Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.[OH:16]S(O)(=O)=O.C1(C)C=CC=CC=1>O.O=[Mn]=O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:16])=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 125 °C
Yield: 69.2 %

Procedure:
To a 250 mL round bottomed flask equipped with a heating mantle, overhead agitator, thermometer, condenser, and addition funnel with a tube protruding below the liquid level was added 10.6 g 4,4'-difluorodiphenylmethane (0.051 moles). Agitation was begun and a slurry of 20.5 g MnO2 (0.195 moles) in 30 g water was added to the flask. About 30 g of water were used to wash the MnO2 beaker and were added to the flask. The mixture was allowed to reach about 100° C. at which point 50 g H2SO4 (0.487 moles) were added to the addition funnel. The H2SO4 was then added dropwise into the flask and the reaction temperature slowly rose to about 125° C. when all of the acid had been added. The mixture was heated to maintain the temperature at about 125° C. until gas chromatography showed complete conversion after approximately 12 hours. The reaction mixture was allowed to cool to 100° C. and 50 g toluene were added to the mixture. A slurry of 6 g diatomaceous earth in 30 g water was poured into a vacuum Buchner funnel fitted with No. 42 filter paper to form a filter pre-coat. The contents of the round bottomed flask were then vacuum filtered. 10 g toluene was used to wash the flask and, subsequently, the filter cake. The filter cake was then washed with 100 g toluene heated to about 50° to 70° C. and the filtrate phase separated. The toluene was removed from the organic phase by heating to approximately 65° C. at 10 mm Hg. The 10 g yellow solids assayed as 95% pure 4,4'-difluorobenzophenone for an 84% yield. The solids were recrystallized from a hexane solvent leaving 7.7 g crystalline 4,4'-difluorobenzophenone for a 68% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[C:30]([F:42])=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:30]([F:42])=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(F)cc1F

Procedure:
Example 165 was prepared from bis(4-fluorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.25 (t, 1 H, J=8.4 Hz), 7.67–7.57 (m, 1 H), 7.51 (s, 1 H), 7.36–7.25 (m, 4 H), 7.03–6.91 (m, 4 H), 6.81 (t, 1 H, J=9.6 Hz), 4.81 (s, 1 H), 3.45–3.31 (m, 2 H), 2.92 (m, 2 H), 2.83–2.67 (m, 1 H), 2.63–2.47 (m, 1 H), 2.47–2.33 (m, 2 H), 2.05–1.90 (m, 2 H), 1.82–1.72 (m, 2 H), 1.72–1.56 (m, 4 H), 1.22 (d, 6 H, J=6.8 Hz); ESMS m/e: 570.2 (M+H)+.
Reaction SMILES: [C:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:19]1CCC[CH2:20]1.C([Li])CCC.CN(C)C=O>C(Cl)Cl>[F:18][C:13]1[C:12]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:20]=[O:19]
Reactant: C1CCOC1
Reactant: CCCCCCCCCC#Cc1ccccc1F
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a solution of 2-(1-undecynyl)fluorobenzene (7.00 g) and tetrahydrofuran (70 ml) was added slowly n-butyllithium (1.6M, 17.8 ml) at -78° C. The reaction mixture was stirred at -78° C. for 1.5 hrs. Dimethylformamide (2.28 ml) was added slowly, and the solution was allowed to warm to room temperature over 1 hr, with stirring. Methylene chloride (300 ml) was added, and the solution was washed with 50% hydrochloric acid. The aqueous phase was extracted with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (250 g), eluting with hexane followed by ethyl acetate/hexane (1:4). The appropriate fractions were collected and evaporated to provide 3.53 g (45.2%) of product as an oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3].C1N2CN3CN(C2)CN1C3.C(O)(=[O:35])C.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:35])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:3]
Reactant: CC(=O)O
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1

Procedure:
10 g of N-[(dimethylamino) methylene]4'-bromomethyl(1,1'-biphenyl)2-sulfonamide, 8.14 g of hexamethylene-tetramine and 80 ml of 50% acetic acid are were stirred for one hour at 120° C. and after the addition of 220 ml of water, the reaction mixture was neutralized with a saturated solution of sodium bicarbonate and extracted with dichloromethane. The extracts were dried and evaporated to obtain 7.99 g of the expected product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CS(C)=O>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][O:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (7.55 g, 54.6 mmol) was added to a solution of N-hydroxyphthalimide (13.93 g, 85.4 mmol) in 150 mL of DMSO to give a wine-red colored solution. 4-Bromo-2-methyl-2-butene (20 g, 134 mmol) was added to the solution dropwise and the reaction was stirred for 16 hours at room temperature. The reaction was poured into 600 mL of ice water to give a white crystalline solid. The crude crystalline product was filtered, washed with ice water, and air dried. The crystalline product was recrystallized from ethanol to give 15.7 g, mp 97°-98° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23](Br)=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.C(OCC)(=O)C>[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: COCCO
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1ccc(Cl)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCCOc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h

Procedure:
2-Methoxyethanol (0.04 g) was added to a stirred suspension of sodium hydride (0.05 g of 60%) in 1,2-dimethoxyethane (5 mL). After 10 minutes, 5-chloro-N-(3,5-dibromo-2-pyrazinyl)-2-thiophenesulphonamide (0.2 g) was added. After 30 minutes, 5% aqueous citric acid and ethyl acetate were added. The organic layer was separated dried (MgSO4) and the solvent was evaporated. Chromatography on silica eluting with hexane/ethyl acetate gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[C:21](=O)[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14]2)([F:12])[CH:6]2[C:10]=1[O:9][CH:8]([CH3:11])[CH2:7]2.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[Cl:25][C:21]1[N:13]([C:5]2([F:12])[CH:6]3[CH2:7][CH:8]([CH3:11])[O:9][C:10]3=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][CH2:17][CH2:16]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CC2C(=C(Cl)C=CC2(F)n2[nH]c3c(c2=O)CCCC3)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC1CC2C(=C(Cl)C=CC2(F)n2nc3c(c2Cl)CCCC3)O1

Procedure:
0.25 g of 39C was mixed with 0.14 g of phosphorous oxychloride and 0.15 g of N,N-diethylaniline and heated under nitrogen at 135°-140° C. for three hours, cooled, and diluted with ethyl acetate. The organic phase was washed with water, 10% hydrochloric acid, saturated sodium bicarbonate solution, brine, dried (MgSO4) and stripped of solvent. The residue was purified by flash chromatography on silica gel, using a 1:4 v:v mixture of ether and hexane as eluent to afford the title compound as a yellow glass.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CCc1ccccc1

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: ethyl-4-phenyl-2-oxobutyrate (substrate): 0.352 g (1.7 mmol); solvent: 10 ml of toluene/methanol (1:1); hydrogen: 50 bar, temperature: 50° C.; reaction time: 19 hours. The conversion is 100%, ee: 44% (R).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:18][CH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C)cc(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1cc(CBr)cc(-c2ccccc2)c1
Yield: 80 %

Procedure:
A solution of methyl 3-methyl-5-phenylbenzoate (3.5 g; 15.6 mmol); N-bromosuccinimide (2.78 g; 15.6 mmol), 2,2′-azobis(2′-methylpropionitrile) (0.12 g; 0.72 mmol) and benzoylperoxide (0.12 g; 0.48 mmol) in tetrachloroamethane (120 ml) was heated at reflux for 5 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate (97/3) to give methyl 3-bromomethyl-5-phenylbenzoate as a solid. Yield=80%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nccs2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (200 mg, 0.82 mmol), 2-tributylstannylthiazole (Frontier Scientific) (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (Aldrich Chemical Company) (19 mg, 0.021 mmol) and triphenylphosphine (Aldrich Chemical Company) (43 mg, 0.16 mmol) in anhydrous toluene (2 mL) was refluxed under N2 for 4 d. TLC showed that the reaction was not complete. Therefore, additional portions of 2-tributylstannylthiazole (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.021 mmol) and triphenylphosphine (43 mg, 0.16 mmol) were added to the reaction mixture, and the mixture was stirred at 120° C. for 3 d. Upon cooling to the room temperature, the reaction was quenched with 5% HCl (50 mL) and the solution was extracted with CHCl3 (3×100 mL). The organic extracts were washed with H2O (2×150 mL), filtered through a pad of Celite, washed with saturated NaCl (150 ml), dried over Na2SO4 and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (1-3%):CH2Cl2 (99-97%) afforded 119 mg (50%) of the title compound as a yellow solid. Mp: 248-250° C. 1H NMR (acetone-d6; 400 MHz): δ 2.69 (s, 3), 7.01(s, 1), 7.57-7.47 (m, 3), 8.06 (d, 2, J=7.17), 8.97 (s, 1), 9.18 (s, 1), 10.76 (s, 1). MS m/z: 293 (M+1), 291 (M−1). HRMS: Calcd for M+H: 293.0861. Found: 293.0866.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Cl:1][CH2:2][CH2:3][CH:4]([O:5][S:20]([CH3:19])(=[O:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCCl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCCl)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (R) 3-chloro-1-phenyl-propan-1-ol (Aldrich) (0.250 g) in 40 ml dichloromethane was added triethylamine (0.272 g) at 0° C. followed by the dropwise addition of methanesulfonyl chloride (0.185 g). The reaction mixture was stirred at this temperature for 2 hours and then quenched by the addition of sodium bicarbonate solution. The phases were separated and the organic phase was evaporated to dryness to afford methanesulfonic acid 3-chloro-1-phenyl-propyl ester as an oil which was used directly in the next step.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:2].Cl[CH2:17][C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2>>[N:22]12[CH2:23][CH2:24][CH2:25][C:18]1([CH2:17][N:3]([CH:1]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=1)[CH2:19][CH2:20][CH2:21]2
Reactant: O=CNc1cccc(-c2ccccc2)c1
Reactant: ClCC12CCCN1CCC2
Product: O=CN(CC12CCCN1CCC2)c1cccc(-c2ccccc2)c1

Procedure:
The procedures described in Example 2 were repeated except that 3-formylamino-1,1'-biphenyl (286 mg, 1.45 mmol) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 800 mg, 1.53 mmol) were employed. In this case, the desired compound was obtained as pale yellow solids (385 mg, 82.7%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:15]([NH:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)CN
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCC(CC)CCCC
Temperature: 0 °C

Procedure:
128.98 Grams (1 mole) of 2-ethyl-1-hexylamine and 500 ml of toluene were charged to a flask equipped with dropping funnel, thermometer, condenser, stirrer, Dean & Stark trap and condenser. The contents of the flask were refluxed for 3 hours to remove water, then cooled to 0° C. 99.6 Grams (1 mole) of butyl isocyanate were charged to the dropping funnel and added during 1 hr 5 min to the stirred flask contents. The flask contents remained at 30° C. or less during the addition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH2:5][OH:6].[CH3:11][O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: OCc1ccc(O)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-4-hydroxybenzyl alcohol (1.22 g, 6.0 mmol) prepared from i) and sodium methoxide (0.36 g, 6.6 mmol) as base were added to N,N-dimethylformamide (100 ml), and the mixture was stirred for 30 min at room temperature. Chloromethyl resin (Merrifield resin, 1 mmol of chloromethyl site, formula 4; 1.22 g, 2.0 mmol) was added to the reaction solution and stirred for 24 hr at 50° C. The same was filtrated and washed repeatedly with water, methanol and dichloromethane. IR and XPS analyses were performed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10]N(C)C)=[CH:2]1.[C-:14]#[N:15].[Na+]>CS(C)=O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:14]#[N:15])=[CH:2]1
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1c[nH]c2ccccc12
Temperature: 80 °C
Yield: 153.7 %

Procedure:
Dissolve a mixture of the (1H-Indol-3-ylmethyl)-dimethylamine (3.54 mmol), sodium cyanide (0.500 g, 10.62 mmol), and ethyl acetate (1.7 mL, 17.7 mmol) in dry dimethyl sulfoxide (12 mL) and heat to 80° C. under nitrogen for 3 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate (150 mL), and wash with water (50 mL), Dry the organic layer over anhydrous magnesium sulfate, and remove the solvent in vacuo to yield (1H-indol-3-yl)-acetonitrile 0.850 g (96%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2]1.[C:15](Cl)(=[O:19])[C:16](Cl)=[O:17]>O1CCCC1>[O:17]=[C:16]1[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2][N:1]3[C:15]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C1CCNc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)C1CCN2C(=O)C(=O)c3cccc1c32
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate (51.0 g) in tetrahydrofuran (THF, 200 ml) was heated under refluxing and a solution of oxalyl chloride (30 ml) in dry THF was added thereto. The mixture was refluxed for 4 hours, then cooled and concentrated. The residue was dissolved in carbon disulfide (800 ml) and aluminum chloride (66.7 g) was added portionwise. The mixture was refluxed for 4 hours, and then allowed to stand overnight. The solvent was eliminated by decantation and to the residue was added ice-water (1 litter). The mixture was extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous sodium sulfate and concentrated to give the title compound (55.15 g, 83.3%) which was recrystallized from acetonitrile to dark red crystals, mp 135° C.-136° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>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.C(N(CC)CC)C>[CH3:19][Si:20]([C:23]#[C:24][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1)([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Cc1nccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccnc1C#C[Si](C)(C)C
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of the ethyl 2-(3-chloropyrazin-2-yl)acetate (I99) (0.410 g, 2.04 mmol), DMF (6 mL), triethylamine (2 mL), bis(triphenylphosphine)palladium(II) chloride (72 mg, 5 mol %) and copper(I) iodide (19 mg, 5 mol %) in a Schlenk tube was degassed with three vacuum/nitrogen cycles, then trimethylsilylacetylene (0.866 mL, 6.13 mmol) was added under nitrogen. The tube was flushed with nitrogen, sealed and heated to 90° C. After 18 hours the mixture was cooled and poured into water (50 mL). Saturated ammonium chloride (50 mL) was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined ether phases were washed with brine, dried (sodium sulphate) and evaporated. The residue was chromatographed (40 g silica cartridge, 0-30% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I100) (0.386 g, 72% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.47-8.41 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.1 Hz), 0.28 (s, 9H). LCMS Method C: rt 6.20 min; m/z 263.1 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]([OH:25])(=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(C(C)=O)C(C)C>[C:21]([O:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])(=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:25]
Reactant: NCCCCCCO
Reactant: O=C(O)CCCCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCCCCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
6.0 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 7.0 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.). After stirring for 10 minutes, 5.2 g of suberic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) suberate.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])([O-:8])=[O:7].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][C:3](=[O:4])[CH2:2][Br:1])([O-:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Under argon atmosphere bromo-acetyl bromide (2.67 mL, 30.66 mmol) dissolved in DCM (15 mL) was added within 15 min to a mixture of 2,4-dinitro-phenol (5.13 g, 27.88 mmol) and pyridine (2.92 mL, 36.24 mmol) in DCM (40 mL) at 0° C. After 1 h at RT, aqueous citric acid solution (10%, 30 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue recrystallized from diethyl ether (75 mL) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH:20][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1]
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: NCc1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 42.6 %

Procedure:
A mixture of 2,2,2,2′,4′-pentafluoroacetophenone (1.05 g, 5.0 mmol), 3,5-dichlorobenzylamine (0.88 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (0.78 g, 43%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1H), 7.88 (m, 1H), 7.34 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.30 (dd, 1H), 4.43 (d, 2H).