Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=O)=O)[CH:24]=1.[ClH:30]>C(OCC)C>[S:25]([C:23]1[CH:24]=[C:19]([C:9]2[C:10]([Cl:30])=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:20]=[CH:21][C:22]=1[CH3:29])[C:23]1[CH:24]=[C:19]([C:9]2[C:8]([Cl:7])=[CH:13][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:10]=2[Cl:18])[CH:20]=[CH:21][C:22]=1[CH3:29]
Reactant: Cl
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To 0.7 g (18.4 mmol) of lithium aluminum hydride in 30 ml of diethyl ether, 7.2 g (17.8 mmol) of 5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzenesulfonyl chloride in 30 ml of diethyl ether was added dropwise at −10° C. After 12 hours of stirring at room temperature, the reaction mixture was poured into 1N aqueous hydrochloric acid for separation. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography affored 4.3 g of 1,1′-thiodi-[5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzene] (yield 75.0%) as a pale yellow dough (nD20 1.6066), which was used in Example 2 (1) as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].FC1C=CC(CN)=CC=1.[Br:20][C:21]1[S:22][C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=1>>[Br:20][C:21]1[S:22][C:23]([C:27]([NH:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:28])=[C:24]([CH3:26])[N:25]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 50 %

Procedure:
Following the procedure as described in Preparation 15, making variations only as requires to use (3,4-difluorophenyl)methanamine to replace (4-fluorophenyl)-methanamine to react with 2-bromo-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 50% yield: 1H NMR (300 MHz, CDCl3) δ 7.16-7.01 (m, 3H), 6.08-5.94 (m, 1H), 4.52 (d, J=5.9 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 347.2 (M+1), 349.2 (M+3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][CH2:10][S:11]([CH2:13][C:14]([OH:16])=O)=[O:12])=[O:7].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH2:56])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH:56][C:14](=[O:16])[CH2:13][S:11]([CH2:10][CH2:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:12])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(O)CS(=O)CCNC(=O)c1ccco1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CS(=O)CCNC(=O)c1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
There was suspended 3.0 g (0.0122 mol) of 2-[2-(2-furoylamino)ethylsulfinyl]acetic acid in 100 ml of dichloromethane and added 1.87 g (0.0122 mol) of HOBt and 2.52 g (0.0122 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.04 g (0.0122 mol) of N-3-[3-(piperidinomethyl)phenoxy]propylamine, and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 3.0 g of the titled compound as crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:8][CH:7]=2)[CH3:2].CC1[C:24](=O)[NH:25][C:26]2[C:31](N=1)=[CH:30][C:29](OCCCCC(O)=O)=[CH:28][CH:27]=2.CNC1CCCCC1.C(NC1CCCCC1)C>>[CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:24])=[O:20])=[CH:8][CH:7]=2)[CH3:2]
Reactant: Cc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Reactant: CCc1nc2cc(OCCCCC(=O)O)ccc2[nH]c1=O
Agent: CCNC1CCCCC1
Solvent: CNC1CCCCC1
Product: CCc1nc2cc(OCCCCC(=O)N(C)C3CCCCC3)ccc2[nH]c1=O
Yield: 77.4 %

Procedure:
In Example 72 the compound 1013 was replaced by compound 1037 and N-methylcyclohexylamine was replaced by N-ethylcyclohexylamine 0.77 ml to obtain the compound 1035.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH:24][CH3:25]>CC(C)=O>[NH:8]([C:6]1[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([NH:1][CH2:22][CH:23]=[CH:24][CH3:25])[N:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC=CCBr
Reactant: Cc1cc(Nc2ccccc2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC=CCNc1nc(C)cc(Nc2ccccc2)n1

Procedure:
A mixture of 2-amino-4-anilino-6-methylpyrimidine (1 g) (5 mM), potassium carbonate (0.4 g, 5.5 mM), crotyl bromide (0.61 ml) (5 mM) and acetone (25 ml) was heated at reflux for 20 hours. The solvent was then evaporated and the residue triturated with methylene chloride. The methylene chloride extracts were combined and the solvent removed by evaporation. The residual syrup was purified by flash chromatography using Merck 9835 silica (200 g) and eluting with 5% v/v methanol/methylene chloride. There thus was obtained 4-anilino-2-crotylamino-6-methylpyrimidine as a viscous oil (0.36 g) which was used without characterisation.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1.[CH3:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:35][C:33]3[S:34][C:30]([CH3:29])=[N:31][N:32]=3)=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1
Reactant: Cc1nnc(N)s1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nnc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c([N+](=O)[O-])c2)s1

Procedure:
A solution of Example 162b (300 mg, 0.6197 mmol) and 5-Methyl-[1,3,4]thiadiazol-2-ylamine (71 mg, 0.6197 mmol) in toluene (10 mL) was reacted as in Example 162c to give the title compound as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C@@H:24]1[CH2:28][CH2:27][C:26](=[O:29])[O:25]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31]N1C(=O)N(C)CCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C@@H:24]1[CH2:28][C@@H:27]([CH3:31])[C:26](=[O:29])[O:25]1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCCN(C)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCC(=O)O
Solvent: CI
Product: C[C@@H]1C[C@@H]([C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
[(S)-2-(4-Benzyloxy-phenyl)-1-((S)-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester (2.9 g, 7.04 mmol) is dissolved in THF (10 ml) and DMPU (1.34 ml, 10.6 mmol, 1.5 eq). A 1 M solution of lithium hexamethyldisilazide in THF (14.1 ml, 14.1 mmol, 2 eq) is added at −78° C. over 40 min and the mixture is stirred for another 20 min. Methyliodide (0.88 ml, 14.1 mmol, 2 eq) is added dropwise and the mixture is stirred for another 3 h at −78° C. before adding propionic acid (2.69 ml, 36 mmol, 5 eq) and water. After warming up to rt the mixture is poured on 10% citric acid (50 ml) and extracted with EtOAc. The organic layer is washed with bicarbonate and brine, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica (hexane/EtOAc 8/2 to 7/3) followed by recrystallization from hexane/DCM to give 2.2 g white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:20][C:2]1([CH3:1])[CH2:6][S:5](=[O:7])(=[O:8])[N:4]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:32]3[CH2:33][CH2:34][N:29]([C:23]4[C:22]([CH3:21])=[CH:27][C:26]([CH3:28])=[CH:25][N:24]=4)[CH2:30][CH2:31]3)=[O:15])=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CC(C)(C)CS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 21.2 %

Procedure:
Using ethyl 4-(4,4-dimethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (127 mg) described in Preparation Example 30 and 1-(3,5-dimethylpyridin-2-yl)piperazine (82 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (40 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18](O)=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]glycinate (M.P. 127° to 129°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]glycine (M.P. 200° to 201°).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]3[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
Ethyl 4-bromoacetylphenoxyacetate (6.0 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed by filtration. The filtrate was evaporated in vacuo and the solid residue triturated with water, filtered, then washed with water and dried. Recrystallisation from a small volume of ethanol gave the title compound, 1.71 g, as a cream coloured solid: m.p. 113°-114° C.; NMR (d6DMSO) δ8.15 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.89 (2H, d), 4.17 (2H, q), 3.84 (2H, s), 3.32 (4H, t), 2.62 (4H, t), 1.22 (3H t); m/e 384 (M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found: C, 65.5; H, 6.6; N, 10.8%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:21][CH3:22].[Na+].C(I)C>C(O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: Oc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-(3-Hydroxyphenyl)-5H-s-triazolo[5,1-a] isoindole (1.25 g, 0.05 mole) is added to 20 ml of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 0.49 ml (0.06 mole) of ethyl iodide in 5 ml of ethanol. After stirring for one hour at room temperature, a further amount of 0.49 ml of ethyl iodide is added. After refluxing for one hour the solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 1 g (73%) of the title product, m.p. 166°-7° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[C:1]([C:4]1[C:5]([O:24][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 25 mL rb flask equipped with a magnetic stir bar was added 0.309 g(0.86 mmol) of the product of Step A, 0.422 g (1.29 mmol) of cesium carbonate, 3 mL DMF and finally 145 μL of 1-bromopinacolone was added. The reaction mixture was stirred at room temperature for 1.5 h then partitioned between EtOAc and water. The organic layer was separated, washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on s silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([Cl:28])[C:17]=1[CH2:18][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9]
Reactant: FC(F)(F)c1cc(Cl)c(CBr)c(Cl)c1
Reactant: N#CC(C#N)CCC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 52.1 %

Procedure:
Using 0.15 g of (3,4,4-trifluoro-3-butenyl)malononitrile, 5 ml of N,N-dimethylformamide, 38 mg of sodium hydride (60% in oil), and 0.27 g of 2,6-dichloro-4-(trifluoromethyl)benzylbromide, and according to the process described in the Production Example 1, there was obtained 0.18 g of 2-(2,6-dichloro-4-(trifluoromethyl)benzyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile (the present compound (66)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH:7]([NH2:11])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCOC(C)=O.CCCCCC>C(#N)C>[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:23]=[CH:24][C:25]([S:28](=[O:29])(=[O:30])[NH:11][CH:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12])[CH:8]([CH3:9])[CH3:10])=[CH:26][CH:27]=1
Reactant: CC(C)C(N)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 2-Amino-3-methyl-butyric acid tert-butyl ester (H-D-Val-OtBu.HCl) (500 mg, 2.38 mmol) in acetonitrile (20 ml) was added pyridine (767 μl, 9.52 mmol) at ambient temperature. A clear and colourless solution was quickly obtained. Then a solution of 4-chlorosulfonyl-benzoic acid methyl ester (670 mg, 2.86 mmol) in acetonitrile (6 ml) was added dropwise and the mixture became slightly yellow coloured and was stirred at ambient temperature for 4 hours. The reaction was monitored by TLC (EtOAc/Hexane, 1:1). The solvents were evaporated and ethyl acetate (50 ml) and saturated sodium bicarbonate solution (10 ml) were added. The mixture was transferred into a separatory funnel and vigorously shaken. Then the phases were separated and the ethyl acetate phase was extracted once with brine (10 ml), dried (MgSO4), filtered and evaporated to afford the crude product. Flash chromatography using (Ethyl acetate/Hexane, 1:1) gave the pure product as a white solid. Yield 880 mg (99.55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([N:30]6[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]6)=[CH:26][CH:25]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([N:30]6[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]6)=[CH:28][CH:29]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCN(C)CC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCN(C)CC5)cc4)ccnc3[nH]1)cn2C
Yield: 12.9 %

Procedure:
The product is prepared by following the procedure described in example 34, stage (k), starting with 0.08 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[4-(4-methyl-piperazin-1-yl)benzyl]amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34, stage (k) and 0.471 cm3 of 5N potassium hydroxide. 0.008 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[4-(4-methyl-piperazin-1-yl)-benzyl]amine is obtained with the following characteristics:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:23][C:24]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:25]=1[CH2:26][N:27]1[C:31]2=[CH:32][N:33]=[C:34]([C:36]([OH:38])=O)[CH:35]=[C:30]2[CH:29]=[CH:28]1.C(N(CC)CC)C.[CH2:51]([O:58][NH2:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.O>[CH2:51]([O:58][NH:59][C:36]([C:34]1[CH:35]=[C:30]2[CH:29]=[CH:28][N:27]([CH2:26][C:25]3[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:24]=3[F:23])[C:31]2=[CH:32][N:33]=1)=[O:38])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC, 126 mg, 0.67 mmol) and 1-hydroxybenzotriazole (HOBt, 56 mg, 0.56 mmol) was added to a the stirred solution of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (70 mg, 0.24 mmol) in DMF (8 mL). The mixture was stirred for 1 h, and then triethylamine (0.33 ml, 2.37 mmol) and O-benzylhydroxylamine (231 mg, 1.80 mmol) were added. The resulting mixture was stirred for 24 h at ambient temperature, and then water (50 mL) was added. The precipitates were collected, and dried to give the title compound (60 mg, 63%). 1H NMR (DMSO-d6) δ: 11.71 (s, 1H), 8.81 (s, 1H), 8.20(s, 1H), 7.74 (s, 1H), 7.15-7.45 (m, 7H), 7.02 (m, 1H), 6.68 (s, 1H), 5.60 (s, 2H), 4.88 (s, 2H). HRMS calcd for C22H8F2N3O2 (M+H) 394.1367, found 394.1388.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:49]([O:50]CC2C=CC=CC=2)[C@H:48]([O:58][C@H:59]2[O:88][C@H:87]([CH3:89])[C@@H:78]([O:79]CC3C=CC=CC=3)[C@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]2[O:61]CC2C=CC=CC=2)[C@@H:47]([CH2:90][O:91]CC2C=CC=CC=2)[O:46][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16](C(OCC3C=CC=CC=3)=O)[O:17][CH2:18]2)[C@H:14]([O:30]CC2C=CC=CC=2)[C@@H:13]1[O:38]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@H:59]1([O:58][C@@H:48]2[C@@H:47]([CH2:90][OH:91])[O:46][C@H:10]([O:11][C@@H:12]3[C@@H:19]([CH2:18][OH:17])[C@@H:15]([NH2:16])[C@H:14]([OH:30])[C@H:13]3[OH:38])[C@H:9]([OH:8])[C@H:49]2[OH:50])[O:88][C@H:87]([CH3:89])[C@@H:78]([OH:79])[C@H:69]([OH:70])[C@H:60]1[OH:61]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4[C@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N)[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 0 %

Procedure:
The compound (53 mg, 40.4 mmol) synthesized in Example 14 (14f) was dissolved in methanol (10 mL) and hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon (53 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After celite filtration, the solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water—5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (5 mg, 26%) as a colorless solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
1-BOC-4-piperidone (2.00 g) and 2-methoxyethylamine (872 μl) were stirred together in methanol (20 ml) at room temperature for 12 hours. Sodium borohydride (760 mg) was added in several aliquots over 30 minutes and the reaction mixture stirred for a further 12 hours at ambient. The solvents were removed in vacuo and the residue diluted with dichloromethane (50 ml) and washed with brine and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by flash silica chromatography to give 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.69 g) as a colourless oil.