Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][C:24]1([CH3:32])[CH2:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([CH:28]1[C:26](=[O:27])[CH2:25][C:24]([CH3:32])([CH3:23])[CH2:31][C:29]1=[O:30])=[O:6]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CC(C)(C)CC2=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 g (2.9 mmol) of 2-chloro-3-[(1-methylpyrazol-5-yl)oxymethyl]-4-methylsulfonyl benzoic acid, 0.4 g (2.9 mmol) of dimedone and 0.72 g of N,N-dicyclohexylcarbodiimide in 50 ml of acetonitrile are heated at 40° C. for 4 h. After the reaction mixture has been stirred for 12 h at room temperature, 0.87 g of triethylamine and 0.57 g of trimethylsilylnitrile are added. Afterwards the reaction mixture is heated at 40° C. for 6 h, filtered, freed from the solvent under reduced pressure and the residue is purified over silica gel (eluent: toluene/tetrahydrofurane/acetic acid: 100/0/0→4/1/0.1). Yield: 0.25 g; m.p.82° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N:25]([CH:28]([CH3:30])[CH3:29])=[C:26]=[O:27]>O1CCCC1>[CH:28]([NH:25][C:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:30])[CH3:29]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (65 μL), is dissolved in tetrahydrofurane (2 mL), treated with triethylamine (890 μL) and 2-isocyanatopropane (420 μL) and the mixture is stirred for 12 hours at 80° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(C(C)=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: OCCCl
Reactant: Cc1nccn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Cc1nccn1-c1ccc(OCCO)cc1

Procedure:
4-(2-Methyl-1H-imidazol-1-yl)phenol (10.0g, 0.057 mole), 2-chloroethanol (13.88 g, 0.172 mole) and potassium carbonate (23.74 g, 0.172 mole) were combined in methyl ethyl ketone (200 ml) and heated at reflux temperature for four days. The solution was cooled and the solid filtered and rinsed with acetone. The filtrate was concentrated to a residue and the residue triturated with hot acetone (2×50 ml). The remaining solid (1.5 g) was dissolved in methylene chloride. Insoluble materials were removed by filtrateion, and the filtrate concentraed to obtain 0.50 g (4%), mp 125°-127° C. Proton NMR indicates that methylene chloride is present in the sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[C:7]1[C:14]([O:16][CH3:17])=[O:15])[CH3:31]
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (7.5 g) in N,N-dimethylformamide (100 ml) was added oily sodium hydride (60%, 1.6 g) and the mixture was stirred for 30 minutes at room temperature. After dropwise addition of ethyl iodide (4.8 ml), the reaction mixture was further stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethyl ether to give methyl 1-ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (6.38 g, 77%) as pale red prisms.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: c1ccc2c(c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 80 °C
Yield: 20.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 174 mg of 2,3-dihydro-1H-indole, and 185 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N,N-dimethylformamide. After silica column purification, eluent: 93/07 CH2Cl2/MeOH, the solid is taken up with 4 ml of methanol and a few drops of acetone. The suspension is heated at a temperature of 80° C., filtered while hot, and then recrystallized at a temperature of 20° C. and then of 0° C. The solid is filtered off, rinsed with diethyl ether, and then dried under a vacuum bell jar. 52 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of white crystals, the characteristics of which are the following:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[C@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:35].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C@@H:18]([OH:22])[CH2:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:35])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@@H]1C[C@@H](Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@@H](O)C[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
Analogously to Example 1 i), 1.05 g of 5(S)-[1(S)-(Boc-amino)-2-(p-fluorophenyl)ethyl]-3(R)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one in 35.5 ml of dimethoxyethane and 17.9 ml of water are hydrolysed with 8.7 ml of 1 M lithium hydroxide solution to form the title compound which is used further directly.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13]=O)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:16][NH:17][C:18]([NH2:20])=[O:19].C(N(CC)CC)C>CO>[CH:1]([C:4]1[C:12](/[CH:13]=[N:16]/[NH:17][C:18]([NH2:20])=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: NNC(N)=O
Reactant: CC(C)c1nn2ccccc2c1C=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)c1nn2ccccc2c1/C=N/NC(N)=O
Yield: 70.6 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g, 1 equivalent), semicarbazide hydrochloride (0.35 g, 1.2 equivalents), and triethylamine (0.4 mL, 1.1 equivalent) in 5 mL of methanol was reflux for 30 minutes. The solution was concentrated and the crude solids produced were extracted with THF, and the mixture was filtered through a 1 inch thick layer of sodium sulfate on top of a thin pad of silica gel to remove the ammonium salt. The filtrate was concentrated and the solid deposited was recrystallized from THF and hexanes to give (E)-2-((2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methylene)hydrazinecarboxamide (0.46 g, 70% yield) as a yellow solid. Compound 1074.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][OH:7])(=[O:5])[CH3:4].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:7][NH:6][C:3](=[O:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)NO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
60% sodium hydride (11.68 g, 0.292 mol) was added to a dimethyliformamide solution (200 ml) of acetohydroxamic acid (21.9 g, 0.292 mol) with cooling in an ice bath. After stirring for 1 hour at room temperature, benzylbromide (50 g, 0.292 mol) was added thereto and allowed to react for 24 hours at room temperature. The reaction solution was poured into 500 ml of water. and extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 31.3 g of N-benzyloxyacetamide (yield: 65%). The proton NMR spectrum of the compound is 1.85 s (3H); 4.89 bs (2H); 7.37 s (5H); 8.30 bs, 8.81 bs (1H) (solvent: CDCl3).
Reaction SMILES: [N:1]1([CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:24]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:24][C:9]1[CH:10]=[CH:11][C:2]2[N:1]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3ccccc32)C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of compound 2 (3.15 g, 9.97 mmol) in DMF (15 mL) was cooled to 0° C. and treated drop wise with a solution of N-bromosuccinimide (1.77 g, 9.97 mmol) in DMF (15 mL). The reaction mixture was stirred at 0° C. for 3 hours then diluted with H2O (100 mL) and extracted into EtOAc (2×100 mL). The combined organic fractions were washed with brine (100 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (EtOAc:hexanes, 1:9) to obtain compound 3 (3.26 g, 83%) as a foam. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.41-1.52 (m, 5H), 1.80-1.87 (m, 1H), 2.12-2.17 (m, 1H), 2.65-2.69 (m, 2H), 2.79-2.92 (m, 2H), 3.00-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.53-3.59 (m, 1H), 3.96-4.04 (m, 1H), 6.93-6.96 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4, 8.4 Hz), 7.29 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %): 395 (MH+, 7), 341 (92), 339 (100).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([C:20]#[N:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile (5.1 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL water, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.6 g (15.5 mmol, 90%) of 6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile as an oil. MS: 298 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:52])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:51]=[CH:50][C:38]([C:39]([NH:41][NH:42]C(OC(C)(C)C)=O)=[O:40])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:42][NH:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:52])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:51][CH:50]=1)=[O:40]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. for 60 min gave 206 mg of the title compound (87%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 40 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (246 mg, 2.00 mmol), 2,4,5-trichloropyrimidine (367 mg, 2.00 mmol, 1 equiv.) and Na2CO3 (233 mg, 2.20 mmol, 1.1 equiv.) in EtOH (10 mL) was heated at 40° C. for 16 h. The crude reaction mixture was diluted with EtOAc and sequentially washed with: water (3×) and saturated aqueous NaCl (1×). The resulting EtOAc layer was dried over Na2SO4 and then concentrated in vacuo, providing 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 270.0 (M+H+).
Reaction SMILES: CON(C)[C:4](=[O:30])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1.[CH3:32][Mg]Cl.O>O1CCCC1>[F:29][C:26]([F:28])([F:27])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH:9]3[CH2:10][CH2:11][C:6](=[CH:5][C:4](=[O:30])[CH3:32])[CH2:7][CH2:8]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 114 mg (0.25 mmol) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexylidene)acetamide in 5 mL of dry tetrahydrofuran cooled to 0° C. is added 0.2 mL (0.50 mmol) of a 22% methylmagnesium chloride solution in tetrahydrofuran. The mixture is warmed up to 5° C. and stirred for 90 minutes. Hydrolysis is performed by slow addition of 3 mL of water. The product is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified over 5 g of silica gel (eluant dichloromethane/methanol 95/5) to give 43 mg (44%) of 1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)propan-2-one as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([NH2:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([NH2:26])([CH3:21])[CH2:23]4)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC1(N)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86.9 %

Procedure:
A mixture of 0.5 g (1.8 mmol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.34 g (2.1 mmol) of 3-methyl-3-aminoazetidine hydrochloride and 0.5 ml of triethylamine in 10 ml of pyridine is heated to reflux for 3 hours. The mixture is allowed to cool and is filtered and the product is washed with water. 0.52 g of 1-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting point 285°-7° C., is thereby obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16]Br.O>CCCCCC>[Br:16][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,3-dihydrobenzofuran (11.06 g) and sodium carbonate (14.8 g) in hexane (100 ml) was added dropwise at 0° C. a solution of bromine (4.8 ml) in hexane (20 ml) for 1.5 hours, and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give gray crystals of 5-bromo-2,3-dihydrobenzofuran (17.64 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.174 g, 0,151 mmol) were added to toluene (30 mL) and the resulting solution was heated to reflux for 18 hours. After cooling to room temperature the reaction mixture was poured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography using 1% ethyl acetate in hexane yielding a white solid. Recrystallization from hexane afforded the ester as a white solid (0.79 g, 64%): mp 114.2–115.9° C. 1H NMR (CDCl3/300 MHz) 7.69 (s, 1H), 7.41 (s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H, J=6.9 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434 (M+NH4+). FABHRMS m/z 434.0574 (M+NH4+, Calc'd. 434.0538). Anal. Calc'd. for C19H13Cl2F3O3: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H, 3.18; Cl, 16.65.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(c1ccc(-c2ccccc2)cc1)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccc2)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A solution of 10.4 g of 4-(4-phenylbenzoyl)-piperidine, 8.8 g of 3-(2-bromoethyl)indole and 4.5 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure outlined in Example 3(b) to produce 3-{2-[4-(4-phenylbenzoyl)piperidyl]-ethyl}indole. The indole is recrystallized twice from an ethanol-water mixture (one charcoal treatment), thrice from a pyridine-water mixture, and twice from an acetone-water mixture to give the product, mp 189°-192° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[NH:32]N>>[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 1. MS: M=384.1 (M+H)+