Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])(=O)[C:2]([CH3:4])=C.[CH2:12]([O:15][C:16]1C=CC(O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:7]([O:6][C:1]1[CH:2]=[CH:4][C:12]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:13][CH:14]=1)(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=CCOc1ccc(O)cc1
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(OC(=O)C(=C)C)cc1
Temperature: 37 °C
Yield: 84.5 %

Procedure:
Methacrylic anhydride (6.92 g; 0.045 moles) was added dropwise to a chilled solution of purified 4-allyloxyphenol (7.0 g; 0.047 moles), triethylamine (3.55 g; 0.035 moles), 4-dimethylaminopyridine (0.43 g; 0.004 moles), 2-6-di-tert-butyl-4-methylphenol (0.018 g; 0.08 m moles) and toluene (20 ml) in a stirred 100 ml reaction flask fitted with a reflux condenser, magnetic stirrer and thermocouple probe. During the addition the reaction temperature increased to 37° C. The mixture was heated at 110° C. for 1.5 hour, cooled and washed sequentially with equal volumes of saturated sodium bicarbonate, dilute hydrochloric acid and water. The solution was dried over magnesium sulfate and the solvent removed under reduced pressure to yield 4-allyloxyphenyl methacrylate (8.3 g; 90% yield) as a clear yellow liquid. The structure of the monomer was confirmed by proton and infrared spectral analysis and GC analysis indicated a purity of 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([OH:11])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[H-].[Na+].Br[CH2:20][C:21]1[C:25]2[C:26]([Cl:31])=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[O:23][CH:22]=1.[Cl-].[Na+].[N+:34]([O-:37])([OH:36])=[O:35]>CN(C)C=O.C(OCC)C.C(OCC)(=O)C.C(O)(=O)C.O>[N+:34]([O-:37])([OH:36])=[O:35].[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([O:11][CH2:20][C:21]1[C:25]2[C:26]([Cl:31])=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[O:23][CH:22]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: Clc1cc(Cl)c2c(CBr)coc2c1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Clc1ccc(C(Cn2ccnc2)OCc2coc3cc(Cl)cc(Cl)c23)c(Cl)c1
Reaction time: 2 h

Procedure:
A stirred solution of 0.51 g (0.002 mol) of 2,4-dichloro-α-[(1-imidazolyl)methyl]benzyl alcohol was cooled to 0° C. and treated with 48 mg (0.002 mol) of sodium hydride (60 mg of an 80% dispersion in mineral oil). Stirring was continued and, after the effervescence had ceased (about 0.5 hour), the mixture was treated with a solution of 0.56 g (0.002 mol) of 3-bromomethyl-4,6-dichlorobenzofuran in 2 ml of dry dimethylformamide. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 2 hours. The mixture was treated with 50 ml of water containing 0.5 ml of glacial acetic acid and then saturated with sodium chloride. The product was extracted with three 30 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulphate and evaporated at 30° C./12 mmHg to give a pale brown viscous oil. This oil was dissolved in 15 ml of dry diethyl ether by the addition of the minimum volume of ethyl acetate and treated with 0.2 ml of concentrated nitric acid. The precipitated product was crystallised from ethanol to yield 0.57 g of 1-[2,4-dichloro-β-[(4,6-dichlorobenzofuran-3-yl)methoxy]-phenethyl]imidazole nitrate of melting point 105° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To an ice-cooled and stirred solution of the crude 26.0 g trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester and 5.77 ml (92.6 mmol) methyliodide in 300 ml of N,N-dimethylformamide was added within 15 minutes 4.04 g (92.58 mmol) sodium hydride (55% in oil). After stirring over night at room temperature, additional 1.65 ml (26.5 mmol) methyliodide and 1.16 g (26.5 mmol) of sodium hydride were added and the reaction-mixture was then stirred for another 1 hour at room temperature. It was then partitioned between ether, 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 4:1 v/v mixture of hexane and ethylacetate as the eluent giving 18.7 g (67.7% over 3 steps) of pure trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless viscous oil, MS: 214 [(M-(tert-butoxycarbonyl))H+].
Reaction SMILES: [CH2:1](O)C.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([N+:15]([O-])=O)[CH:7]=1>[Fe].C(O)(=O)C>[CH3:1][CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][C:8]=1[NH2:15])=[O:14]
Reactant: COc1ccc(C(C)=O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: [Fe]
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(OC)cc1N
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 1:1 mixture of ethanol and acetic acid was added 1-(4-methoxy-2-nitrophenyl)ethanone (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 1 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl 1-(4-methoxy-2-aminophenyl)ethanone in 85% yield. ES/MS m/z 196 (MH+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[C:19]2[CH:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:22]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:19]2[CH:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:22]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=2)=[O:39])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(C(O)c2ccc(F)cc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(C(=O)c2ccc(F)cc2)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Dimethylsulphoxide (16.2 ml) was added dropwise to a stirred solution of oxalyl chloride (11.55 g) in dry dichloromethane (500 ml) at -78° C. under an atmosphere of dry nitrogen. The mixture was stirred for 10 minutes and then a solution of diethyl 5-[(4-fluorophenyl)hydroxymethyl]-1,3-benzenedipropanoate (30.65 g) in dry dichloromethane (150 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes, triethylamine (23.03 g) was added, and stirring was continued for a further 10 minutes. The temperature was allowed to rise to room temperature, and the mixture was washed with water. The organic layer was separated, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel. Elution with dichloromethane followed by dichloromethane/methanol (50:1) gave the title compound as an oil (28.92 g), Rf 0.75 (SS 4). Found: C,69.08; H,6.46. C23H25FO5 requires: C,68.98; H,6.29%.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:21]1([C:27]2[S:28][CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:20])[C@@H:15]([NH:19][C:32]([C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)=[O:33])[CH:16]([CH3:17])[CH3:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)C(C)C)CC1
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2csc(-c3ccccc3)n2)C(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.3, 4-((S)-2-amino-3-methyl-butyryl)-piperazine-1-carboxylic acid butyl ester (prepared as described in WO2008044217) replacing piperazine-1-carboxylic acid butyl ester, phenyl-1,3-thiazole-4-carboxylic acid replacing intermediate 8.2 and using CH2Cl2 instead of CH2Cl2/THF. The compound was however purified by CC (EtOAc/Hept 0:1 to EtOAc/Hept 1:0).
Reaction SMILES: [CH3:1][C:2]([CH2:4][OH:5])=[O:3].[C:6]([C:10]([C:13](F)=[O:14])([F:12])[F:11])([F:9])([F:8])[F:7]>C(N(CC)CC)C>[CH3:1][C:2]([CH2:4][O:5][C:13]([C:10]([C:6]([F:9])([F:8])[F:7])([F:12])[F:11])=[O:14])=[O:3]
Reactant: CC(=O)CO
Reactant: O=C(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)COC(=O)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
CH3COCH2OH (150.0 g) and triethylamine (225.4 g) were put into a flask and stirred under cooling in an ice bath. CF3CF2COF (377.5 g) diluted with nitrogen gas was blown into the flask over a period of 4 hours, while maintaining the internal temperature to be at most 10° C. Then, the mixture was stirred at room temperature for 2 hours and then added to 500 mL of ice water.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2>C(O)(=O)C>[Cl:11][C:8]1[S:9][C:10]2[C:2]([N:1]3[C:17](=[O:18])[C:16]4[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=4[C:14]3=[O:19])=[C:3]([F:13])[CH:4]=[C:5]([Cl:12])[C:6]=2[N:7]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 0 °C

Procedure:
A solution of 6 g 7-amino-2,4-dichloro-6-fluoro-benzothiazole and 4.3 g 3,4,5,6-tetrahydrophthalic anhydride in 50 ml acetic acid was heated under reflux for 5 hours. After cooling, the reaction solution was poured into 200 ml ice-water and the resulting crystals were separated off. They were dried at 50° C. in vacuo and then purified by column chromatography. Yield: 6.6 g=70% of theory m.p.: 139°-141° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([N:17]1[C@H:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][O:19][C:18]1=[O:29])(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].[Cl-].[NH4+]>O1CCCC1>[CH:13]([C@@H:12]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=1)[C:11]([N:17]1[C@H:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][O:19][C:18]1=[O:29])=[O:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
30 ml of tetrahydrofuran are added to a solution of 31 ml of 1M lithium hexamethyldisilazide and the mixture is stirred at -70° C. A solution of 3-isovaleroyl-4(R)-benzyl-oxazolidin-2-one in 20 ml of tetrahydrofuran is then added dropwise thereto and the reaction mixture is stirred for a further 1 hour at -70° C. A solution of 9.6 g of p-tert-butyl-benzyl bromide in 20 ml of tetrahydrofuran is then added dropwise thereto and the reaction mixture is stirred for a further 1 hour at -25° C. and then for 4 hours at 0° C. 6 ml of saturated ammonium chloride solution are then added to the reaction mixture, which is freed of tetrahydrofuran by means of concentration and then subjected to extraction with diethyl ether. The extract is concentrated by evaporation and the residue is purified by FC (700 g of silica gel, eluant: dichloromethane/hexane=1:1), yielding the title compound: Rf (dichloromethane/hexane=1:1)=0.30; m.p.=123.5°-124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[O:25]=[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:3]=1)[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Reactant: OB(O)c1cncnc1
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cncnc2)c1
Yield: 41 %

Procedure:
The title compound was prepared from 107.1.B and pyrimidin-5-ylboronic acid according to the procedure described in Example 107.1.C. The crude product was purified to give 108.1.A (85 mg, 41% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (s, 1H), 9.23 (s, 1H), 8.99 (s, 2H), 7.98 (t, J=1.9 Hz, 1H), 7.66-7.62 (m, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.37-7.27 (m, 6H), 4.17-4.12 (m, 2H), 3.51 (dd, J=9.1, 4.1 Hz, 1H), 3.36 (s, 2H), 3.35 (dd, J=14.1, 4.3 Hz, 1H), 2.92 (dd, J=14.1, 9.0 Hz, 1H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])[CH2:9][CH3:10].CN1CCN(C)C1=O.O.C(O[CH:30](OCC)[N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[N:36][N+:37]([O-:39])=[O:38])C>>[CH2:8]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]=[CH:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[N:36][N+:37]([O-:39])=[O:38])[CH2:9][CH3:10]
Reactant: CCCc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCN(C)C1=O
Product: CCCc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 31.7 %

Procedure:
0.05 g of trifluoroacetic acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 2.48 g of o-n-propylaniline and 2 ml of 1,3-dimethyl-2-imidazolidinone at 90° C., followed by agitation at the same temperature for 45 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.6 g of 1-(2-n-propylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]=[C:39]=[O:40]>CN(C)C=O>[C:22]([CH:21]=[C:7]1[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11](=[O:17])[NH:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:4]([NH:3][C:39]([NH:38][CH3:37])=[O:40])=[CH:5][C:6]1=2)([OH:24])=[O:23]
Reactant: Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reaction time: 30 h

Procedure:
To 11 g of 8-amino-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride dissolved in 110 ml of dimethylformamide and 110 ml of dioxane at a temperature in the region of 20° C. are added 12.42 g of potassium carbonate, followed by dropwise addition of 5.3 ml of methyl isocyanate. The stirring is continued for 30 hours at the same temperature. The reaction medium is then filtered. The solid recovered is dried under reduced pressure (15 mmHg; 2 kPa). The residue is taken up in 50 ml of water and the precipitate is filtered off. The solid is acidified with 2 ml of concentrated hydrochloric acid in 50 ml of water and then filtered and dried under reduced pressure (15 mmHg; 2 kPa). The insoluble product thus formed is taken up in 700 ml of dimethylformamide and brought to 50° C. in the presence of 1 g of animal black. The solution is filtered on Celite and the filtrate is concentrated on a rotary evaporator at 40° C. under reduced pressure (15 mmHg; 2 kPa). (1 mmHg; 0.13 kPa). The residue is taken up in 200 ml of ethyl ether and then filtered and dried for 8 hours at 50° C. under reduced pressure (1 mmHg; 0.13 kPa). 3.67 g of 10-(carboxymethylene)-8-(3-methylureido)-5H,10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C17 H13N5O4.0.9 DMF.0.9 H2O, % calculated C: 58.12; H: 3.73; N: 19.93, % found C: 58.1; H: 3.4; N: 19.6).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]#[C:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([C:24]#[C:25][CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The mixture of 2-(3-methyl-2-pent-1-ynyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (122) (180 mg, 0.46 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. After filtration, the solid is purified by HPLC to give a pure product (123) as white solid (114 mg, 69%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12](Cl)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O-:19].[Na+]>O1CCOCC1.CO>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([O:19][CH3:18])[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 50 °C

Procedure:
6.87 g (28 mmol) of 2-phenylamino-4-chloro-6-cyclopropyl-pyrimidine in 25 ml of dioxane are added dropwise to 5.8 g (32.2 mmol) of sodium methylate in 10 ml of absolute methanol at room temperature in the course of half an hour, while stirring, and the mixture is then heated at 50° C. for 6 hours. To bring the reaction to completion, a further 0.76 g (4.2 mmol) of sodium methylate is added and the mixture is heated at 50° C. for a further 20 hours. After evaporation of the solvent, 300 ml of diethyl ether are added to the residue, the suspension is washed twice with 100 ml of water each time and then dried over sodium sulfate and filtered and the diethyl ether is evaporated off. 6.7 g of yellow oil which remain are purified by column chromatography over silica gel using toluene as the mobile phase. After evaporation of the toluene, a pale yellow oil of refractive index nD25 : 1.6225 remains. Yield: 5.8 g (24 mmol; 86% of theory).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:18][CH:19]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.6 mg, 0.012 mmol, 5 mol % Pd), 2 [Example 1] (11.0 mg, 0.028 mmol, 5.5 mol %), Cs2CO3 (230 mg, 0.75 mmol) and indole (60 mg, 0.51 mmol). The tube was purged with argon then toluene (1.0 mL) and 4-chlorotoluene (60 μL, 0.51 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at 100° C. for 24 h. The reaction was then diluted with ether (20 mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 94 mg (89%) of a colorless oil.
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:18]N(C)C=O.[H-].[Na+].CI>O>[CH:1]([N:4]([C:12](=[O:17])[CH:13]([CH3:18])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A one liter reaction flask equipped with a power stirrer, condenser, drying tube, thermometer and nitrogen inlet tube was charged with 48.5 g (0.19 mole) of N-isopropyl-4'-chloroacetoacetanilide and 145 ml of dry dimethylformamide. With efficient stirring in a nitrogen atmosphere, portionwise addition of 7.2 g of 57% sodium hydride in mineral oil (0.17 mole) was completed in one hour (excessive foaming). Methyl iodide (24.1 g, 0.17 mole) was added dropwise and the reaction mixture was stirred for two hours at ambient temperature. The mixture was poured into one liter of cold water and stirred. The organic material was extracted into toluene and the latter was water washed. Most of the toluene was removed on the rotary evaporator. Hexane was added which caused the mass to crystallize. There was obtained 36.4 g (80%) of white material, M.P. 77°-79°. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 2.0 (O=C-CH3), 2.9-3.2 (CH), 4.7-5.2 (CH, isopropyl), 6.9-7.5. (aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:32])[N:15]([CH2:17][C:18]4[C:19]([C:28]([O:30]C)=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:32])[N:15]([CH2:17][C:18]4[C:19]([C:28]([OH:30])=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was also prepared as follows: A solution of methyl 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinate (60 mg, 0.11 mmol) in a mixture of 1 M aqueous NaOH (1 mL) and THF (1 mL) was stirred at room temperature for 4 h. After cooling to 0° C., the reaction mixture was neutralized to pH 6-7 by addition of 1 M aqueous HCl solution, then extracted with EtOAc (30 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound.