Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=2)=[CH:4][C:3]=1[CH:17]([S:22][CH:23]([C:28]1[CH:33]=[C:32]([C:34]2[C:35]([C:39]([F:42])([F:41])[F:40])=[N:36][NH:37][CH:38]=2)[CH:31]=[CH:30][C:29]=1[CH3:43])[C:24]([F:27])([F:26])[F:25])[C:18]([F:21])([F:20])[F:19].ClC1C=CC=C(C(OO)=[O:52])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][NH:11][CH:12]=2)=[CH:4][C:3]=1[CH:17]([S:22]([CH:23]([C:28]1[CH:33]=[C:32]([C:34]2[C:35]([C:39]([F:42])([F:40])[F:41])=[N:36][NH:37][CH:38]=2)[CH:31]=[CH:30][C:29]=1[CH3:43])[C:24]([F:25])([F:26])[F:27])=[O:52])[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1C(SC(c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1C(S(=O)C(c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C)C(F)(F)F)C(F)(F)F
Yield: 20 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl]2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the Present Invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl]2,2,2-trifluoroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: Br[C:2]1[S:12][C:5]2[N:6]=[CH:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[N:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[NH:24][CH2:23][CH2:22]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.CO.[Cu]I.C(O)(=O)C>[N:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[N:24]([C:2]1[S:12][C:5]3[N:6]=[CH:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[CH:3]=1)[CH2:23][CH2:22]2
Reactant: C1CN2CCC(CC2)N1
Reactant: Cn1cnc2sc(Br)cc2c1=O
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cn1cnc2sc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 90 °C
Yield: 2.1 %

Procedure:
A mixture of 6-bromo-3-methylthieno[2,3-d]pyrimidin-4(3H)-one (70 mg, 0.28 mmol), copper(I) iodide (13.6 mg, 0.071 mmol), L-proline (16.4 mg, 0.143 mmol), 1,4-diazabicyclo[3.2.2]nonane (54.1 mg, 0.428 mmol) and potassium phosphate (132 mg, 0.571 mmol) in DMSO (1 mL) was heated at 90° C. in a sealed vessel for 3 days. The reaction was acidified with acetic acid, diluted with methanol and purified on a scx cartridge (1 g), further purified by acid prep HPLC, passed through a scx cartridge (500 mg) and evaporated to dryness to afford 6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-3-methylthieno[2,3-d]pyrimidin-4(3H)-one (1.8 mg, 0.006 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Cl:1][C:2]1[C:3]([NH:9][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[S:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ncc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 3,5-dichloropyridin-2-amine (3.87 g, 23.73 mmol) in acetone (20 mL) was added benzoyl isothiocyanate (3.2 mL, 23.73 mmol). The mixture was stirred at ambient temperature for 1 h, and the resultant precipitate was collected by filtration (3.89 g). The filtrate was returned to the reaction flask and heated to reflux 1 h. At this time, the reaction had gone dry. The solids were suspended in acetone and collected by filtration to give 2.24 g. of N-(3,5-dichloropyridin-2-ylcarbamothioyl)benzamide (5.93 g, 18.18 mmol, 77% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 12.78 (br. s., 1H) 9.25 (br. s., 1H) 8.46 (br. s., 1H) 7.94 (d, J=7.63 Hz, 2H) 7.88 (d, J=2.44 Hz, 1H) 7.69 (t, J=7.48 Hz, 1H) 7.58 (t, J=7.78 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][NH:12]C(=O)CCl)[C:8]([OH:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18].S(=O)(=O)(O)O>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][NH2:12])[C:8]([OH:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:18]
Reactant: Cc1cc(CNC(=O)CCl)c(O)c2c1CCC2=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(CN)c(O)c2c1CCC2=O

Procedure:
3 Grams of 4-methyl-6-α-chloroacetylaminomethyl-7-hydroxy-1-indanone and a solution of 30 ml of concentrated sulfuric acid in 60 ml of ethanol were refluxed by heating for 8 hours. The solvent was removed by evaporation, the residue thus obtained was recrystallized from ethanol to obtain 1 g of 4-methyl-6-aminomethyl-7-hydroxy-1-indanone.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)CCCCC[CH2:15]1.C1(C(C)=O)CC1>>[C:1]([NH:5][NH:6][C:7]1([C:12]#[N:13])[CH2:8][CH2:15][CH2:14][CH2:10][CH2:11][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NNC(C)(C#N)C1CC1
Reactant: O=C1CCCCCC1
Agent: CC(=O)C1CC1
Product: CC(C)(C)NNC1(C#N)CCCCCC1
Yield: 95 %

Procedure:
1-t-Butylhydrazo-1-cyanocycloheptane was prepared in 95% yield using the same procedure described in Example XIIIB for the preparation of 1-t-butylhydrazo-1-cyano-1-cyclopropylethane, substituting the t-butylhydrazone of cycloheptanone for the t-butylhydrazone of methyl cyclopropyl ketone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[N:17]1C=CC=C[CH:18]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([C:18]#[N:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C#N)c2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxynaphthalene-2-carboxylic acid ethyl ester (2.16 g) and pyridine (1.60 mL) in dichloromethane (100 mL) was added trifluoromethanesulfonic anhydride (2.5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added water (30 mL), and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N-methylpyrrolidone (33 mL). To the solution were added zinc cyanide (1.41 g) and tetrakis(triphenylphosphine)palladium (0.58 g), and the resulting mixture was stirred at 110° C. for 40 minutes. After the reaction mixture was cooled to room temperature, water (50 ml) and dichloromethane (50 mL) were added to the reaction solution. The insoluble material was removed by filtering through a Celite pad. The aqueous layer was separated, and the organic layer was filtered through an aminopropyl silica gel (eluent: dichloromethane). The organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), and the mixture was washed with water (30 mL, 5 times). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give 4-cyanonaphthalene-2-carboxylic acid ethyl ester (2.25 g). To a mixed solution of this compound (0.45 g) in tetrahydrofuran (10 mL), ethanol (5.0 mL) and water (5.0 mL) was added lithium hydroxide monohydrate (0.25 g), and the mixture was stirred for 1 hour. To the reaction solution was added water (20 mL), and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/L hydrochloric acid (3.3 mL), and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure at 50° C. to give the title compound (0.37 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]=[S:27]>CS(C)=O.O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[S:27])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cc(C)nn3C)c2)cn1
Reaction time: 15 h
Yield: 103.6 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (184 mg, 0.569 mmol) in DMSO (4 mL) was added ethyl isothiocyanatoformate (89.6 mg, 0.682 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (268 mg, 99%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:22]2[CH:23]=[CH:24][C:25]([N:26]3[CH2:27][CH:28]([OH:30])[CH2:29]3)=[C:20]([F:19])[CH:21]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(N3CC(O)C3)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 97.4 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (106 mg, 0.398 mmol, 1.0 eq) in acetonitrile (9 mL) was added TEA (0.22 mL, 1.6 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (122 mg, 0.406 mmol, 1.02 eq) and the mixture was stirred at reflux for 16 h. The reaction mixture was evaporated and the residue was purified by CC (EtOAc/n-hexane 2:1 as eluent) to obtain 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (183 mg; 97%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CN1CCN(c2ccc(O)cc2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)phenol 1.080 mg (5.59 mmol) and TEA 1.72 ml (12.3 mmol) in DCM was cooled in an ice bath and 0.44 ml (6.15 mmol) of acetyl chloride were added dropwise. After completion, the reaction was filtered, the organic phase quickly extracted with water, dried over Na2SO4 and evaporated down to give a light pink solid. LC/MS (m/z): 235.4 [M+H]+, HPLC (254 nm) method 3 Rt 1.89 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([NH:21][C:22](=O)[CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])([CH3:20])[CH3:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:37])[N:13]2[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36].B.C1COCC1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([NH:21][CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])([CH3:19])[CH3:20])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:37])[N:13]2[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36]
Reactant: CC(C)NCC(=O)NC(C)(C)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)NCCNC(C)(C)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 80 °C

Procedure:
Dissolved N1-{1-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}-N2-isopropylglycinamide (COMPOUND DDD-4) (53 mg) borane-THF solution (3 mL of a 1M solution). The mixture was brought to and maintained at reflux for 4 h. The mixture was cooled. Aqueous 6N HCl (6 mL) was added and the mixture was heated to 80° C. for 30 min. The reaction was cooled and diluted with ethyl acetate. The aqueous layer was made basic by addition of 2N NaOH. The layers were mixed and then separated. The ethyl acetate layer was washed with aqueous 2N NaOH. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by preparative reverse phase HPLC [Waters Xterra C8 ms 19×50 mm column using a gradient elution of 90% water (+0.1% TFA)/10% CH3CN (+0.1% TFA) to 100% CH3CN (+0.1% TFA) over 12 min at 20 mL/min] giving 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(1-{[2-(isopropylamino)ethyl]amino}-1-methylethyl)-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 545 (M+1); 547 (M+3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:2][CH2:3]2)=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CN2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
To a solution of 15.3 g. (50 mmole) methyl 4-(piperazin-1-ylmethyl)-benzoate and 175 ml. anhydrous pyridine, there is added dropwise, at 0°-5° C., 8.7 g. (50 mmole) 4-chlorobenzoyl chloride and the reaction mixture kept for a further hour at 0° to 5° C., then overnight at 20° C. The reaction mixture is stirred into ice water and the precipitated product is filtered off with suction, washed with water and dried to give 18.5 g. (quantitative) of the desired product; m.p. 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1.[C:12](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:13]>ClCCl>[N:1]([C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1)=[C:12]=[S:13]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1cc(N)nc(C)c1C#N
Solvent: ClCCl
Product: Cc1cc(N=C=S)nc(C)c1C#N
Temperature: 40 °C
Reaction time: 3 h
Yield: 790 %

Procedure:
To 6-amino-2,4-dimethylnicotinonitrile (0.14 g, 0.95 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.23 g, 0.1 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.15 g, 0.79 mmol, 83% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37 (s, 1H), 2.63 (s, 3H). MS (LC/MS) R.T.=2.40; [M+H]+=190.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8](Cl)=[C:9]([CH:27]=1)[C:10]([NH:12][C:13](=[NH:26])[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])=[O:11])[CH2:2][CH2:3][CH3:4].CC([O-])(C)C.[K+]>CS(C)=O>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[N:26]=[C:13]([CH2:14][O:15][CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[NH:12][C:10](=[O:11])[C:9]=2[CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCc1cnc2nc(COCCc3cc(F)ccc3F)[nH]c(=O)c2c1

Procedure:
In analogy to the procedure described in example 78.4, 5-butyl-2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu in DMSO to obtain 6-butyl-2-[2-(2,5-difluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=374.4 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17](=[O:19])[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CCC(=O)O)ccc2[nH]1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(CCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 5-(2-carboxy-ethyl)-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 5 mmol) in 10 mL of dimethylformamide, was added 1,1′-carbonyldiimidazole (973 mg, 6 mmol). The mixture was stirred under nitrogen at room temperature for 30 mins. To the reaction mixture was added pyrrolidine (1.3 mL, 15 mmol) dropwise. After stirring at room temperature for overnight, the reaction was diluted with dichloromethane (300 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried and concentrated to give 1.5 g (95%) of 5-(3-oxo-3-pyrrolidin-1-yl-propyl)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:12]([O:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]1[C:7]([CH:8]=[N:9][NH:10]1)=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[C:12]([O:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]1[C:7]([CH:8]=[N:9][N:10]1[CH2:29][C:30]#[N:31])=[CH:6][CH:5]=2
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.1 %

Procedure:
To a solution of 7-iodo-8-phenylpyrano[3,2-g]indazol-6(1H)-one (350 mg, 0.903 mmol) in DMF (10 mL) was added potassium carbonate (415 mg, 3 mmol) and the reaction stirred at RT. After 5 minutes, bromoacetonitrile (162 mg, 1.353 mmol) was added and the reaction stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and water. The resulting biphasic mixture was separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 70% EtOAc in cyclohexane) to afford the title compound (116 mg, 30%), 1H NMR (500 MHz, CDCl3): δ 8.18 (br s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.90-7.88 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.64-7.60 (m, 3H), 5.52 (s, 2H). LCMS (Method J) RT=1.29 min, [M+H]+=428.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[C:6]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=1>O1CCOCC1>[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=1
Reactant: COC(=O)COc1ccc(Cl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(Cl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (35 ml.) was added to a solution of methyl 2-[4-chloro-2-(4-nitrobenzoyl)phenoxy]acetate (11.5 g.) in dioxane (60 ml.) and stirred at room temperature for 1.5 hours. Dioxane was distilled off under reduced pressure, and the residue was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and then extracted with ethyl acetate (each 400 ml. and 100 ml.). The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to a volume of about 100 ml. The precipitating crystals were collected by filtration to give 2-[4-chloro-2-(4-nitrobenzoyl)phenoxy]acetic acid (10.1 g.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:30][CH3:31])[C:28]=1[CH3:29])[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[CH3:29])[C:23]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][C:9]=1[N+:15]([O-:17])=[O:16])=[O:24]
Reactant: Cc1nc(-c2ccc(CN)c([N+](=O)[O-])c2)no1
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2[N+](=O)[O-])cc(OC)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of compound 1e (3.34 g, 14.3 mmol), 3,5-dimethoxy-4-methylbenzoic acid (4.2 g, 21.4 mmol), EDCI (4.1 g, 21.4 mmol), and HOAt (190 mg, 1.4 mmol) in a mixture of dichloromethane (60 mL) and DMF (30 mL) was stirred at rt for 12 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCl. The solid which precipitated was recovered by filtration. The ethyl acetate layer was washed with saturated NaHCO3 solution and brine, dried Na2SO4, and concentrated on a rotary evaporator. The residue was recrystallized (ethyl acetate/hexane/petroleum ether) and combined with the filtered solid to afford compound 1f (5.55 g, 94%) as a cream colored solid. ESI-MS m/e 413.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.[Pd]>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Yield: 95.4 %

Procedure:
A solution of 5.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 150 ml of iso-propyl alcohol was hydrogenated in the presence of 0.500 g of 5% palladium-on-carbon for 1 hour. The mixture was filtered and evaporated to give 4.8 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleric acid in the form of a yellow oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(OCC)C>[CH2:17]([O:16][C:14]([C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH2:10][CH2:9][CH2:8][C:6]([OH:7])=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1ccccc1OCCCC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1OCCCC(=O)O
Yield: 95.2 %

Procedure:
Ethyl 2-(3-tert-butoxycarbonylpropoxy)benzoate (3.60 g, 11.7 mmol) was treated with an excess of trifluoroacetic acid at room temperature over one hour. The solution was concentrated in vacuo and the oily residue purified by silica gel flash chromatography using (10:1) hexane:ethyl acetate to pure ethyl ether to provide 4-(2-ethoxycarbonylphenoxy)butyric acid as a colorless crystalline solid (2.81 g, 95% yield); 1H NMR (300 MHz, CDCl3): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).