Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)N2CCNCC2)=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)CC(O)=[O:30])C=CC=CC=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:30])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
To a solution of 1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine (0.59 g, 2.08 mmol) in dry CH2Cl2 (40 ml) was added 3,3-diphenylpropanoic acid (0.472 g, 2.08 mmol) under nitrogen. To the reaction was added EDC (0.797 g, 4.16 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temp. over night. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane: ethyl acetate (3:1) to give desired product in 78% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCCCC1)C(C)(C)CCC2(C)C
Yield: 93.9 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) and 760 mg (4.08 mmol) of 1-(2-chloroethyl)-piperidine hydrochloride, 1.57 g (89%) of the expected compound was obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1.C(=O)(O)[O-].[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:27])[CH2:9][N:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=[C:7]3[C:6]=2[CH:20]=1
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: S=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Yield: 40 %

Procedure:
A mixture of 3.74 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 2.58 g sodium bicarbonate, and 13.67 g P2S5 in 85 ml diglyme was heated at 105°-120° C. under nitrogen for one and a half hours. The cooled reaction mixtre was diluted with water to precipitate a solid. Recrystallization from toluene yielded 1.58 g solid, which decomposed at 265° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[H-].[Na+].[CH2:15]([N:17]=[C:18]=[O:19])[CH3:16]>O1CCCC1>[CH2:15]([NH:17][C:18]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:19])[CH3:16]
Reactant: CN(C)C=Nc1ccncc1O
Reactant: CCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Oc1cnccc1N=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a warm solution of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.12 g) in dry tetrahydrofuran (150 mL) were added sodium hydride (173 mg) and ethyl isocyanate (3.59 mL). The reaction mixture was stirred at room temperature overnight, cooled in an ice bath and filtered, and the solid was washed with diethyl ether. The solid was distributed between methylene chloride (250 mL) and saturated ammonium chloride (30 mL) and extracted twice more with methylene chloride (100 mL). The solution was dried (MgSO4) and concentrated, and the solid was recrystallized from ethyl acetate to yield 5.7 g of needles, m.p. 138° C. (dec.).
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[O:22])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2].S([O-])(O)=O.[Na+].C(OCC)(=O)C.[C-:45]#[N:46].[K+]>O>[C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]([OH:22])[C:45]#[N:46])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](C=O)Cc2ccccc2)C(=O)C1C(C)C
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C#N)C(=O)C1C(C)C
Reaction time: 0.5 h

Procedure:
(2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal (630 mg, Compound No. 7-1) is suspended in water (6 ml). Sodium hydrogensulfite (160 mg), water (6 ml) and ethyl acetate (18 ml) are added to the suspension, and the mixture is stirred for 30 minutes. Potassium cyanide (105 mg) is added to the mixture, and the whole is stirred for one day. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (624 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](C3CCN(C(OC(C)(C)C)=O)CC3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[ClH:26].C(O[CH2:31][CH3:32])(=O)C>>[ClH:26].[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:9]3[CH2:32][CH2:31][CH2:4][CH2:5][CH2:8]3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Product: Fc1ccc(-c2csc(N3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of tert-butyl 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (2.49 g, 6.85 mmol) in ethyl acetate (100 ml) was added a 4N solution (100 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to give 1.88 g (82.0%) of the desired product as a solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19].Cl.[CH3:23][NH:24][OH:25]>C(Cl)(Cl)Cl>[CH3:23][N:24]([OH:25])[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1)=[O:17]
Reactant: CNO
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(O)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
33 ml of triethylamine and then 44.3 g of 4-chloro-3-trifluoromethylphenyl isocyanate in 200 ml of chloroform were added to a mixture of 21 g of N-methyl hydroxylamine hydrochloride and 200 ml of chloroform at 0° C and the mixture was stirred at 20° C for 16 hours. The mixture was washed with water and was reduced to a volume of 100 ml under reduced pressure. The mixture was iced and vacuum filtered. The crystals were washed with water and dried to obtain 37 g of N-methyl-N-hydroxy-N'-(4'-chloro-3'-trifluoromethylphenyl)-urea melting at 114°-115° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: Fc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(F)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 35.5 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 71 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=4[CH3:24])[CH2:33][CH2:34]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2-c2ccccc2)cc1

Procedure:
117 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(2,3-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[C:17]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1nccs1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nccs1)C(=O)OCC

Procedure:
2-Aminothiazole (10.0 g., 0.10 mole) and diethyl ethoxymethylenemalonate (23.8 g., 0.11 mole) were combined and heated on a steam bath for 1.25 hours. The reaction mixture was cooled and the resulting semisolid recrystallized from hexane to yield purified 2-(2,2-dicarbethoxyethenyl)thiazole (17.2 g. in two crops, Rf 0.6 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([O:27]CC2C=CC=CC=2)=[O:26])=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:35][CH:36]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)OCc2ccccc2)cc1)Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
H2 (1 atm) was bubbled slowly trough a suspension of 10% Pd/C (917 mg) in EtOH (25 mL) for 15 min at rt. To this suspension was then added a solution of benzyl 4-({(tert-butoxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)benzoate (4.303 g, 8.61 mmol) diluted in EtOH (5 mL). The resulting reaction mixture was stirred under 1 atm H2 for 4.5 h at rt. The reaction mixture was filtered over a pad of celite to remove the catalyst. EtOH was evaporated to afford the title compound as a colorless oil used in the next steps without further purification (3.520 g, 99%). 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.45-7.21 (m, 4H), 5.54 (s, 2H), 4.45 (s, 2H), 1.50 (s, 9H). HPLC (Condition A), Rt: 5.42 min (HPLC purity: 96.1%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[Cl:14][C:15]1[C:20](Cl)=[N:19][CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: Clc1nccnc1Cl
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1[N+](=O)[O-])c1nccnc1Cl
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 1.52 g of N-methyl-2-nitroaniline in N,N-dimethylformamide (50 ml) was added in a nitrogen atmosphere 0.44 g of sodium hydride. After stirring for 30 minutes, 1.75 g of 2,3-dichloropyrazine was added thereto and the resulting mixture was stirred at room temperature for additional 6 hours. Then the reaction mixture was distributed into ethyl acetate and a saturated aqueous solution of sodium dihydrogenphosphate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.586 g of the title compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:2][OH:3])=[O:30])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1ccc(CCCCCCCCC(=O)NO)cc1
Reaction time: 72 h
Yield: 30 %

Procedure:
To a cold, stirring suspension of 1.1 gm hydroxylamine hydrochloride and 1.5 gms sodium carbonate in 25 ml CH2Cl2 was added dropwise 3.7 gms 9(4-butoxyphenyl)nonanoyl chloride. This mixture was stirred in the cold for 1/2 hr and then for 72 hrs at room temperature. The reaction mixture was filtered. The precipitated solid was crystallized three times from CH2Cl2 (treating with charcoal during the second crystallization) to give 1.1 gms of product of m.p. 99°-101°. Elemental analysis: calculated C 70.99, H 9.72, N 4.36% found C 70.75, H 9.64, N 4.34%.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]([O:21]C)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>ClCCl>[C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]([OH:21])=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C=C(C#N)C(=O)Nc2ccccc2)c2c1CCCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC(=Cc1ccc(O)c2c1CCCC2)C(=O)Nc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred solution of N-phenyl β-(4-methoxy-5,6,7,8-tetrahydronaphth-1-yl)-α-cyanoacrylamide (3.324 g, 0.01 mol) in anhydrous dichloromethane (100 ml) was added at -78° C. under nitrogen, over a period of 20 min, a 1M boron tribromide solution in dichloromethane (30 ml, 0.030 mol). The resulting mixture was stirred for another 1 h at -78° C. and then allowed to warm up to room temperature. After stirring for 1.5 h at room temperature the mixture was cooled to -10° C. and then quenched by dropwise addition of water (100 ml) over a 10-min period. After addition of ethyl acetate (100 ml) the organic layer was separated, washed with water, dried over Na2SO4 and evaporated under vacuum to dryness. The residue was crystallized from ethanol thus giving pure title compound in 65% yield (2.070 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Cl)=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:20]=1B(O)O)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:20]2[C:21]([CH2:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:17][CH3:18])=[N:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1C(F)(F)F
Reactant: CCc1cccc(CC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)c(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-2-trifluoromethyl-nicotinic acid methyl ester (1.0 g, 3.7 mmol), 2,6-diethyl-phenyl boronic acid (0.78 g, 4.4 mmol), sodium carbonate (2 M aqueous solution, 4.4 mL, 8.8 mmol), and Pd(PPh3)4 (206 mg, 0.18 mmol) is refluxed in toluene for 48 hours and then cooled to room temperature. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are dried and the solvent removed. The crude product is purified by flash column (hexanes/ethyl acetate 8:1) to give 4-chloro-6-(2,6-diethyl-phenyl)-2-trifluoromethyl-nicotinic acid methyl ester as a white solid. 1H NMR: (CDCl3) 7.58 (s, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 4.02 (s, 2.28 (q, 4H), 1.04 (t, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][C@@H:5]2[S:6][C@@H:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:9][C@@H:4]2[C@H:3]1/[CH:18]=[CH:19]/[C@@H:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+].Cl>CO>[OH:1][C@@H:2]1[CH2:17][C@@H:5]2[S:6][C@@H:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C@@H:4]2[C@H:3]1/[CH:18]=[CH:19]/[C@@H:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Reaction time: 8 h
Yield: 72 %

Procedure:
The compound 14 (6.9 mg) was dissolved in methanol (0.4 mL), a 2M aqueous sodium hydroxide solution (0.1 mL) was added at room temperature, and the mixture was stirred overnight. Dilute hydrochloric acid was added to the reaction liquid, and the mixture was then extracted with ethyl acetate two times. The organic layers were combined, washed with a saturated saline, and dried with anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol=100:1→10:1) to obtain a titled compound (4.8 mg) having the following physical property values.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21
Yield: 85 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution. Yield: 85% of theory, C24H22N6O4 (458.5) ##EQU26##
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.Cl>ClCCl.C(OCC)(=O)C>[C:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Heptanoyl chloride was added to a suspension of aluminum chloride in dichloromethane. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of indole in dichloromethane. The mixture was stirred at room temperature for 1 hour and poured into a mixture of hydrochloric acid and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ether to give 3-heptanoylindole as a white powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[CH:18]([O:21]C)(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:9]=1)[CH:18]=[O:21])[C:4]([F:6])([F:5])[F:7]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Yield: 90.9 %

Procedure:
To a stirred and ice-cooled solution of Compound 8 (650 mg, 2.5 mmol) in dry CH2Cl2 (15 ml) was added neat TiCl4 (950 mg, 5.0 mmol) followed by Cl2CHOMe (600 mg, 5.0 mmol). After the addition was complete, the mixture was stirred at room temperature for 5 hr, poured into H2O (60 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give a yellow oil, which was purified by a column chromatography on silica gel to give Compound 9 (650 mg, 90%)
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1C=CC=CC=1>[ClH:26].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 42 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (7.73 g, 30 mmol), triethylamine (8.37 ml, 60 mmol) and 2-chloro-1-phenylethanone (6.12 g, 39 mmol) in 100 ml of benzene was refluxed for 5 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-4), yield 59.51%, mp 236-238° C. M+ 339.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:5])[CH3:2].[Cl-].[CH3:14][NH2+]C.C=O>>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:14])[CH:11]=[O:12])=[O:5])[CH3:2]
Reactant: C[NH2+]C
Reactant: CCOC(=O)COCCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCOCC(=O)OCC

Procedure:
11 g (63.1 mmol) of 4-ethoxycarbonylmethoxybutanal, 5.8 g (71.4 mmol) of dimethylammonium chloride and 5.5 ml (73.5 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated by evaporation giving 4-ethoxycarbonylmethoxy-2-methylene-butanal as a yellowish liquid which is further reacted without purification.