Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:15][C@H:16]([NH:25][CH3:26])[C@@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[N:25]([CH3:26])[C@@H:16]([CH3:15])[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24]1)[CH:2]=[CH2:3]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (101 mL, 0.696 mol) in methylene chloride (1.8 L) under argon was added triethylamine (170 mL, 1.21 mol). (1S,2S)-pseudoephedrine (100 g, 0.605 mol) was then added portionwise over 30 min, to maintain internal temperature below 15° C. After the addition was complete the mixture was stirred for 12 hours at ambient temperature. The methylene chloride was removed by distillation and the residue was diluted with pentane (1.5 L). The mixture was vigorously stirred for 12 hours to ensure complete precipitation of the triethylamine salts. Filtration of the resulting suspension through a pad of celite and concentration of the filtrate by distillation afforded the crude product as a pale yellow oil. Purification by distillation under reduced pressure (bp˜120 C, 5 mm Hg) provided 149 g (92%) of (4S, 5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 2,5-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 130. 1H NMR(CDCl3) δ: 7.98 (s, 1H), 7.82 (d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=8.1 Hz), 6.37 (d, 1H, J=2.5 Hz), 6.18 (d, 1H, J=2.5 Hz), 4.58 (ABq, 2H, JAB=14.1 Hz), 4.51 (s, 2H), 4.18 (app d, 1H, J=12.5 Hz), 3.90 (m, 1H), 3.74 (app t, 1H), 3.36-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.20-3.08 (m, 2H), 3.03 (dd, 1H), 2.93-2.85 (m, 2H), 2.64 (app t, 1H), 2.46 (dd, 1H, J=12.1, 10.6 Hz), 2.00-1.80 (m, 2H). LRMS (ES)+: 472.4 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7](Cl)=[O:8]>O1CCCC1>[CH3:1][NH:2][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:4]([CH3:3])[CH:5]=1
Reactant: CN
Reactant: Cc1ccc(C(=O)Cl)cc1C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
108 ml of a 40 % strength aqueous solution of methylamine were dissolved in 300 ml of tetrahydrofuran. 53 g of 3,4-dimethylbenzoyl chloride were added dropwise to this solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 1 hour. Then the reaction mixture was concentrated to half its volume under reduced pressure, saturated sodium chloride solution was added, and the mixture was acidified with concentrated hydrochloric acid. The product which then precipitated was filtered out with suction and dried at 40° C. over potassium hydroxide in a drying cabinet. 47 g of N-methyl-3,4-dimethylbenzamide were obtained.
Reaction SMILES: C1C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:11][NH:12][C:13](=[O:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH3:22])[CH:16]=1.[Cl:24][CH:25]([CH3:29])[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:11][NH:12][C:13](=[O:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:26](=[O:27])[CH:25]([Cl:24])[CH3:29])=[C:17]([CH3:22])[CH:16]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NC(=O)C(C)Cl)c(C)c1
Yield: 95.7 %

Procedure:
Utilizing benzene and chloroform as the solvent and triethylamine as the acid acceptor, 3-methyl-4-aminophenyl N-methylcarbamate (2.5g., 0.0139 mole) was reacted with α-chloropropionyl chloride (1.79g., 0.0141 mole) to yield the desired product as a white powder (3.6g.). Recrystallization from ethanol/water to give material with m.p. 167°-70° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH2:3][CH2:2]1.Cl.[O:26]1CC[O:29][CH2:28][CH2:27]1>CCOCC>[ClH:18].[OH:29][CH2:28][C:27]([N:11]1[C:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)=[C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[N:10]1)=[O:26]
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncn2)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOCC
Product: O=C(CO)n1nc(-c2ccc(Cl)cc2)c(-c2ccncn2)c1C1CCNCC1
Reaction time: 2 h

Procedure:
A 25 mL round bottom flask was charged with 65 mg (0.164 mmol) of N-(2-hydroxyacetyl-(5-(4piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole and 2.5 mL of dioxane. To this suspension was added 0.0.82 mL of 4 N HCl in dioxane. The mixture was stirred for 2 hours. The mixture was diluted with 5 mL of Et2O and filtered. The solid was dried over solid CaSO4 under vacuum for 12 h to afford 68 mg of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride. 1H NMR (DMSO-d6) 9.18(s, 1H), 8.63(d, J=5.37 Hz, 1H), 7.40(d, J=8.59 Hz, 2H), 7.33(d, J=8.59 Hz, 2H), 7.15(m, 1H), 4.40(m, 1H), 4.06(m, 2H), 3.72(m, 1H), 3.33(m, 1H), 2.97(m, 1H), 2.62(m, 1H), 1.83(m, 2H), 1.64(m, 2H); MS (M+H): 398
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.[CH:11](O)=[O:12].OO.S([O-])([O-])=[O:17].[Na+].[Na+]>O>[OH:17][CH:3]1[CH:2]2[CH:1]3[CH:6]([CH2:5][CH:4]1[CH2:7]3)[C:11](=[O:12])[C:8]2=[O:10]
Reactant: O=CO
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1C(=O)C2C(O)C3CC1C2C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
With 328.2 g of 5-norbornene-2-carboxylic acid was mixed 240.6 of formic acid. Below 50° C., 254.5 g of 35% aqueous hydrogen peroxide was added dropwise to the mixture over 6 hours. After the completion of addition, the reaction mixture was poured into a mixture of 1.5 liters of water and 0.8 kg of sodium sulfite. After three times of extraction with 1 liter of ethyl acetate, the organic phase was washed with water, dried, and concentrated in vacuum. The residue was dissolved in 1.2 liters of methanol, to which a catalytic amount of potassium carbonate was added. This was agitated for one hour at room temperature. The methanol was distilled off under vacuum, followed by conventional extraction and washing. There was obtained 247.6 g of 2-hydroxy-4-oxotricyclo[4.2.1.03,7]nonan-5-one. The yield was 65.5%.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>CCCCCC.CCOCC>[OH:17][C:11]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1cscn1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCCCC1
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of n-BuLi (22 mL of a 2.5M solution in hexane, 55 mmol) in anhydrous ether (60 mL) at −78° C. was slowly added a solution of thiazole (3.94 g, 46 mmol) in anhydrous ether (30 mL). The resulting mixture was stirred for 1 h and then cyclohexanone (9.6 mL, 93 mmol) in ether (25 mL) was added over 5 min. The mixture was stirred for 2.5 h at −78° C. and then sat. aq. NH4Cl was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the 2-[(1-Hydroxy)cyclohexyl]thiazole compound (5.8 g).
Reaction SMILES: C(N[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:14])(=O)C.[OH-].[Na+].[CH2:17]([O:19][CH2:20][CH2:21]Br)[CH3:18].[CH2:23]([OH:25])[CH3:24]>>[CH2:17]([O:19][CH2:20][CH2:21][O:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=1[C:23](=[O:25])[CH3:24])[CH3:18]
Reactant: CCOCCBr
Reactant: CC(=O)Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOCCOc1cccc([N+](=O)[O-])c1C(C)=O

Procedure:
1g of 2-acetylamino-3-nitrophenol was mixed with an aqueous solution of sodium hydroxide (0.21g of NaOH in 5ml H2O) with stirring. 5ml of ethanol was added to the deep red solution formed and then 0.64ml of 2-bromoethyl ethyl ether added and the reaction mixture stirred for 1 hour at room temperature and refluxed overnight. After cooling 5ml of 2M sodium hydroxide was added to the mixture to increase the pH to pH 12. Then extraction with 2×15ml of dichoromethane was carried out, the combined dichloromethane extracts dried over sodium sulphate, the solvent evaporated off and the product purified by recrystallisation from ethanol/hexane/dioxan to leave 1.0g of 2-acetyl-3-nitrophenyl (2-ethoxyethyl) ether as a fine yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(#N)C>[C:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: OCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
To a solution of 4-piperidine ethanol (1.95 g) in acetonitrile (25 mL) was added triethylamine (2.53 mL) followed by tert-butyl dicarbonate (3.63 g). The mixture was stirred at room temperature for 22 hours and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated to give 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (3.46 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6].[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([I:12])=[C:2]([NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[CH:3]=1
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)c1ccc(I)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)Nc1cc(C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of Methyl 3-amino-4-iodobenzoate (1.67 g, 6 mmol) and Methacrylic acid (568 mg, 6.6 mmol) in dichloromethane (60 mL) and DMF (60 mL) were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.5 g, 6.6 mmol) and then a solution of N,N-diisopropylethylamine (1.16 g, 1560 μL, 9 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 24 h. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), and concentrated to give the amide which was purified by flash chromatography (AcOEt/heptane: 5/5).
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].CO[C:18](OC)([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:15][C:2]([CH3:1])([CH3:14])[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[O:4]1
Reactant: CC(C)(O)C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)C(C)(C)O1
Yield: 84.1 %

Procedure:
A solution of 2-methyl-1-(4-nitrophenyl)propane-1,2-diol (1.5 g, 7.1 mmol), 2,2-dimethoxypropane (1.45 g, 14.2 mmol) and TsOH (cat., 260 mg, 1.5 mmol) in acetone (40 mL) was stirred at 30° C. for 16 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography, eluting with PE:EA (8:1), to obtain the desired product (1.5 g, 85% yield) as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 8.23 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz), 4.93 (s, 1H), 1.59 (s, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]([CH3:14])([CH2:12]O)[CH2:10][OH:11].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH3:6])[O:11][CH2:10][C:9]([CH3:14])([CH3:12])[CH2:8][O:7]1
Reactant: CC(=O)CCCCl
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(C)(CCCCl)OC1
Temperature: 25 °C

Procedure:
A one liter, round bottom flask is equipped with a magnetic stir bar, a Dean-Stark water separator, a reflux condenser and a nitrogen inlet. This apparatus is dried in an oven overnight at 120° C., assembled hot, and is allowed to cool to room temperature in a stream of nitrogen. The flask is charged with 144.70 grams (1.20 moles) of 5-chloro-2-pentanone, 185.00 grams (1.32 moles) of 2,2-dimethyl-1,3-propandiol, 300 ml of toluene and 0.05 grams of p-toluenesulfonic acid catalyst. The flask is placed in a heating mantle and the reaction mixture is heated to reflux until close to the theoretical amount of water (21.6 ml) is collected in the Dean-Stark trap. The reaction mixture is allowed to cool to room temperature, transferred to a separatory funel and washed with 200 ml portions of saturated sodium bicarbonate solution, and three times with water. The resulting organic layer is separated, dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure on a rotary evaporator. This affords a clear, pale yellow oil, which is employed in the subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]([CH3:21])[CH:12]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
10.0 g (61.3 mmol) of 3,4-dichlorophenol, 10.4 g (55.8 mmol) of 4-chloro-2,5-dimethylnitrobenzene and 10.0 g (72.5 mmol) of potassium carbonate are stirred in 200 ml of N,N-dimethylformamide at 100° C. for 6 h, and the mixture is applied to ice, stirred at 0° C. for 15 min and then filtered. The solid is washed with water and hexane and dried under reduced pressure (18.0 g, 98.3% purity, 98.0% yield, log P (pH 2.3)=5.19).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH:12]1([C:17]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=3[C:7]=2[CH3:10])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1coc2ccc(F)cc12
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized above, cyclopentanecarbonylchloride (1.94 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-95:5, v/v) to give the title compound (2.11 g, 64%) as a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)CCC4)c2cc1OCC
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 205 mg (1.54 mM) of 5-Aminoindan in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The brown solid was dissolved digested in 200 ml of ethanol and the volume was reduced to 100 ml. The solid was isolated from the warm solution and washed with ethanol followed by ether and dried under vacuum at 80° C. to yield 435 mg of 6,7-Diethoxy-4-(indan-5-ylamino)-quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 374.0, mp=85-88° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:8][C:7]2[CH:9]=[N:10][CH:11]=[CH:12][C:6]=2[NH:5][N:4]=1.[C:13]([Cl:24])(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[ClH:24].[C:13]([N:5]1[C:6]2[CH:12]=[CH:11][N:10]=[CH:9][C:7]=2[NH:8][C:3]([CH3:2])=[N:4]1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC1=NNc2ccncc2N1
Agent: Cl
Product: CCCCCCCCCC(=O)N1N=C(C)Nc2cnccc21
Yield: 62.7 %

Procedure:
3.7 g (0.02 moles) of 3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with an excess of caprinic acid chloride as described in Example 2, to obtain 1-caprinoyl-3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 62.7%; m.p.: 237°-238° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:28]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)/C(C)=C/c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
3 b) The ester from 3 a, 3 eq. of potassium carbonate and 1.1 eq. of 3-hydroxypyridine were heated under reflux in DMF for 3 hours. After standard working up and purification, ethyl E-3-[4-(3-pyridyloxy)-3-(trifluoromethyl)phenyl]-2-methyl-propenoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27].C1(C)C=CC=CC=1.Cl.[CH3:38][NH:39][O:40][CH3:41]>O.C1(C)C=CC=CC=1>[CH3:41][O:40][N:39]([CH3:38])[C:26](=[O:27])[O:19][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]1[CH2:18][CH2:17]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)Oc1cc(Cl)nnc1Oc1c(C)cccc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was mixed with toluene (3 mL) and the mixture was ice-cooled. To the mixture were added 60 L (0.742 mmol) of pyridine, then 0.67 mL (0.724 mmol) of 1.08 mol/L phosgene-toluene solution under nitrogen atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, 120 L (1.48 mmol) of pyridine, then 70.4 mg (0.722 mmol) of N,O-dimethylhydroxylamine hydrochloride were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane: ethyl acetate, gradient) to obtain 100 mg (0.275 mmol, Yield: 38.1%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxy(methyl)carbamate (Compound No. 3564).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Temperature: 10 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10° C. under argon. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25° C. and stirred under argon for 16 hours. The reaction mixture was concentrated in vacuo Brine (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo). The crude material was purified by flash chromatography to furnish 2.49 g (37% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 3.43 (t, 4H), 3.69 (t, 4H), 6.87 (d, 2H).