Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(COC)OC>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1ccc2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccc21

Procedure:
A mixture of 0.4 g (E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide, 0.231 g N-Methylindol-5-boronic acid and 14 ml dimethoxyethane is slightly heated and to this mixture are added bis(triphenylphosphine)palladium(II)chloride and 1.5 ml of a 2M aqueous sodium sulfate solution. This mixture is heated to reflux temperature under an inert gas atmosphere overnight. After cooling the mixture is filtered, evaporated and the residue is partitioned between ethyl acetate and a 5% aqueous solution of sodium bicarbonate. The organic phase is dried and evaporated and the residue is purified by silica gel flash chromatography.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[C:19]([OH:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[OH:21].I[CH2:23][CH3:24]>O>[Br:8][C:9]1[C:10]([OH:21])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][C:19]=1[O:20][CH2:23][CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c(Br)c(OCC)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil, 3.86 g) was added to a DMF (100 mL) solution of ethyl 4-bromo-3,5-dihydroxybenzoate (12.3 g), and the mixture was stirred at 00° C. for 30 minutes in a nitrogen atmosphere. Iodoethane (4.15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.87 g).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7]([C:9]1([CH2:19][CH2:20][CH2:21]Br)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=O)=[O:8].C(OC)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]12[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][CH:10]1[NH:1][CH2:21][CH2:20][CH2:19]2)=[O:8]
Reactant: COC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)C12CCCNC1Cc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NaN3 (0.44 g) is added to a solution of 1-(3-bromo-propyl)-2-oxo-indan-1-carboxylic acid methyl ester (2.06 g) in dimethylformamide (10 mL) at room temperature. The solution is stirred at room temperature for 4 h and then tBuOMe and ethyl acetate are added. The resulting mixture is washed with water and brine and dried (MgSO4). Most of the organic solvent is evaporated and tetrahydrofuran (10 mL), acetic acid (0.5 mL), and finally 10% Pd/C (150 mg) are added to the residue. The resulting mixture is shaken in hydrogen atmosphere (1 bar) at room temperature for 14 h. Then, the mixture is filtered, the filtrate is concentrated, and the residue is taken up in tBuOMe. The organic phase is washed with aqueous Na2CO3 solution and brine and dried (MgSO4). Then, the solvent is evaporated and the residue is dissolved in methanol (10 mL). To the solution is added acetic acid (0.5 mL) and 10% Pd/C (50 mg) and the resulting mixture is shaken under hydrogen atmosphere (1 bar) at room temperature for 6 h. Then, the mixture is filtered and the filtrate is concentrated under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:12]([C:13](O)=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[CH2:13][OH:14]
Reactant: O=C(O)c1cc(F)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)ccc1O
Yield: 95.3 %

Procedure:
1.98 g of lithium aluminum hydride were added to 50 ml of tetrahydrofuran, and a solution of 5.44 g of 5-fluorosalicylic acid in 50 ml of tetrahydrofuran was then added dropwise at room temperature to the resulting solution. The resulting mixture was then heated under reflux for 1 hour. At the end of this time, it was cooled, and sodium sulfate decahydrate was added in order to decompose any excess hydride. Insoluble substances were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.72 g (yield 95%) of the title compound as a solid substance.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:15])[CH3:14].Br[CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N:13]([CH3:14])[CH3:15]
Reactant: CC(=O)c1ccc(O)c(N(C)C)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCCCl)c(N(C)C)c1
Temperature: 3 °C
Reaction time: 0.75 h
Yield: 179 %

Procedure:
To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oil dispersion) with dimethylformamide (75 ml), and cooled to 3° C. in an ice-salt bath and under a stream of nitrogen was added, dropwise, 1-(4-hydroxy-3-dimethylamino-phenyl)ethanone (8.7 g, 48.5 mmol) dissolved in dimethylformamide (150 ml) so that the temperature did not go over 7° C. After the addition was over, the bath was removed and the reaction was stirred at ambient temperature for 45 minutes. The ice bath was reapplied and a solution of 1-bromo-3-chloropropane (8.4 g, 53.4 mmol) in dimethylformamide (25 ml) was added dropwise. After the addition was complete, the reaction was stirred for 18 hours at ambient temperature under nitrogen. The reaction was chilled to 7° C. in an ice bath and water (200 ml) was carefully added. After stirring for 5 minutes, the aqueous mixture was extracted with ethyl acetate (5×200 ml). The ethyl acetate extract was washed with water (2×50 ml), dried with MgSO4, and concentrated to yield 22.2 g of a black oily liquid. The compound was purified by prep HPLC, and combination of appropriate fractions gave 5.0 g of brown oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2[CH3:33])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:18][C:17]1[C:12]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]([CH3:33])[N:9]([C@H:7]3[CH2:8][C@H:5]([CH2:3][OH:2])[CH2:6]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@H](n2c(C)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@H](CO)C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
2.94 g (6.64 mmol) trans-3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester of Example 104 in 35 ml dry THF are added during 45 min to an ice-cold solution of 0.281 g (7.17 mmol) lithium aluminiumhydride in 30 ml dry THF. The reaction mixture is stirred at 0° C. for additional 20 h. Water is added slowly to the mixture (0.914 ml in 20 min; T≦4° C.), followed by 0.11 ml 4N NaOH. The precipitate is filtered off, the residue on the filter washed with ethyl acetate and water. The filtrate is extracted with ethyl acetate. After drying the organic phase with sodium sulfate, the solvent is evaporated and the residue purified by chromatography (solvent: ethyl acetate-MeOH 95:5). The title compound is obtained as a foam. Analytical HPLC: tR=3.06 min (shorty); ES-MS: m/eo=415; NMR (DMSO-d6): 8.10/s (1H), 7.25-7.5/several m's (6H), 7.25/“d” (1H); 6.95/s (1H); 6.90/1“d” (1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.04/m (1H); 4.69/t (OH); 3.57/t (2H); 3.15-3.25/m (2H); 2.4-2.5/m (1H); 2.23/s (3H); 2.15-2.25/m (2H).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2)(O)=O.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[NH2:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Temperature: 50 °C

Procedure:
A stirred mixture of (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (1.50 g, 5.76 mmol), and sodium azide (749 mg, 11.53 mmol) in conc. H2SO4 (30 mL) was heated to 50° C. for 2 h, then allowed to cool to ambient temperature. The mixture was adjusted to pH 8 by addition of 6 N aqueous NaOH and concentrated in vacuo to precipitate a solid. The precipitate was collected by filtration and washed extensively with H2O. Drying in vacuo afforded the title compound. MS: m/z=232 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7]2=[O:20].CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:9]1[N:8]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7](=[O:20])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CS(=O)(=O)CCCn1c(=O)[nH]c2c(I)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCn1c(Cl)nc2c(I)cccc2c1=O
Temperature: 120 °C

Procedure:
A pressure vessel was charged with 8-iodo-3-(3-(methylsulfonyl)propyl)-quinazoline-2,4(1H,3H)-dione (1.09 g, 2.67 mmol), DIEA (1.858 mL, 10.68 mmol) and phosphorus oxychloride (1.222 mL, 13.35 mmol). The tube was sealed and heated in an oil bath at 120° C. for 3 h, then cooled to RT. The solvent was removed in vacuo and the residue was poured into ice/water (50 mL) and 1 M NaOH was added until pH 10. The suspension was filtered and the solid was dried to give the crude product. MS (ESI, pos. ion) m/z: 426.8 (M+1).
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:14]=[N-:15].O>CCO>[CH2:11]([O:10][C:8]([C:7]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[NH2:6])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC#N
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a freshly prepared NaOEt (1.18 mmol) solution in EtOH (0.75 mL) is added ethyl cyanoacetate (100 mg, 0.88 mmol) at 0° C. After stirring at 0° C. for 10 min., azido-benzene (100 mg, 0.84 mmol, prepared according to the method reported by M. Kurumi et al. Heterocycles. 2000, 53, 2809) is added. After the addition, the mixture is allowed to slowly warm up to room temperature and stirred for 14 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined extracts is concentrated and purified by flash column chromatography (silica gel, 0%-70% EtOAc/hexane) to provide 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a white solid (100 mg, 51%). HPLC-MS calculated C11H12N4O2 (M+1+): 233.1. Found: 233.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].CS[C:17](=[NH:19])[NH2:18]>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC(=N)N
Reactant: NCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N=C(N)NCCc1ccccc1
Yield: 127 %

Procedure:
2-Phenylethylamine (8.49 g, 70.1 mmol) and S-methylisothiourea sulfate (9.43 g, 33.9 mmol) was dissolved in 100 ml distilled water. Air was passed over the reaction mixture and through 50% NaOH (500 ml) and then through 5% cuprous sulfate (250 ml). The reaction mixture was heated at reflux for 5 hours. Evaporation of the solvent yielded a white powder. The product was isolated by crystallisation from 96% ethanol, washed with cold acetone and diethyl ether and dried in a desicator. After three crystallisations, the product contained only minor amounts of starting material. The reaction yielded 61.5% (9.14 g) 2-phenylethylguanidine hemisulfate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4n3)cc2)ccc1Cl
Yield: 55.5 %

Procedure:
2-(4-aminophenylthio) quinoline (3.9 mmoles, 1.0 g) and 4-chloro-3 -trifluoromethylphenylisothiocyanate (3.9 mmoles, 0.92 g) were reacted according to procedure A to yield 1.06 g, 56% of the title compound. Mass spec (FD) 490. Calculated for C23H15ClF3N3S2 : C, 56.38; H, 3.09, N, 8.58. Found: C, 56.60; H, 3.11; N, 8.42.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:27]([NH:37][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 8.0 g. of 3-phenyl-3-(3-nitrophenyl)propenoic acid in 260 ml. of methylene chloride was added 3.3 g. of triethylamine. The mixture was stirred for 20 minutes and then it was cooled in an ice-bath. To the cooled solution was added, dropwise, during 15 minutes, a solution of 3.6 g. of ethyl chloroformate in 30 ml. of methylene chloride. Stirring was continued for 20 minutes, and then a solution of 5.2 g. of decylamine in 30 ml. of methylene chloride was added, dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium hydroxide, 1 N hydrochloric acid, water, and saturated sodium chloride solution. The resulting solution was dried (Na2SO4) and evaporated in vacuo to give the 10.7 g. of the title compound as a oil.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[F:14][CH:15]([F:40])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]2[CH:24]=[C:25]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][CH:36]([OH:39])[CH2:37][OH:38])[CH:34]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)[N:17]=1>CN(C=O)C.CCOC(C)=O>[Si:10]([O:38][CH2:37][CH:36]([OH:39])[CH2:35][N:33]1[CH:34]=[C:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([CH:15]([F:14])[F:40])[CH:21]=[CH:20][N:19]=3)[CH:24]=2)[CH:31]=[N:32]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO)c2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Imidazole (0.28 g, 4.16 mmol) and tert-butylchlorodimethylsilane (0.574 g, 3.81 mmol) were added to a solution of 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propane-1,2-diol (1.3 g, 3.46 mmol) in DMF (12 mL) at 0° C. The mixture was stirred at 0° C. for 90 minutes. The mixture was allowed to warm to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/Hexane) to afford 1-((tert-butyldimethylsilyl)oxy)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-ol. MS ESI calc'd. for C24H34F2N5O2Si [M+H]+ 490. found 490.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.CC(=O)OCC.O>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])[CH2:23][CH2:22]3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: O=C(OCc1ccccc1)N1CCC(Br)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCN(C(=O)OCc3ccccc3)CC2)cn1
Yield: 30 %

Procedure:
A solution of 60.1 mg (0.23 mmol) of the compound from example 1g, 68.9 mg (0.23 mol) of 4-bromo-1-benzyloxycarbonylpiperidine, 97 μl (0.69 mmol) of triethylamine in 1 ml of absolute THF was treated in a microwave at 180° C. for 2 h. The reaction solution was then mixed with 2 ml of EA/water (1:1), and the EA phase was separated off and dried over Na2SO4. Filtering, stripping off the solvent and purifying the remaining residue by chromatography on RP silica gel with CH3CN/water/0.1% TFA as mobile phase afforded 33 mg of the title compound as bistrifluoroacetate.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:40]1([NH2:43])[CH2:42][CH2:41]1>ClCCl.CN(C=O)C>[CH:40]1([NH:43][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:29])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:42][CH2:41]1
Reactant: NC1CC1
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (236 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (70 mg, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:16][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:13]([OH:15])[CH3:14]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-butyric acid (2 g, 9.12 mmol) was dissolved in N,N-dimethylformamide (15 mL), under an atmosphere of nitrogen. Potassium carbonate (2.02 g, 14.6 mmol) was added and the reaction was cooled using an ice bath. Iodomethane (679 μL, 10.9 mmol) was added and the reaction was stirred for 2 h, and allowed to slowly warm to room temperature. The reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.85 g, 87%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J=6.6 Hz, 3H), 1.47 (s, 9H), 2.24-2.45 (m, 1H), 3.78 (s, 3H), 4.15-4.37 (m, 2H), 5.21-5.45 (m, 1H). LCMS (m/z) 234.0 [M+H], Tr=1.57 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C.[N:18]1([C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28]CC)=[O:27])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCOCC1>[C:26]([C:25]1[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH2:20][CH2:19]1)([OH:28])=[O:27]
Reactant: CCOC(=O)c1ccccc1N1CCNCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(CN2CCN(c3ccccc3C(=O)O)CC2)cc1
Yield: 57.3 %

Procedure:
Using 2.4 g of methyl 4-bromomethylphenylacetate, 2.9 g of ethyl 2-piperazinylbenzoate acetate, 3 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was recrystallized from ethanol-water to provide 2.0 g of the title compound melting at 179° C.-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=NOC)[CH:6]([C:11](=O)[CH3:12])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][NH2:28]>C(O)(=O)C.COCCO>[CH2:1]([O:3][C:4]([C:5]1[N:27]([C:21]2[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:26])[N:28]=[C:11]([CH3:12])[C:6]=1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:17])[CH3:2]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=NOC)C(CC(C)C)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: CCOC(=O)c1c(CC(C)C)c(C)nn1-c1c(Cl)cccc1Cl
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetyl-2-methoxyimino-5-methyl-hexanoic acid ethyl ester (1 g, 4.1 mmol), 2,6-dichlorophenylhydrazine hydrochloride (1.76 g, 8.2 mmol) in glacial acetic acid (10 mL) and 2-methoxy-ethanol (5 mL) is stirred at 105° C. for 3 hours. The reaction is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and purified by column chromatography (0-20% EtOAc in hexanes) to give the title product as an oil, 1.1 g (76%).