Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].S(=O)(O)[O-].[Na+].S(=O)(O)[O-].[C-:17]#[N:18].[Na+]>C(Cl)Cl.O>[C:17]([CH:4]([OH:5])[CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])#[N:18]
Reactant: CCC(C=O)CC
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(O)C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-ethyl butyraldehyde (6 g, 60 mmol) in CH2Cl2 (75 mL) was stirred vigorously with a solution of sodium bisulfite (9.4 g, 90 mmol) in water (35 mL). The thick precipitate which had formed was collected by filtration and washed with CH2Cl2 and dried in vacuo. The bisulfite adduct (10 g, 49 mmol) was dissolved in water (60 mL) and to the solution was added sodium cyanide (3.6 g, 73 mmol). The resulting solution was stirred at ambient temperature for 48 h. The mixture was extracted with ether (2×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified by flash silica gel column chromatography using a gradient elution of 10%, 12.5%, 15% EtOAc in hexanes. The product-containing fractions were combined to give 1-cyano-2-ethylbutanol as a liquid after removal of the solvents in vacuo (5.0 g; TLC Rf=0.4 (9:1 hexanes:EtOAc); 400 MHz 1H NMR, CDCl3, 4.51 ppm (dd, 1H), 2.45 ppm (d, 1H), 1.4-1.7 ppm (overlapping m, 5H), 0.98 ppm (overlapping t, 6H)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[NH2:6].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:18])[CH:10]=1)[NH2:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
To a suspension of 4-nitroanthranilic acid methyl ester (16.5 g, 84 mmol) in glacial acetic acid (500 mL), a solution of sulfuryl chloride (13.6 g, 0.1 mol) in glacial acetic acid (20 mL) was added dropwise. The homogeneous mixture was stirred at room temperature for 18 h and the solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with saturated NaHCO3 (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The 1H NMR spectrum of the crude compound revealed the formation of a mixture of products, namely the desired 5-chloro regioisomer, and the byproducts 3-chloro regioisomer and the 3,5-dichlorinated compound. The crude mixture was purified by flash chromatography (silica gel, gradient 30-100% hexanes/CH2Cl2) to afford the desired 5-chloro-4-nitroanthranilic acid methyl ester (7.1 g, 36%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
40 g of 4,4-diphenylpiperidine, 24.7 g of 3-bromopropanol, 116.4 g of powdered potassium carbonate and about 1 g of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in 500 ml of a 1:1 mixture of dioxane and 1-butanol for about 48 hours. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate, and the solution is filtered again. After the filtrate has been concentrated to dryness, the title product is obtained as a yellowish oily residue which slowly solidifies as a wax. Yield: 44.8 g. With ethereal hydrochloric acid, the hydrochloride is obtained, and is recrystallized from 2-propanol. m.p.: 226°-227° C.
Reaction SMILES: C([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][NH:33]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:53]>>[ClH:53].[ClH:53].[ClH:53].[ClH:53].[NH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH2:20]
Reactant: c1ccc(C(NCCNCCCCCCNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: NCCNCCCCCCNCCN

Procedure:
A mixture of N,N′-bis(2′-tritylaminoethyl)-1,6-diaminohexane (1.0 g. 1.45 mmol) and 6 M HCl (30 ml) was refluxed for 3 h. Then the mixture was filtered and the filtrate was concentrated to about 3 ml over vacuo. Addition of methanol into the concentrated solution afforded a white salt.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.[CH3:12][C:13]([CH3:15])=[O:14].[NH4+].[Cl-]>O>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:13]([OH:14])([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(C)c(C(C)(C)O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
According to Example 3, mesitylmagnesium bromide (1.20 M in THF; 1.83 mL; 2.20 mmol; 1.10 equiv) was placed in a flame dried schlenk flask under an argon atmosphere and cooled to 0° C. At this temperature, LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv) was slowly added. The resulting mixture was allowed to warm up to room temperature and stirred for 4 h. Then, after cooling to 0° C., acetone (116 mg; 2.00 mmol) was added and the reaction was warmed up to room temperature and stirred for another hour at this temperature. When the end of the reaction was reached (GC-monitoring of aliquots), sat. aq. NH4Cl (2 mL) and water (2 mL) were added. The aqueous layer was extracted with ether (4×10 mL), the combined extracts were dried (Na2SO4) and evaporated in vacuo. Column chromatographical purification (silica; pentane:Et2O 9:1) afforded the desired product as colorless, crystalline solid, mp=106−107° C. (245 mg, 69%).
Reaction SMILES: C(CC[O:12][C:13]([CH2:15][NH:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([O:30]CC)=[O:29])=[O:14])C(C1C=CC=CC=1)=O.[OH2:33].[OH-].[Li+]>O1CCCC1.O>[CH2:18]([N:16]([CH2:15][C:13]([OH:12])=[O:14])[C:17]1[C:25]2[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=2[Cl:26])[NH:19][C:18]=1[C:28]([OH:30])=[O:29])[C:17]([C:25]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:33]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)OCCCC(=O)c1ccccc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN(CC(=O)c1ccccc1)c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12

Procedure:
Dissolve 3-[(phenacyl)carbethoxymethyl-amino]-2-carbethoxy-4,6-dichloroindole (0.29 g, 0.626 mmol) in tetrahydrofuran (27 mL) and water (13 mL). Add lithium hydroxide monohydrate (0.158 g, 3.76 mmol) and stir overnight. Pour into 1N hydrchloric acid (100 mL) and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.15 g, mp 235°-7° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3].N1C=CC=CC=1.ClC([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:22])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CS(C)(=O)=O)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CS(C)(=O)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (8D, 420 mg, 1.3 mmol) in 4M HCl in dioxane (3 ml) was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in pyridine (3 ml, 37.1 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (385 mg, 1.936 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (8E, 160 mg, 0.40 mmol, 31% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H) 3.90 (s, 3 H) 5.88 (s, 2 H) 6.73 (d, J=2.78 Hz, 1H) 7.49 (d, J=3.28 Hz, 1 H) 8.01-8.12 (m, 2 H) 8.12-8.19 (m, 2 H) 8.46 (s, 1 H) 8.70 (s, 1 H) 10.93 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18](OC)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35]Br.C[N:38](C=O)C>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([C:18]([NH2:38])=[O:19])[CH2:35][CH2:34]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:3][CH2:2]1
Reactant: BrCCBr
Reactant: CN(C)C=O
Reactant: COC(=O)CS(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(C(N)=O)CC3)ccc2n1CC1CC1
Reaction time: 30 h
Yield: 80 %

Procedure:
To a solution of methyl {[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}acetate (Example 1, Step F, 620 mg, 1.64 mmol) in N,N′-dimethylformamide (6.0 mL) was added potassium carbonate (680 mg, 4.91 mmol) and 1,2-dibromoethane (170 μL, 1.97 mmol) at room temperature and stirred for 30 h. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2 as eluent) to afford the title compound (533 mg, 80%) as a white amorphous.
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:22]([O-:25])([O-:24])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([C:22]([O:25][CH2:21][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:24])[CH2:16][CH2:17][N:18]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Agent: Br
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl)-1,4,7-triazacyclononane dihydrobromide (1.3.13.31), K2CO3 and benzyl chloroformate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].C([O-])(=O)C.[Na+].CN([CH:20]=[C:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=O)C>CCCCO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[CH:20]=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 55.9 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)hydrazine hydrochloride (6.78 g, 31.8 mmol) and anhydrous sodium acetate (2.60 g, 31.8 mmol) in n-BuOH (20 mL) is slowly added to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (5.32 g, 31.8 mmol) in n-BuOH (100 mL) and acetic acid (5 mL). The resulting mixture is heated to reflux during 2 hours, effecting follow-up of the reaction by TLC. The solvent is evaporated at reduced pressure, the residue is diluted in AcOEt and washed with H2O. The solvent is next evaporated, and the crude is purified by silica-gel chromatography, to obtain 1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (5.0 g, 17.79 mmol, 56%, orange solid). 1H RMN (300 MHz, CDCl3): δ 2.17 (m, 2H), 2.51 (m, 2H), 2.96 (t, J=6.1 Hz, 2H), 7.36 (t, J=8.6 Hz, J′=2.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1)=[CH2:6]>CC(C)=O>[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:1][C:2]#[N:3])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: N#C[S-]
Reactant: C=Cc1ccc(CCl)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: C=Cc1ccc(CSC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
Ammonium thiocyanate (2 equiv., 43 g, 0.50 mol) was dissolved in acetone (200 ml) and 4-vinylbenzyl chloride (43 g, 0.25 mol) was added to the reaction flask. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and acetone removed under reduced pressure. The resulting product was dissolved in hexane, filtered, and the solvent removed under reduced pressure. The monomer was isolated as a red-orange, slightly viscous liquid (26 g, yield 52%). 1H NMR (CDCl3) δ (ppm) 4.13 (s, 2H), 5.29 (d, 1H), 5.76 (d, 1H), 6.67 (dd, 1H), 7.31 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:5]=2[N:4]=1.[Na+].[I-].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(#[N:26])C>>[O:21]1[CH2:22][CH2:23][N:18]([NH:26][CH2:2][C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:5]=3[N:4]=2)[CH2:19][CH2:20]1
Reactant: CC#N
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2[nH]c(CCl)nc2c1
Agent: [I-]
Agent: [Na+]
Product: COC(=O)c1ccc2[nH]c(CNN3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
Methyl 2-(chloromethyl)-1H-benzimidazole-5-carboxylate (5) (0.5 g, 2.2 mmole), NaI (30 mg, 0.2 mmole), in 25 ml of anhydrous acetonitrile, add morpholine (0.48 ml, 5.50 mmole) and stir at ambient temperature for 5 hours. The solution was concentrated under reduced pressure and the resulting yellow solid redissolved in dichloromethane (20 ml) and washed with 10 ml of saturated bicarbonate solution. The organics were dried over anhydrous sodium sulfate and then concentrated to yield a fluffy solid (0.5 g, yield 81%) of 6.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])=[O:8].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([CH3:33])[C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7]([C:3]1[N:2]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:33])[CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cccc(C)c1NC(=O)c1cccn1N
Product: Cc1cccc(C)c1NC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 74.8 %

Procedure:
The title compound was prepared from 1-amino-N-(2,6-dimethylphenyl)-1H-pyrrole-2-carboxamide (324 mg, 1.41 mmol) and (S)-2-(benzyloxycarbonylamino)propanoic acid (347 g, 1.55 mmol) following the experimental procedure described in Preparation 73a. 458 mg (75% yield) of the desired compound were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH3:17])=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4].[C:18]([OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:26][CH2:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH3:17])=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)CCl)c(N(C)C=O)cc1C
Reactant: O=C(O)c1ccccc1
Product: COc1cc(C(=O)COC(=O)c2ccccc2)c(N(C)C=O)cc1C

Procedure:
The solution of 2'-(2-chloroacetyl)-4'-methoxy-5'-methyl-N-methylformanilide may be reacted with benzoic acid by a method analogous to that of Example 2(d) to give the novel compound 2-[5-methoxy-4-methyl-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[OH:13]>CC(C)=O>[O:13]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[O:15][CH2:5][CH:2]1[C:3]#[N:4]
Reactant: C=C(Cl)C#N
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1COc2ccccc2O1

Procedure:
1.45 g (15.5 mmol) of 2-chloroacrylonitrile and 6 g (43.5 mmol) of dry potassium carbonate are added in succession to 6.6 g (60 mmol) of catechol dissolved in 80 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the mixture is then heated to boiling. After 18 hours at reflux under argon, the reaction mixture is cooled and then filtered over Celite. After evaporation of the solvent, the residue is taken up in a water/ethyl acetate mixture (50:50) and then the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is evaporated under reduced pressure. The title nitrile is obtained pure in the form of a white solid after purification on a silica column (eluant:AcOEt/PE 30/70).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH:21]=[N:20][N:19]=[C:18]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[CH2:28]=[O:29]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:17]2[C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:19][N:20]=[C:21]2[CH2:28][OH:29])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Reactant: C=O
Solvent: CC(=O)O
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(CO)nnc3-c3cccnc3)c2nc1OC
Temperature: 125 °C
Yield: 55.4 %

Procedure:
A suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 98, 1.008 g, 2.5 mmol) and paraformaldehyde (0.75 g, 25 mmol) in acetic acid (14 mL) was heated at 125° C. for 3 hours in a sealed vessel. After being cooled, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 95:5, by volume) to afford the title compound (0.60 g, 56%) as a white solid, mp 209-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: Cc1ccc(C=O)c(C)c1
Product: Cc1ccc(CNc2ccc(C(C)C)cc2)c(C)c1
Yield: 97.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dimethylbenzaldehyde (1.3 g) and 4-isopropylaniline (1.4 g) as starting material, [(2,4-dimethylphenyl)methyl](4-isopropylphenyl)amine (2.4 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][C:15](NN)=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.I[CH2:20][CH3:21].C([O-])([O-])=[O:23].[K+].[K+]>CN(C=O)C>[CH2:20]([O:23][C:15](=[O:16])[CH2:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)[CH3:21]
Reactant: NNC(=O)CCc1nc(-c2cccc(Cl)c2)no1
Reactant: O=C([O-])[O-]
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1nc(-c2cccc(Cl)c2)no1

Procedure:
3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated with succinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at 150° C. for an h. The reaction mixture was cooled down and diluted with ethyl acetate. The organic solution was washed with water and brine, concentrated by vacuum. The residue was triturated with 20% ethyl acetate in hexanes to give 4.0 g (60%) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as white solid. ). 1H-NMR(CDCl3) d(ppm): 8.08 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide: This acid was reacted with iodoethane (1.6 g, 10.5 mmol) and K2CO3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min to form 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid ethyl ester. The ethyl ester was then treated with 37% hydrazine (2 ml) in ethanol (5 ml) at 80° C. for 2 h to give 595 mg (65% in 3 steps) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide as off-white solid 1H-NMR(CDCl3) d(ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95 (w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.C[C:15]([CH3:18])([O-:17])C.[K+].C1C[O:23][CH2:22][CH2:21]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:21][C:22]([O:17][CH2:15][CH3:18])=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one 46.1 (10.0 g, 56.7 mmol, Aldrich) and triethyl phosphonoacetate (13.6 mL, 68.1 mmol) in THF (250 mL) was added potassium tert-butoxide (1.0M solution in THF (68.1 mL, 68.1 mmol)) via addition funnel over 15 minutes. The resulting mixture was stirred at room temperature for 16 hours (LC-MS showed no difference between 15 minutes and 16 hours) after addition. The mixture was concentrated and re-suspended in hexanes (250 mL). The mixture was passed through a silica gel plug (50 g silica) and rinsed with 1 L of hexanes. The resulting mixture was concentrated to give two pure products (535 mg and 267 mg). Both products were dissolved in EtOH and stirred with Pd/C under H2 for 16 hours. LC-MS showed that both gave the same desired product. The mixture was combined, filtered, and concentrated to give 46.2 (0.77 g, 5.5% yield). MS ESI (pos.) M/E: 249 (M+H).
Reaction SMILES: OC1C=CC(C=O)=CC=1.BrC1CC1.[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)#[N:26]>>[F:24][C:15]([F:14])([F:23])[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: BrC1CC1
Agent: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(COc2ccc(C(F)(F)F)nc2)cc1
Yield: 96.7 %

Procedure:
Instead of 4-hydroxybenzaldehyde and bromocyclopropane, 6-(trifluoromethyl)pyridin-3-ol (1.21 g) and 4-cyanobenzylbromide (1.45 g) were respectively used and treated by the same technique as in Reference Example 10-1 to give 4-({[6-(trifluoromethyl)pyridin-3-yl]oxy}methyl)benzonitrile as a pale brown solid (1.99 g).