Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[Na].CO.Cl.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18]>O>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(=O)C(OCC)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 40 g of ethyl diethoxyacetate (227 mmol) in 67 mL of ethyl acetate there are added under argon, in portions, 6 g of sodium (261 mmol). The reaction mixture is then stirred at ambient temperature for 48 hours. There are added 10 mL of methanol, and then the mixture is hydrolysed with 65 mL of water. The pH of the reaction mixture is adjusted to pH 6 by adding 1N aqueous HCl solution. The mixture is separated and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and piperidine monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml) The mixture was then heated under reflux under nitrogen for 18 h and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 h. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3000 ml) and stirred for 1 h and the precipitated solid isolated by filtration and dried at 50C in vacuo to give a solid.
Reaction SMILES: FC(F)(C[CH2:18][CH2:19][N:20]1C(=O)C=CC1=O)C(F)(F)C(F)(C1C=CC=CC=1)C([O-])=O.[C:28](=O)([O:36][C:37]1[CH:42]=CC=CN=1)[O:29][C:30]1[CH:35]=CC=CN=1>C(Cl)Cl.CCOCC>[NH2:20][CH2:19][CH2:18][CH:28]([O:29][CH2:30][CH3:35])[O:36][CH2:37][CH3:42]
Reactant: O=C1C=CC(=O)N1CCCC(F)(F)C(F)(F)C(F)(C(=O)[O-])c1ccccc1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(CCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 981 mg (3 mmol) of pentafluorophenyl-6-maleimido-hexane-1-carboxylate (1) (Example 11) dissolved in dry methylene chloride (30 ml) was added 10 g (1 mmol) of •-amino-•-amino PEG (2) (MW 10,000, n=226) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for 2 h and the product 3 obtained as a white powder by precipitation in ether (100 ml). The product was then dried under vacuum for 4 h.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:8](=[CH:13][C:14]=1[N+:15]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].CO.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>[Pt].C1(C)C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[CH3:2][C:1]1[NH:15][C:14]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:5]=2[N:4]=1
Reactant: COC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc2nc(C)[nH]c2cc1C(=O)OC
Reaction time: 2 h

Procedure:
A mixture of dimethyl 4-acetamido-5-nitrophthalate, methanol and 5% platinum on carbon is hydrogenated in a Parr hydrogenator. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated in vacuo. The thus-obtained crude diamine intermediate (48.09, 0.180 mol) is mixed with p-toluenesulfonic acid (51.4 g, 0.270 mol) and toluene (400 mL), and stirred for 2 hours at reflux temperatures with azeotropic removal of water, cooled and concentrated in vacuo. The resultant residue is recrystallized from methanol to afford the p-toluene sulfonate salt of the title product. The salt is dissolved in hot water, made basic with sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a red solid. Recrystallization of a portion of the red solid affords the title product as white crystals, mp 151°-152° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([OH:21])C>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([OH:21])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)c(O)cnn1Cc1ccccc1

Procedure:
To the mixture of 60 g of 2-benzyl-4,5-dichloro-3(2H)-pyridazinone and 38.8 g of potassium hydroxide was added 250 ml of ethanol and 150 ml of water and heated in an oil bath to the refluxing temperature for 10 hours. After reaction the solvent was distilled off under reduced pressure, and to the residual solution was added 200 ml of water and washed twice with chloroform, the water layer was acidified with concentrated hydrochloric acid. The white solid thus separated was filtered off, washed with water and dried to obtain 55 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone. Subsequently, in aqueous sodium hydroxide solution (NaOH 1.82 g, water 20 ml) were added 5.0 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 200 mg of 5 % Pd/C , then 474 ml of hydrogen gas was absorbed in the solution under normal pressure. After reaction, Pd/C was filtered off and to the solution was added concentrated hydrochloric acid to be acidified. The white solid thus separated was filtered off, washed with water and dried to obtain 4.1 g of 2-benzyl-5-hydroxy-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Li+:18].[OH-]>C1COCC1.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Li+:18]
Reactant: COC(=O)CCCCc1ccc(C=O)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(CCCCC(=O)[O-])ccc1C=O

Procedure:
Methyl 5-(3-amino-4-formylphenyl)pentanoate (447 mg) was treated with LiOH (88 mg) in 8.0 mL THF/water(v/v=3/1). Removal of the solvent after the reaction completed afforded lithium 5-(3-amino-4-formylphenyl)pentanoate (X3547-30). MS (ESI+): 222.10 (MH+). H NMR (400 MHz, MeOD): δ 9.72 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 6.55 (d, J=8.0 Hz, 1H), 2.56 (m, 2H), 2.19 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[Li+].[OH-].Cl>C1COCC1.CO>[Cl:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77.6 %

Procedure:
4,5-Dichloro-2-nitrobenzoic acid piperidine amide. A solution of 4,5-dichloro-2-nitrobenzoic acid methyl ester (0.29 g, 1.16 mmol) in 1:1 THF/methanol (4 mL) was stirred as 1 N aqueous LiOH (2 mL) was added. After 1 h, the mixture was acidified with 1 N HCl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to provide crude 4,5-dichloro-2-nitrobenzoic acid as a light yellow solid (0.26 g, 0.90 mmol, 77%). The acid was refluxed in 4 mL thionyl chloride for 2 h, and the crude reaction mixture was concentrated in vacuo. Residual thionyl chloride was removed by the repeated addition and in vacuo stripping of DCM. The acid chloride was placed under high vacuum for 10 min, and then taken up in dry DCM (5 mL). The mixture was cooled in an ice bath. Piperidine (0.46 g, 5.4 mmol, 0.53 mL) was added, and the reaction mixture was allowed to stand at 0° C. overnight. The mixture was diluted with DCM, washed with 1 N HCl (2×), 5% aqueous NaHCO3 and brine, and dried (MgSO4). Filtration and concentration provided 0.32 g of the desired amide, which could not be separated from an impurity (10%) that corresponded to the product of displacement of a chlorine by an additional equivalent of piperidine. HPLC (reversed-phase): RT=9.35 min (90%), 10.58 (10%). MS (ESI): m/z 303 [M+H]+, minor m/z 352 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][C:11]=3[O:19][CH3:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][C:11]=5[O:19][CH3:20])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cc(C(F)F)ccc1-c1cccn2nc(Cl)nc12
Product: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
4-{4-[8-(4-Difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.150 g, 0.484 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.161 g, 0.581 mmol) in a manner analogous to Example 311a and 311b to give product (0.191 g, 72%). MP=95-100° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.57 (s, 1H), 8.78 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.32 (s, 1H), 7.25 (m, 1H), 7.15 (d, 2H), 7.10 (br m, 1H), 7.05 (m, 1H), 4.10 (m, 2H), 3.78 (s, 3H), 2.78 (br m, 2H), 2.55 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H): MS=550 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: N#Cc1nc(-c2ccc(-c3ccccc3C(=O)N3CCOCC3)cc2F)cnc1N

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-bromophenyl)(morpholino)methanone and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C22H18FN5O2, 403.14; m/z found, 404.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.45 (d, J=2.1, 1H), 6.71 (m, 1H), 6.32-6.21 (m, 3H), 6.17-6.10 (m, 2H), 6.07 (dd, J=12.4, 1.8, 1H), 2.40-2.22 (m, 3H), 2.13-2.03 (m, 2H), 1.86-1.77 (m, 1H), 1.62-1.49 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: N#Cc1ccnc(Sc2ccc(CO)cc2)c1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2ccc(Sc3cc(C#N)ccn3)cc2)c(C)c1O
Yield: 69.4 %

Procedure:
Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.10 g, 4.54 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (754 mg, 4.54 mmol) affords the title compound (1.23 g, 69%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
5-Nitroindole-1-carboxylic acid phenylamide (3.53 g, 12.3 mmol) was dissolved in ethanol (250 ml); water (50 ml), electrolytic iron powder (2.75 g, 49.2 mmol), ammonium chloride (5.26 g, 98.4 mmol) were added thereto; and the reaction mixture was heated and stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered off; insoluble portions were washed with ethyl acetate; and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and a solvent mixture of ethyl acetate and tetrahydrofuran; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified by diethyl ether; the crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound as pale red powder (681 mg, 2.71 mmol, 22.0%). The mother liquor was concentrated under reduced pressure, which was then treated by the similar methods to yield the title compound (590 mg, 2.35 mmol, 19.1%) as pale red powder (secondary crystals).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:20][C:19]([CH2:21][O:22]CC4C=CC(OC)=CC=4)=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.ClCCl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:20][C:19]([CH:21]=[O:22])=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1COCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To 10.3 g (20.6 mmol) of ethyl 5-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(4-methoxybenzyloxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 45-(c) were added 100 ml of dichloromethane and 10 ml of water, then, 5.15 g (22.7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction suspension was filtered through Celite, the filtrate was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, and then, with a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added 100 ml of a mixed solvent (diisopropyl ether/hexane=1/1 (V/V)), and the precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether, and dried under reduced pressure to obtain 3.98 g of the title compound as a pale yellowish solid. (Yield: 49%)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([CH:16]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]>CCCCCC.C(OCC)(=O)C>[CH2:12]([C:16](=[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(C(=O)OCC)=C(Nc1ccc(C(=O)OC)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 30 h
Yield: 100.8 %

Procedure:
27.8 g of methyl 4-aminobenzoate and 47 g of diethyl 2-butyl-3-oxo-butanedioate were mixed and 2 g of activated siliporite were added. The mixture was stirred for about 30 hours at 60° C. and after chromatography (eluant: hexane-ethyl acetate 95-5), 70 g of the expected product were obtained.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>CCO>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][NH:15][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[I:1]
Reactant: CCOC(=O)COc1ccccc1I
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1ccccc1I)NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of ethyl 2-(2-iodophenoxy)acetate (900 mg, 2.94 mmol) in EtOH (3 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (677 mg, 3.24 mmol). The reaction mixture was heated under microwave conditions at 80° C. for 3 h, cooled and concentrated. The crude product was used in the next step without further purification. (1.3 g, yield 95%) MS (ESI+) e/z: 467.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.80 (dd, J=1.0, 7.8 Hz, 1H), 7.41-7.30 (m, 1H), 7.15-7.05 (m, 3H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87-6.76 (m, 1H), 4.66-4.53 (m, 2H), 4.06 (quin, J=5.9 Hz, 1H), 3.77-3.63 (m, 2H), 3.58 (dd, J=4.5, 13.6 Hz, 1H), 3.38 (dd, J=6.4, 13.7 Hz, 1H), 2.98-2.86 (m, 2H), 2.86-2.76 (m, 2H), 2.66-2.57 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[O:12])[CH:6]=1.N>C(O)(=O)C>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[O:12])[CH:6]=1
Reactant: COc1cc(C(=O)c2cccnc2)ccc1O
Reactant: O=[N+]([O-])O
Agent: N
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
da) 0.38 ml of 65 percent nitric acid is added dropwise at room temperature to 1.15 g of 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone dissolved in 15 ml of acetic acid. After stirring for 2 hours, the reaction mixture is poured into 120 ml of ice-water, whereupon the mixture is adjusted to pH 5 with conc. ammonia and the precipitate formed is filtered off. The thus-obtained residue is heated under reflux in 20 ml of acetonitrile, whereupon it is again filtered off. There is obtained 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone as brown crystals of m.p. 193°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[C:22]([O:23]C)=[CH:21][CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][C:1]([C:21]3[CH:20]=[CH:19][CH:15]=[C:14]([OH:13])[C:22]=3[OH:23])=[N:5][C:4]=2[CH:6]=1
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc2oc(-c3cccc(O)c3O)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2,3-dimethoxybenzoic acid. The product was obtained as a tan solid, m.p. 239-241° C.; MS m/e 244 (M+H)+
Reaction SMILES: C(Cl)(=O)OCC.[OH:7][C:8]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:7][C:8]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:9]=1[C:10]([NH:28][CH2:27][C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: CCCc1c(OC)ccc(C(=O)O)c1O
Reactant: NCc1cccs1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OC)ccc(C(=O)NCc2cccs2)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, a solution of ethyl chlorocarbonate (7.65 ml) in methylene chloride (90 ml) was cooled to -15° C., and to the solution was added dropwise a solution of 2-hydroxy-3-n-propyl-4-methoxybenzoic acid (8 g) and triethylamine (11.1 ml) in methylene chloride (160 ml) for 30 minutes, and the mixture was agitated for another 15 minutes. 2-thiophenemethylamine (4.7 ml) was added to the mixture and the mixture was agitated for 3 hours while the temperature of the mixture was elevated to 0° C. The reaction mixture was poured into 1N aqueous hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with a mixed solution of saturated aqueous solution of sodium chloride and saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was dissolve in methanol (100 ml), and the solution was cooled to 0° C. The solution was added to 8.5% aqueous solution of sodium hydroxide (50 ml) and the mixture was agitated at room temperature for 4.5 hours. The reaction mixture was acidified by adding 6N aqueous hydrochloric acid thereto, and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained N-(2-hydroxy-3-n-propyl-4-methoxybenzoyl)-2-thiophenemethylamine (5.7 g) from fractions eluted with n-hexane-methylene chloride (2:1).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=1)[C:24](O)=[O:25]>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:18][C:24](=[O:25])[C:23]2[C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=[C:21]([Br:20])[C:22]=2[O:33][CH3:34])[C:3]([OH:2])=[O:19])=[CH:7][CH:8]=1
Reactant: COc1c(Cl)cc(Br)c(OC)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COc1c(Cl)cc(Br)c(OC)c1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 80.6 %

Procedure:
2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5 mmol) was reacted with 3-bromo-5-chloro-2,6-dimethoxybenzoic acid (148 mg, 0.5 mmol) as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (209 mg) as a pure white solid.
Reaction SMILES: N[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.BrC1C(C)=C(C2C=CC=C(C(F)(F)F)C=2)C([Cl:42])=NC=1>>[Cl:42][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.22 mmol) using a similar method to that used for Intermediate 14 (73 mg).