=CC=1>[CH3:39][N:28]1[C:29](=[O:30])[CH:31]([C:34](=[O:35])[NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:21])([F:20])[CH:10]([O:9][C:2]([F:23])([F:1])[C:3]([F:7])([F:8])[CH:4]([F:5])[F:6])[F:22])=[CH:14][CH:15]=2)[C:32](=[O:33])[N:25]([CH3:24])[C:26]1=[O:27]
Reactant: Nc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)cc2)C(=O)N(C)C1=O

Procedure:
14.50 g (40.6 mmol) of 4-(2-(1,1,2,2,3,3-hexafluoropropoxy)-1,1,2-trifluoroethoxy)-aniline were added to 9.26 g (40.6 mmol) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid in 100 ml of toluene, the mixture was stired under reflux for 2.5 hours and concentrated and the residue was recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:19][CH3:20])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of trans-4-methoxycinnamic acid (18 g, 101 mmol) and concentrated H2SO4 (0.5 ml) in absolute EtOH (100 ml) was refluxed at 90° C. (bath temperature) for 16 h. After the excess EtOH was removed by a rotary evaporator, the residue was treated with H2O (100 ml), and the resulting mixture was extracted with ether (3×120 ml). The combined extracts were washed with 1N aq. NaOH (2×50 ml), H2O (80 ml) and brine (80 ml), and dried (anhydrous Na2SO4). The solvent was evaporated to dryness to give ethyl trans-4-methoxycinnamate (20 g, 96% yield) as light yellow oil, which was pure enough for the next step.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Yield: 87.2 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 1-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (830 mg, 2.35 mmol), iron powder (1.31 mg, 23.5 mmol), and NH4Cl (1.09 g, 18.8 mmol) in EtOH (8 mL) and water (2 mL) to afford 660 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.79 (d, J=6.0 Hz, 1H), 7.71-7.56 (m, 4H), 7.51 (d, J=8.1 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.01 (s, 2H).