Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][NH:24][CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][N:24]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[N:12]=2)[CH2:5][CH2:6]1
Reactant: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCNC4)ccc2N1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Cc2cc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)ccc2N1

Procedure:
Step 3—Synthesis of compound ud: 5-(4-Morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)indolin-2-one (0.083 g, 0.24 mmol), 2-Chloropyrimidine (0.0406 g, 0.354 mmol), N,N-Dimethylformamide (4.00 mL, 51.6 mmol) and N,N-Diisopropylethylamine (0.164 mL, 0.945 mmol) were combined and reaction mixture was microwaved on 300 watts, 120° C. for 30 minutes on a CEM microwave, and vacuum filtered. 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 8.44 (d, J=4.7, 2H), 8.24 (d, J=8.2, 1H), 8.20 (s, 1H), 6.92 (t, J=10.8, 1H), 6.70 (t, J=4.7, 1H), 4.82 (s, 2H), 3.98 (t, J=5.2, 2H), 3.77-3.69 (m, 4H), 3.57 (s, 2H), 3.47 (d, J=4.4, 4H), 2.75 (dd, J=8.8, 3.8, 2H). LC/MS-m/z+430.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:24])(=[O:23])[O:20]CC)=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[OH:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:24])(=[O:20])[OH:23])=[CH:15][CH:14]=3)[CH:9]=2)=[CH:6][N:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Yield: 1.4 %

Procedure:
To a solution of compound 38-g (150 mg, 0.35 mmol) in dioxane (5 mL) was added 3 N NaOH aqueous solution (2 mL). The reaction mixture was refluxed for 1 h, and diluted with water, adjusted pH to 2 with concentrated HCl. The reaction mixture was concentrated and purified by pre-HPLC to afford compound 38-1 (2 mg). 1H NMR (300 MHz, CD3OD) δ 8.84-8.56 (m, 1H), 8.77 (s, 1H), 8.44-8.46 (m, 1H), 8.10-8.14 (m, 3H), 7.89-7.95 (m, 2H), 7.70-7.77 (m, 2H), 7.34 (s, 1H), 7.00-7.16 (d, J=51.3 Hz, 1H), 1.57-1.62 (d, J=14.4 Hz, 3H). LC-MS 395 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6]>O>[CH3:6][S:5][CH2:4][CH2:3][CH:2]1[NH:1][C:7](=[O:9])[CH:2]([CH2:3][CH2:4][S:5][CH3:6])[NH:1][C:7]1=[O:9]
Reactant: CSCC[C@H](N)C(=O)O
Solvent: O
Product: CSCCC1NC(=O)C(CCSC)NC1=O

Procedure:
A suspension of 13.4 g (0.09 mol) of methionine, 17.2 g (0.09 mol, purity: 91%) of methioninehydantoin (IId) and 150 g of water were introduced into a 200 ml Roth steel autoclave with magnetic stirring and stirred at 160° C. for 6 hours, during which the pressure increased to 15 bar. From time to time, the autoclave was decompressed until the pressure settled at a constant 10 bar. The autoclave was then cooled in an ice bath, and the resulting suspension was filtered and the solid was washed with 75 ml of water. Finally, the solid was dried in a vacuum drying oven at 50° C. overnight. Bis[2-(methylthio)ethyl]-2,5-piperazinedione (III) was isolated as yellowish white crystals.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]([C:26](=[O:31])N(OC)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][CH3:33]>C1COCC1.CCOCC>[C:26]([C@@H:11]1[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][C@@H:12]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:31])[CH3:33]
Reactant: CON(C)C(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -22 °C
Reaction time: 0.67 h

Procedure:
Benzyl (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.0 g) was dissolved in THF (40 mL) and cooled to −22° C. prior to the addition of 1.6 M MeLi (14.5 mL) in Et2O. After 40 min at −22° C., the reaction was quenched with 0.5 N HCl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2R,4R)-2-acetyl-4 -(tert-butyldimethylsilyloxy)cyclohexylcarbamate (5.7 g). MS found: (M+H)+=406.3.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(Br)cnc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc.) (12.6 g, 50.3 mmol), piperazine-1-carboxylic acid tert-butyl ester (11.7 g, 62.9 mmol) and DIEA (13.3 g, 102.0 mmol) in DMA at 130° C. for 36 h. Partition the dark brown reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the crude product. Purify by flash chromatography, eluting with 9:1 hexanes:EtOAc, increasing to 3:1 hexanes:EtOAc to provide the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11]C(OC(C)(C)C)=O)([CH3:10])[CH3:9])[CH3:2].[ClH:29]>C(OCC)(=O)C.CO>[ClH:29].[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[NH:6][C:7](=[O:19])[C:8]([NH2:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)N

Procedure:
Into a stirred solution of N-[2-(t-butoxycarbonylamino)-2-methyl-1-oxopropyl]-L-tyrosine ethyl ester (1.46 g, 3.70 mmol) in ethyl acetate (50 mL) and methanol (10 mL) is bubbled hydrochloric acid gas for 10 minutes. The solvent is removed to give N-(2-amino-2-methyl-1-oxopropyl)-L-tyrosine ethyl ester monohydrochloride as a white foam which is used without any further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[O:29])[CH3:26]
Reactant: CCN(CC)C(=O)Cl
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Product: CCN(CC)C(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Yield: 55.4 %

Procedure:
A mixture of 2.0 g (0.006 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 10.0 g (0.074 mole) of diethylcarbamoyl chloride was heated at reflux for two hours. Excess diethylcarbamoyl chloride was removed under high vacuum. The residue was chromatographed on silica gel, eluting with toluene, to give 1.5 g of product, mp 108°-9° (from methylcyclohexane).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=CC=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CCCCCCCCCCCCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: CCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Nc2ccc(-c3ccccc3)cc2)cc1C
Temperature: 230 °C
Reaction time: 14 h

Procedure:
In a 1 liter round bottomed flask equipped with a mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 166.48 grams (1.02 mole) of N-(3,4-dimethylphenyl)acetamide, 233.1 gram (1.02 mole) of 4-bromobiphenyl, 7.5 grams (0.03 mole) of cupric sulfate pentahydrate, 165.86 grams (1.2 moles) of potassium carbonate, and 20 milliliters of tridecane solvent. The resulting reaction mixture was then heated rapidly over a period of about thirty minutes to a temperature of 230° C. (Centigrade) and allowed to proceed for 14 hours at this temperature. The reaction was then allowed to cool to 80° C. and 800 milliliters of denatured alcohol and 165.5 grams (2.95 moles) of flake potassium hydroxide were added. The reaction mixture was then reheated to reflux for 3 hours to complete the amide hydrolysis. The reaction mixture was then cooled to room temperature, about 25° C., and added rapidly to 2 liters of deionized water to provoke precipitation. The intermediate product was filtered and washed liberally with deionized water. The resulting wet cake was taken up in 1 liter of hot isooctane and water was removed by azeotropic distillation. The intermediate product was decolorized by adding 45 grams of Alcoa CG-20 alumina and stirring at reflux for 3 hours. The intermediate product was then recrystallized on cooling to room temperature and was isolated by vacuum filtration. An off-white powder of weight 202.2 grams (74 percent) resulted, suitable for use in the following Example II reaction. Purity of this intermediate product was about 97 to about 99.5 percent as determined by high performance liquid chromatography.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[C:8]([C:24](=[O:26])[NH2:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[CH2:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:27]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH2:28][CH3:29])[CH:34]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)(=[O:26])[NH2:25]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4C)c3n2)cn1
Temperature: 100 °C

Procedure:
A solution of (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (200 mg, 0.455 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (202 mg, 0.911 mmol), and 2M aq K3PO4 (0.683 ml, 1.366 mmol) in dioxane (2 ml) in a reaction vial was purged with N2 for 2 min, followed by addition of PdCl2(dppf) CH2Cl2 Adduct (1:1) (37.5 mg, 0.046 mmol). The reaction mixture was purged with nitrogen for 1 min, sealed and heated at 100° C. for 120 min. The product mixture was partitioned between EtOAc and water. The organic phase was washed with brine, filtered through CELITE®, dried (Na2SO4) and concentrated. The crude product was purified by flash column (ISCO 12 g, 20-80% EtOAc/hexane over 15 min) to afford (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate as an off-white solid, 139 mg. ESI-MS (Method A): m/z 455.2 ([M+H]+).
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:26][C:27]([NH2:29])=O)[CH2:22][C:23]([NH2:25])=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CN(C=O)C.ClC(Cl)(Cl)C(Cl)=O.CCCCCC>C(Cl)Cl>[CH3:31][Si:2]([CH3:1])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:26][C:27]#[N:29])[CH2:22][C:23]#[N:25])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(N)=O)CC(N)=O)c3)ncnc21
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC#N)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and cooled in an ice bath under nitrogen atmosphere. The trichloroacetyl chloride (15 mL, 0.14 mol) was added dropwise turning the reaction to a dark solution. This was stirred at 0° C. for ½ h. The reaction was then concentrated to remove the DCM and the resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was collected and washed with water to give a dark solid. The solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue. The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy. This was stirred at rt to precipitate 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrile as white needle-like crystals (22.7 gm, 85%), LC/MS (M+H)+: 408, 1H NMR (DMSO-d6) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.88 (d, 1H), 7.19 (d, 1H), 5.75 (s, 2H), 5.30 (m, 1H), 3.62 (t, 2H), 3.40 (m, 4H), 0.91 (t, 2H), 0.10 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].[NH3:30].Cl>ClCCCl.C(OCC)(=O)C>[NH2:30][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4]
Reactant: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reactant: N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
23.04 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 65 ml of 1,2dichlorethane and 65 ml of ethyl acetate, into which ammonia gas was passed at -15° C. for 1 hour. This solution was placed in a sealed tube and reacted at 110° C. for 2 hours. In order to complete the reaction, ammonia was again passed into the solution at -15° C. for 30 minutes in the sealed tube where the reaction was continued at 110° C. for 1.5 hours. After ice-cooling, the reaction solution was charged into ice-cooled 2N hydrochloric acid, to which ethyl acetate was added, from which the resultant aqueous phase was collected. Sodium carbonate was added to the aqueous phase under ice-cooling conditions so that the pH was adjusted to 8, followed by extraction with chloroform under salting-out conditions. The extract was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. followed by filtration and concentration to obtain 12.97 g (yield 64%) of the intended compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH2:23][CH2:24][CH3:25])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH2:23][CH2:24][CH3:25])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OC

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): The reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.34 g of (L)-norvaline methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-norvaline methyl ester after flash chromatography (N3). 1H-NMR (DMSO): 0.83 ppm (t, 3H), 1.33 ppm (m, 2H), 1.55 ppm (m, 2H), 3.62 ppm (s, 3H), 3.1 ppm (m, 1H), 7.3-8 ppm aromatics.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([S:35]([C:28]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:37])=[O:36])[C:7](=[O:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1cccc(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(-c3cccc(Cl)c3)c3cc(Cl)ccc32)c(OC)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2 g of 5-chloro-3-(3-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 170 ml of THF is cooled to -40° C. and 0.97 g of potassium tert- butylate is added. The mixture is stirred for 30 minutes at -10° C. and then cooled to -50° C. and a solution of 1.7 g of 2,4-dimethoxybenzenesulfonyl chloride in 70 ml of THF is added. The reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT, and then concentrated under vacuum. The residue is taken up with water, extracted with DCM and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 2.3 g of the expected product after crystallization from a cyclohexane/DCM mixture (90/10; v/v). M.p.=173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.21 g of sodium hydride (60% in oil), and 0.67 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(4-chlorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (24)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(C)=O)c2)c1-c1ccccc1

Procedure:
3′-Amino-acetophenone (5 mmol, 0.7 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The residual oil was purified over silica and yielded the named product (m.p. 100° C.-102° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C.BrC1[S:45][C:46]2[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1.Cl>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:45][C:46]4[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][CH:50]=[CH:49][C:47]=4[N:48]=3)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (117 mg, 0.30 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for one hour. Following concentration under reduced pressure, the residue was dissolved in DMF (3 mL). Diisopropylethylamine (0.32 mL, 1.84 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (87 mg, 0.30 mmol) were added, and the mixture was stirred at 70° C. for two hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, ethyl acetate) to obtain 97 mg of the title compound as a pale yellow solid (65%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45].[CH2:46](O)[CH3:47].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([O:40][CH2:46][CH3:47])=[O:39])=[CH:32][CH:33]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45]
Reactant: CCO
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccn4c(Br)c(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg), ethanol (12 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg), 1-hydroxybenzotriazole (17 mg) and N,N-dimethylformamide (0.6 ml) was stirred for 3 hours at ambient temperature. Ethyl acetate was added thereto, and the mixture was washed with water four times, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-ethoxycarbonylpropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2- methylimidazo[1,2-a]pyridine (7 mg) as an amorphous.