Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]=[CH:10]2.Cl>O1CCOCC1>[O:17]=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:2]=[O:1])=[CH:16][CH:15]=2)[CH:10]=[CH:11][O:12]1
Reactant: O=c1occc2cc(CC3OCCO3)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=CCc1ccc2c(=O)occc2c1
Reaction time: 16 h

Procedure:
6-(1,3-dioxolan-2ylmethyl)-1H-isochromen-1-one (410 mg, 1.77 mmol) was dissolved in dioxane (20 mL) and HCl (20 mL, 3M) was added then stirred for 16 hrs. The reaction was extracted with ethyl acetate then separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. to yield (1-oxo-1H-isochromen-6-yl)acetaldehyde LC-MS (IE, m/z): 189 [M+1]+; 1H-NMR (500 MHz, CDCl3) δ ppm 9.86 (s, 1H), 8.33 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 734(s, 2H), 6.52 (d, J=5.5 Hz, 1H), 3.89 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:23])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: CNc1ccccc1
Product: CCN1c2ncc(CN(C)c3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 72 h
Yield: 41 %

Procedure:
The 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.050 g, 0.15 mmol) was dissolved in N-methylaniline (1 mL) and stirred for 3 days. The mixture was purified by column chromatography (hexanes to ethyl acetate gradient) to give the title compound (0.025 g, 41%), m.p. 55°-57° C., foam.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:8]=[CH:7][C:6]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.[OH-].[Na+].[C:37](OCC)(=[O:39])C>COCCOC>[F:32][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH:21][CH2:37][OH:39])=[O:20])=[N:17][CH:18]=2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)F)nc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)F)nc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-[[[6-(difluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-trifluorophenyl) methyl]-4-methylpyridine-2-carboxamide (90.0 mg, 0.191 mmol) in ethylene glycol dimethyl ether (2 ml), an aqueous solution of formaldehyde (37%, 43.0 μl, 0.573 mmol) and 1 N aqueous sodium hydroxide (9.5 μl) were added at room temperature, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid (5 ml) was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of 2-propanol and hexane, and then was collected by filtration, to obtain the title compound (77.0 mg, 0.154 mmol, 80%) as a white solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br-].[CH:11]1([Zn+])[CH2:14][CH2:13][CH2:12]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH:11]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: [Zn+]C1CCC1
Reactant: O=Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCC2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-iodobenzaldehyde (500 mg), bis(triphenylphosphine)palladium(II) dichloride (75.6 mg), copper(I) iodide (24.6 mg) and dehydrated tetrahydrofuran (10.0 mL), cyclobutylzinc bromide (0.5 mol/L, solution in tetrahydrofuran, 6.46 mL) was added and the mixture was stirred in a sealed tube at 60° C. for 14 hours. After cooling to room temperature, the precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and thereafter purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-90:10) to give the titled compound as a colorless oil (225 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrobromic acid (48% solution) in 135 ml of water was cooled to 0°. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19](C4CCCCO4)[N:18]=3)[C:13]([Cl:29])=[CH:12][N:11]=2)=[C:4]([CH3:30])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:13]1[C:14]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:15][C:10]([NH:9][C:5]2[C:4]([CH3:30])=[CH:3][C:2]([C:36](=[O:38])[CH3:37])=[C:7]([CH3:8])[CH:6]=2)=[N:11][CH:12]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)c(C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Temperature: 100 °C

Procedure:
A mixture of N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (166 mg, 0.34 mmol), tributyl(1-ethoxyvinyl)stannane (146 mg, 0.41 mmol) and Pd(PPh3)4 (39 mg, 0.034 mmol) in toluene (2 mL) was degassed and heated at 100° C. under N2 for 14 h. After cooling down to room temperature, the mixture was concentrated. The resulting residue was redissolved in acetonitrile (2 mL) and treated with 1N HCl (2 mL) for 14 h. After extraction with EtOAc (3×15 mL), the combined organic layers were treated with saturated aqueous KF (10 mL). The resulted organic layer was collected and treated with brine and dried over MgSO4. After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc in hexanes gradient) to provide 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone as a white solid; ESMS m/z 371.1 (M+H+).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C1([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH2:16]2)C=CC=CC=1.IC>C1COCC1>[CH3:2][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A 2 M solution of LDA (21 mL, 1.05 eq, from Aldrich) was added dropwise to 3-phenyl-1-indanone (8.33 g, 40.0 mmol) in THF (300 mL) at −78° C. After 1 h at this temperature, iodomethane (3.00 mL, 1.2 eq) was added. The mixture was stirred at −78° C. for 2 h, at 0° C. for 30 min and quenched with sat NH4Cl (100 mL). After evaporation of THF in vacuo, the aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography (EtOAc-Hex, 5:95 then 7:93 then 10:90) gave the 2-methylindanone (1.93 g, 22%). MS Found: (M+H)+=223.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[C:34]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[C:34]=1[CH3:46])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCl)cc2ccc(F)cc2c1OCc1ccccc1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of triphenylphosphine (41.6 g, 159 mmol) in dry THF (190 mL) was added CCl4 (59 mL). The reaction mixture was stirred for 10 minutes and (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (21.5 g, 79.4 mmol) was introduced as a solid at room temperature under nitrogen. The resulting solution was refluxed for 2 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with water. The resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel column chromatography (100-200 mesh, 5% ethyl acetate in hexanes) provided 1-benzyloxy-3-chloromethyl-7-fluoro-2-methyl-naphthalene (18.5 g, 81%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:25]2[CH2:26][CH2:27][CH:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:23][CH2:24]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1ccnn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccnn2Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (6.3 g) in acetic acid (70 mL) was added 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (12.0 g) was added, and the mixture was stirred for 18 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.27 g, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzoic acid (117 mg, 0.50 mmol) in methanol (1 mL) and dichloromethane (2 mL) at room temperature was slowly treated with 2M trimethylsilyldiazomethane in hexanes until the solution became light yellow. The mixture was concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CN(C)CCN
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.5 g, 6.35 mmol) in DCM (40 ml) at room temperature was added 2-dimethylaminoethylamine (1.387 ml, 12.70 mmol) and AcOH (0.472 mL, 8.25 mmol), followed by Na(AcO)3BH (2.69 g, 12.70 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with DCM, quenched with saturated aqueous NaHCO3 and stirred for 20 min. Phases were separated and the water phase was extracted with DCM. Organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified via silica gel column chromatography eluting with a gradient of MeOH (0-15%) in DCM. Fractions containing the product were combined and concentrated to yield the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[BH4-].[Na+].O>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: O=Cc1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc2ccccc2n1
Yield: 84.1 %

Procedure:
2-Quinolinecarbaldehyde (2.00 g, 12.7 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.24 g, 6.4 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL) and evaporated. The residue was chromatographed in CH2Cl2-methanol gradient, eluting the product at 97:3 CH2Cl2-methanol, and providing 1.7 g of quinolin-2-yl-methanol in 85% yield; 1H NMR (CDCl3) δ 4.92 (s, 2H), 7.26 (d, J=2.1 Hz, 1H), 7.30-7.57 (m, 1H), 7.68-7.75 (m, 1H), 7.82 (dd, J=8.0 Hz, J=0.9 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([OH:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:30]([N:32]([CH2:37][CH3:38])[C:33](=[O:36])[CH2:34]Cl)[CH3:31]>CC(C)=O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH3:38])[CH2:30][CH3:31])=[CH:17][CH:18]=2)([OH:12])[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1

Procedure:
14.8 g. 1-(3-trifluoromethylphenyl)-1-(4-hydroxyphenyl)-propan-1-ol, 7.6 g. of anhydrous potassium carbonate, 2 g. of potassium iodide, 8.2 g. of monochloroacetic acid diethylamide and 150 ml. of dry acetone are boiled for 5 hours, under stirring. The reaction mixture is cooled and the solvent is distilled off under reduced pressure. To the residue water is added and it is extracted with benzene. The benzene phase is shaken with water and subsequently a 5% aqueous sodium hydroxide solution and washed to neutral with water. It is dried over anhydrous sodium sulfate, filtered off and the solution is evaporated in vacuo. The solid residue is crystallized from a mixture of n-hexane and ethyl acetate. 17.6 g. of the named compound are obtained, melting at 83°-84° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([OH:17])=O.S(Cl)([Cl:20])=O>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([Cl:20])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: COCc1onc(-c2ccccc2)c1C(=O)O
Product: COCc1onc(-c2ccccc2)c1C(=O)Cl
Temperature: 60 °C
Yield: 100 %

Procedure:
A suspension of 5-methoxymethyl-3-phenyl-isoxazole-4-carboxylic acid (10.0 g, 43.0 mmol) in thionyl chloride (20 mL) was heated at 60° C. for 3 h. The resulting mixture was concentrated under reduced pressure to afford the crude title compound (11.16 g, 100%) which was obtained as a light yellow liquid. The crude product was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[S:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2].[CH2:17](O)[CH3:18]>CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:17]#[CH:18])[S:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)sc1C(=O)OCC
Reactant: CCO
Solvent: CO
Product: C#Cc1nc(C(=O)OCC)c(C(=O)OCC)s1

Procedure:
4,5-Diethoxycarbonyl-2-ethynylthiazole (539 mg) was prepared from 1.16 g of 4,5-diethoxycarbonyl-2-iodothiazole in the same manner as in step b) in Example 4, except that ethanol was used as the solvent instead of methanol.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][CH:19]([OH:22])[C:20]#[CH:21]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:22][CH:19]([CH3:18])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: C#CC(C)O
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
6.78 g (20 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 7 hours with 1.75 g (25 mmol) of 3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 50 ml of diethylamine and 30 ml of ethylene chloride. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate and hexane there was obtained 4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 161°-162°.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24]([CH:27]=O)[CH:23]=1)[CH3:19]>C1COCC1>[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24](/[CH:27]=[CH:3]/[C:1]#[N:2])[CH:23]=1)[CH3:19]
Reactant: CCOC(OCC)c1cc(C=O)cs1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(/C=C/C#N)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction was cooled to 0° C. and a solution of 5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg, 84.9%). 1H NMR (300 MHz, CDCl3): 7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:4]([CH2:17][CH3:18])[N:3]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(C(=O)c2ccccc2)c(N)n1
Reaction time: 1 h

Procedure:
To a vigorously stirring solution of (3-amino-1H-pyrazol-4-yl)-phenyl-methanone (0.1 g, 0.53 mmol) in dry DMF at RT is added sodium hydride (0.023 g, 0.57 mmol). After 1 h, ethyl iodide (0.042 mL, 0.53 mmol) is added and stirring is continued for 4 h. The reaction mixture is diluted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate. The organic filtrate is concentrated and the crude is chromatographed on silica gel using 50% ethyl acetate in hexanes to provide (3-amino-1-ethyl-1H-pyrazol-4-yl)-phenyl-methanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:15]1([CH2:21][O:22][C:23](=[O:41])[NH:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[Cl:40])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([O:22][C:23](=[O:41])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([NH2:14])[CH:3]=2)=[CH:27][C:26]=1[Cl:40])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)OC1(C)C
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Product: Nc1cnc(OCC(F)(F)F)c(-c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example C) and N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-carbamic acid phenylmethyl ester (CAN 1218791-42-4) as starting materials; MS (EI) 452.1 (M+H)+.