Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:20][C:7]1=2>C(Cl)Cl>[Cl:3][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:20][C:7]1=2
Reactant: CC1(C)COC(c2ccc3c(c2)C(O)c2ccccc2CO3)=N1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ccc3c(c2)C(Cl)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this process, 1.90 g of 11-hydroxy-2-(4,4-dimethyl-2-oxazoline-2-yl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 30 ml of methylene chloride and 0.7 ml of thionyl chloride is added thereto under ice-cooling. After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure to obtain a crude product of 11-chloro-2-(4,4-dimethyl-2-oxazoline-2-yl)-6,11-dihydrodibenz[b,e]oxepin. The crude product as such is dissolved in 10 ml of tetrahydrofuran without purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>C(O)(C)C>[N:13]1([C:4]2[N:3]=[C:2]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1NCc1ccc(F)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (607 mg, 2.0 mmol) in isopropanol (5 mL) were added sodium carbonate (424 mg, 4 mmol) and 4-fluorobenzylamine (313 mg, 4 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether and dried to give the title compound (637 mg, 81%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: COc1nc(N=C=S)nc(OC)n1
Reactant: NS(=O)(=O)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccn2)nc(OC)n1

Procedure:
A mixture of 1.58 g of 2-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3,5-triazine and 1.5 g of anhydrous potassium carbonate is stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture is then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product removed by filtration.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[O:24]>C1COCC1>[C:1]([C:5]1[S:9][C:8]([NH:10][C:23]([NH:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[Cl:14])=[O:24])=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)c(N)s1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)c(NC(=O)Nc2cccc(Cl)c2Cl)s1
Temperature: 70 °C
Reaction time: 21 h
Yield: 81.9 %

Procedure:
To a vial containing 5-tert-butyl-2-aminothiophene-3-carboxylic acid (1 mmol) in THF (7 mL) was added 2,3-dichlorophenyl isocyanate (1 mmol). The vial was capped and the solution was stirred at 70° C. for 21 hours. The reaction was cooled down to room temperature and the solvent was removed under vacuum. The oil residue was treated with dichloromethane and the resulting mixture was left to stand at room temperature for 1 hour. The solids were filtered, washed with minimal amount of dichloromethane and dried under vacuum to yield the expected 5-tert-butyl-2-(3-(2,3-dichlorophenyl)ureido)thiophene-3-carboxylic acid (317.2 mg, 83%). Coupling with the appropriate amine was performed as described above for Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[CH2:15][C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: Cc1n[nH]c2cc(Br)ccc12
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(Br)ccc12
Yield: 62 %

Procedure:
The titled compound (10.4 g) as a white solid was prepared from the 6-bromo-3-methyl-1H-indazole (9.57 g) obtained with the method described in the document (JP 2009-528363 W) and 2,6-dichlorobenzyl chloride (9.79 g) according to the method of the process (1) of Example 66.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]
Reactant: O=C(CBr)c1ccc(Cl)cn1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-5-chloropyridine (Preparation is described in Example 85).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH-].[Na+].CS(C)=[O:17].Cl>O>[Cl:8][C:7]1[C:2](=[O:17])[NH:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CS(C)=O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(C(F)(F)F)cc1Cl

Procedure:
[B] 4 g of 2,3-dichloro-5-trifluoromethylpyridine was added to an aqueous solution of 2.4 g of sodium hydroxide dissolved in 12.5 ml of water, and 12.5 ml of dimethyl sulfoxide was further added thereto. The solution was reacted at 110° C. for 1 hour while stirring. After completion of the reaction, the reaction product was allowed to cool and made acidic with concentrated hydrochloric acid to obtain a precipitate. The thus obtained precipitate was collected by filtration to obtain 2.5 g of the titled compound.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C:6]=1[C:27]([NH2:29])=[O:28])(=O)C.[OH-].[Na+].Cl>CO.O>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C:6]=1[C:27]([NH2:29])=[O:28]
Reactant: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(OC(C)=O)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
8.0 g of 2-acetoxy-6-n-dodecyl aminocarbonylnaphthalene obtained in Example 1 was suspended in 64 g of 50% methanol-water. To the suspension, 3.4 g of 48% sodium hydroxide aqueous solution was added and allowed to react at 60° C. for 1 hour. The reaction liquid was neutralized with 5% hydrochloric acid and stirred for 30 minutes and then precipitation was filtrated, washed thoroughly with methanol and water, dried to give 6.8 g of 2-hydroxy-6-n-dodecyl aminocarbonylnaphthalene (decomposition point: 329° C.). The infrared absorption spectrum (KBr) of the compound is shown in FIG. 2. The triboelectric charge was measured by blow-off method as described in example 1. The triboelectric charge of the compound was +6.7 μC/g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.C=O.[C:52](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=3)[N:9]=[C:10]([CH:42]3[CH2:47][CH2:46][N:45]([CH3:52])[CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3CCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (20.0 mg, 0.0301 mmol), formaldehyde (0.905 mg, 0.0301 mmol), sodium triacetoxyborohydride (6.39 mg, 0.0301 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature for 2 days. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (16.3 mg, 79.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 678 (M+1).
Reaction SMILES: [S:1]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](NO)=[O:29])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].NC1C2C(=CC=CC=2)C=CC=1CCCCCCC(OCOC)=[O:50].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>>[S:1]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:29])=[O:50])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Reactant: Cc1ccc(S(=O)(=O)Nc2c(CCCCCCC(=O)NO)ccc3ccccc23)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2c(CCCCCCC(=O)O)ccc3ccccc23)cc1

Procedure:
7-(1-Tosylamino-2-naphthyl)heptanohydroxamic acid Using methoxymethyl 7-(1-amino-2-naphthyl)heptanoate and tosyl chloride, the procedure of Reference Example 50 was otherwise repeated to provide 7-(1-tosylamino-2-naphthyl)heptanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=O)[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH2:21][N:22]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:24]=3)[C:6]=2[CH:15]=1
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nccn1-2

Procedure:
In the manner given in Example 33, 5-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 8-fluoro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([CH2:23][CH:24]4[CH2:26][CH2:25]4)=[N:21][N:22]=[C:16]3[C:15]=2[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([CH2:23][CH:24]4[CH2:25][CH2:26]4)=[N:21][N:22]=[C:16]3[C:15]=2[CH3:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Yield: 35.1 %

Procedure:
A solution of intermediate D99 (0.606 g, 1.645 mmol) in EtOH (35 ml) was hydrogenated in a H-Cube® reactor (1 ml/min, Pd/C 10% cartridge, full H2 mode, 80° C.). The solvent was concentrated in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/7M solution of NH3 in MeOH up to 6% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D100 (0.214 g, 35%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][CH:8]([CH3:24])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[CH3:7][CH:8]([CH3:24])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(N)cnc2cccnc12

Procedure:
Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution of N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (4.0 g, 16.2 mmol) in ethyl acetate (250 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.
Reaction SMILES: [C:1]1(=[O:13])[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[C:1]1(=[O:13])[CH:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:4]2[CH2:3][CH2:2]1
Reactant: O=C1CCC2=C1Cc1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC2c3ccccc3CC12

Procedure:
3,8-Dihydrocyclopent[a]inden-1[2H]-one (7.6 g.) in ethanol (400 ml) was hydrogenated at atmospheric pressure and room temperature in the presence of 10% palladium on charcoal (0.9 g) until one molar equivalent of hydrogen had been absorbed. The catalyst was filtered off and the filtrate evaporated to dryness to give a brown gum which was distilled at 90° /0.1 torr to produce a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.S(Cl)(Cl)=O.O.[NH2:18][NH2:19]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:18][NH2:19])=[O:12])=[CH:2]1
Reactant: NN
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NNC(=O)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Indole-3-carboxylic acid (500 mg, 3.1 mmol) was stirred at room temperature with thionyl chloride (5 mL, 68 mmol) for 20 hours. The solution was concentrated under vacuum and the residue was taken up in ether (10 mL) and concentrated to dryness (repeated three times) to ensure removal of the thionyl chloride. The resulting solid was dissolved in ether (5 mL) and added to an ice cooled solution of hydrazine hydrate (600 mg, 12 mmol) in tetrahydrofuran (5 mL). After 30 minutes, the solid was collected by filtration, washed with 5% NaOH and water, and dried under vacuum at 50° C. The crude hydrazide was recrystallized from 95% ethanol to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 7.11-7.22 (m, 2 H), 7.42 (dd, J=7, 2 Hz, 1 H), 7.83 (s, 1 H), 8.02-8.08 ppm (m, 1 H); MS (DCI/NH3) m/z 176 (M+H)+.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:21])=[CH:23][CH:24]=1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Yield: 99.9 %

Procedure:
Using 4-(p-tolyloxy)piperidine (765 mg) and 6-bromonicotinic acid (808 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.5 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3cccc(F)c3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3cccc(F)c3)c21
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
In 100 ml of THF was dissolved 3.00 g of 3,4-dihydro-9-(3-fluorobenzylamino)acridin-1(2H)-one. The mechanically stirred solution was cooled in ice under nitrogen and 4.68 ml of 1M lithium aluminum hydride in THF was added dropwise over 15 minutes. After 0.5 hour, analysis by TLC indicated the reaction was complete, so it was neutralized with 1 ml of saturated ammonium chloride solution and the resulting salts were filtered. The filtrate was evaporated to an oil which crystallized on trituration with pentane. The solid was filtered and recrystallized from 1:1 dichloromethane/pentane to yield 2.50 g of solid, mp 128° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Br:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:28]2[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 50.7 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (57 mg, 0.179 mmol), 1,4-dibromobenzene (211 mg, 0.895 mmol), Pd(PPh3)4 (10 mg, 0.00895 mmol), CuI (3 mg, 0.0179 mmol) and triethylamine (0.249 mL, 1.79 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 70 min then diluted with 20 mL ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried with magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (0% to 5% MeOH/DCM) to afford (1-{2-[5-(4-Bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 51%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].C([Li:24])CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[O:19][Li:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: [Li]Oc1c(C(C)(C)C)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 96 %

Procedure:
Both 10 mmol (2.2 g) of monocyclopentadienyl titanium chloride(CpTiCl3) and 100 ml of toluene were added to a 200 ml Schlenk reactor in the atmosphere of inert gas. Then, 10 mmol of 2,4,6-tri-t-butyl phenoxy lithium, so obtained from the reaction between 2,4,6-tri-t-butyl phenol and n-butyl lithium, was slowly added to the mixture. The reactional solution was stirred at room temperature and stood for 1 hour. After 1 hour, some mixture was collected and was analyzed by 1H-NMR spectroscopy to ascertain the reaction results.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15]N(C)C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][N:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
66 g (266 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 50 g (295 mmol) of diphenylamine were dissolved at 40° C. in 1300 ml of isopropanol. The solution was admixed with 60 ml (725 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 10 min. 550 ml of solvent were evaporated off under reduced pressure, the suspension was cooled to 10° C. and the crystallized product was filtered off. Yield: 83.5 g (84% of theory) 1H NMR: 3.62 (s, 3H), 6.95-7.10 (m, 6H), 7.20-7.30 (m, 8H), 7.32-7.40 (m, 1H), 7.61 (s, 1H), 8.70 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:15])[F:14]
Reactant: N#CCc1ccc(Br)c(OC(F)(F)F)c1
Solvent: C1CCOC1
Product: NCCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 75 °C
Yield: 88.8 %

Procedure:
To a solution of 2-(4-bromo-3-(trifluoromethoxy)phenyl)acetonitrile (800 mg, 2.86 mmol) in THF (40 mL) was added a solution of borane dimethyl sulfide complex in THF (2 M, 2.15 mL, 4.3 mmol) at 0° C. The resulting solution was heated at 75° C. for 2 h under nitrogen atmosphere. The reaction was quenched with MeOH (10 mL) at 0° C. and concentrated under vacuum to afford the crude title product (720 mg, 2.54 mmol). MS (ESI) m/z 283.9 M+, 291.1 [M+2]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[C:7]([N:9]([CH2:11][CH2:12][OH:13])[CH3:10])=[O:8].O.[CH3:20]N(C=O)C>>[Cl:3][C:4]1[C:5]2[O:13][CH2:12][CH2:11][N:9]([CH2:10][CH3:20])[C:7](=[O:8])[C:6]=2[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN(C)C=O
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCN1CCOc2c(ccc(F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (35 mg, 0.913 mmol, 60% dispersion in mineral oil) was added slowly to a solution of 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (220 mg, 0.836 mmol) in DMF (4 mL) and the pale yellow solution was stirred at RT for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (3×30 mL). The combined organic phases were washed with water (3×20 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as a colourless oil (180 mg). 1H NMR δ (CDCl3): 1.25 (t, 3H), 3.5 (t, 3H), 3.65 (q, 2H), 4.52 (t, 2H), 6.97 (dd, 1H), 7.72 (dd, 1H). m/z 244 (M+H)+, 242 (M−H)−