Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(#N)C.C(=O)(O)[O-].[Na+].[CH3:55][O:56][C:57]1[CH:65]=[CH:64][C:63]([N:66]2[CH:70]=[N:69][N:68]=[N:67]2)=[CH:62][C:58]=1[C:59](Cl)=[O:60]>O>[CH3:55][O:56][C:57]1[CH:65]=[CH:64][C:63]([N:66]2[CH:70]=[N:69][N:68]=[N:67]2)=[CH:62][C:58]=1[C:59]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:60]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15 mL), acetonitrile (6 mL), water (6 mL), and sodium bicarbonate (0.09 g, 1.03 mmol). Cool to 0° C. in an salt-ice bath. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (0.21 mmol). After 30 minutes, warm to ambient temperature. After 30 minutes at ambient temperature, partition the reaction mixture between ethyl acetate and brine. Extract the organic layer with 1M hydrochloric acid solution, then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:15])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)C>S(=O)(=O)(O)O>[F:14][C:10]1[CH:9]=[C:8]2[C:13]([CH:4]=[C:5]([NH2:15])[N:6]=[CH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(OCC)C(=N)NCc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: Nc1cc2ccc(F)cc2cn1
Yield: 2.4 %

Procedure:
The crude 2,2-diethoxy-N-(3-fluorobenzyl)acetimidamide (22 g) was added dropwise to conc. sulfuric acid (200 mL) at 20˜25° C. with stirring. The mixture was stirred at room temperature for 48 hours. Then this mixture was quenched with ice (1 Kg), and a 12 N NaOH solution (400 mL) was added. The final pH of 9˜10 was reached. The suspension was extracted with CH2Cl2 (5×2 L). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (330 mg, 2.5% yield based on m-fluorobenzylamine) as a yellow solid. 1H NMR (300 MHz, CDCl3): 9.17 (s, 1H), 8.66 (s, 1H), 8.01˜8.07 (m, 2H), 7.68 (dd, J=2.4, and 8.7 Hz, 1H), 7.58 (m, 1H); MS: m/z 163.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]5[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=5)=[O:26])[C:19]=4[CH3:33])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[N:34]([CH:37]([CH3:39])[CH3:38])=[C:35]=[O:36]>ClCCCl>[CH:37]([NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]5[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=5)=[O:26])[C:19]=4[CH3:33])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N=C=O
Reactant: Cc1c(NC(=O)c2nccn2C)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Solvent: ClCCCl
Product: Cc1c(NC(=O)c2nccn2C)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(=O)NC(C)C)ccc3c12
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A solution of 7-amino-4-(2-methyl-3-(1-methyl-1H-imidazole-2-carboxamido)phenyl)-9H-carbazole-1-carboxamide (Example 54-15, 29 mg, 0.066 mmol) and 2-isocyanatopropane (0.019 mL, 0.198 mmol) in 1,2-dichloroethane (3 mL) was stirred at rt for 2.5 h, then at 50° C. for 2 h. Additional 2-isocyanatopropane was added and the mixture was stirred at 40° C. for 16 h. The mixture was concentrated and purified by HPLC. The appropriate effluent fractions were partially concentrated, treated with NaHCO3 (aq) and extracted with EtOAc. The organic phase was dried and concentrated to provide 7-(3-isopropylureido)-4-(2-methyl-3-(1-methyl-1H-imidazole-2-carboxamido)phenyl)-9H-carbazole-1-carboxamide as a pale pink solid (15 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (1 H, s), 9.97 (1 H, s), 8.37 (1 H, s), 8.13 (1 H, br. s.), 7.88 (1 H, d, J=7.9 Hz), 7.81 (1 H, d, J=1.8 Hz), 7.76 (1 H, d, J=7.9 Hz), 7.40-7.48 (2 H, m), 7.38 (1 H, t, J=7.7 Hz), 7.13 (1 H, d, J=7.5 Hz), 7.06 (1 H, s), 6.82-6.92 (2 H, m), 6.73 (1 H, d, J=8.3 Hz), 5.98 (1 H, d, J=7.5 Hz), 4.01 (3 H, s), 3.68-3.81 (1 H, m), 1.89-1.95 (3 H, m), 1.07 (6 H, d). Mass spectrum m/z 524.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2ccc(N)cc2)cc1
Temperature: 60 °C

Procedure:
A portion (20.27 grams, 0.075 mole) of 4,4'-dinitrostilbene from A above, concentrated hydrochloric acid (150 milliliters) and ethanol (300 milliliters) are added to a beaker and heated to provide a 60° C. stirred solution. Over the next eight hour period, 325 mesh powdered iron is added to the reaction mixture in aliquots until a total of 33-51 grams (0.60 mole) has been added. After completion of the iron addition, the mixture is heated for 16 hours at 60° C. then diluted with ethanol (250 milliliters) and deionized water (250 milliliters). After cooling to 25° C. , the product is filtered. The resultant solution is treated with 50% aqueous sodium hydroxide sufficient to induce precipitation of a pale tan colored product which is recovered by filtration. The recovered filter cake is washed with deionized water (500 milliliters) then dried in a vacuum oven at 100° C. and 2 mm Hg to a constant weight of 11.3 grams. The product is recovered as a pale tan colored solid. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product confirms the product structure: Disappearance of the absorbances observed for the conjugated nitro group, appearance of --NH2 stretching absorbances at 3436 (3462 shoulder) and 3356 (3376 shoulder) cm-1, a --NH2 bending absorbance at 1616 cm-1 (1603 cm-1 shoulder due to aromatic ring absorbance) , an out-of-plane C--H deformation at 970 cm-1 due to the trans substituted ethylene group and a C--H out-of-plane bending vibration at 832 cm-1 due to the paradisubstituted aromatic rings. Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: Cl[C:2]1(Cl)[C@H:9]2[C@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10]>C(O)(=O)C.[Zn]>[C@H:9]12[CH2:2][C:3](=[O:10])[C@H:4]1[CH2:5][CH2:6][CH:7]=[CH:8]2
Reactant: O=C1[C@H]2CCC=C[C@H]2C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1C[C@@H]2C=CCC[C@H]12
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 1.1 g (1R,6S)-8,8-dichlorobicyclo [4.2.0]oct-2-en-7-one, prepared as shown in Example 3A, in 10 ml of glacial acetic acid was added 2.0 g of zinc dust in portions over a period of 15 minutes. The mixture was then stirred at 65° C. for 1 hour, then a further 0.5 g of zinc dust was added and the mixture stirred at 75° C. for 1 hour. The mixture was cooled, filtered, the solid washed with hexane, the filtrate and combined washings diluted with water and extracted with hexane. The hexane layer was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue distilled under vacuum to give 500 mg of (1R,6S)-bicyclo[4.2.0]oct-2-en-7-one, the compound of formula (2), [α]D =+171.4°, (C=0.5, CHCl3).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][OH:14])[CH3:12].[H-].[Na+].[Cl:17][C:18]1[N:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31]Cl)[C:20](=[O:24])[N:21]([CH3:23])[N:22]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[N:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][O:14][N:13]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH3:12])[C:20](=[O:24])[N:21]([CH3:23])[N:22]=1
Reactant: CC(=NO)c1ccc2c(c1)CCCC2
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the title compound of Step C (700 mg, 3.7 mmol) in dimethylformamide (10 mL) was added sodium hydride as a 60% oil dispersion (160 mg) followed by the title compound of Step B. The mixture was stirred at room temperature for 4 h and then was diluted with ethyl acetate. The solution was washed with water and then saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford an oil. Chromatography of this oil on silica gel with 20-30% ethyl acetate in hexanes afforded 1.0 g of the title compound of Step D, a compound of the invention, as an oil which solidified on standing. 1H NMR (CDCl3): δ 7.68 (m,7H), 5.2 (m,2H), 3.47 (s,3H), 2.75 (m,4H), 2.15 (s,3H), 1.78 (m,4H). This material was used in the preparation of Example 4 without further characterization.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.FC1C=CC=CC=1C(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Agent: CC(=O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2F)[nH]n1
Reaction time: 8 h
Yield: 31.67 %

Procedure:
DIPEA (160 mg, 1.3 mmol) was added to a stirred solution of 5-(2-Fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (77 mg, 0.37 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 2′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (52 mg, 0.39 mmol) and EDCI.HCl (74 mg, 0.39 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (125 mg, 0.37 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. Washing with ethyl acetate afforded 57 mg (31.67% Yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 491, 93.63%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (d, 1H), 8.7 (m, 1H), 7.8 (m, 1H), 7.2 (m, 6H), 6.9 (m, 2H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[N:4][CH:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:10][CH3:9])[CH:5]=[N:4][CH:3]=1
Reactant: C[S-]
Reactant: Nc1cncc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cncc(N)n1
Temperature: 100 °C

Procedure:
A MIXTURE OF 6-AMINO-2-CHLOROPYRAZINE (5.2 G, 40 MMOL) AND SODIUM THIOMETHOXIDE (3.3 G, 47 MMOL) IN DRY DMF (30 ML) WERE HEATED IN A SEALED TUBE AT 100°C. FOR 16 H. THE REACTION WAS COOLED AND PARTITIONED BETWEEN WATER AND METHYLENE CHLORIDE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:11]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (917 mg, 1.72 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting mixture stirred for 3 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a colourless oil (647 mg, 87%). LCMS (method H): RT 1.83 min [M+H]+ 433.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[C:5]([NH:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1.ClC1C=C2C(C(CC(O)=O)=[C:32]([C:36]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=3)=[O:37])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[NH:15][C:32]=1[C:36]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=1)=[O:37]
Reactant: COC(=O)/C=C/c1ccc(OC)cc1NS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(OC)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-methoxy-2-(p-toluenesulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[N:7]([CH2:21][CH2:20][CH2:19][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:5]1=[O:6]
Reactant: C=CCCCC(Br)CCC
Reactant: Cn1ccc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
This example illustrates a synthesis of 1-Methyl-3-(8,9-oxidononyl)uracil (inventive compound no. 1804). Sodium hydride (365 mg, 16 mmol) was added to a stirring solution of 1-methyluracil (2.00 g, 16 mmol) in dimethyl sulfoxide (40 mL). After 15 minutes, 6-bromo-1-nonene (3.26 g, 16 mmol) was added and the mixture stirred for 3 days. The reaction was then poured into water (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were washed with water (50 mL), and aqueous saturated salt solution (30 mL) was then dried over sodium sulfate. The solvent was evaporated under vacuum to yield 3.72 g (94%) 1-methyl-3-(8-nonenyl)uracil (inventive compound no. 1817) as a colorless oil which solidified upon standing.
Reaction SMILES: [ClH:1].O[C@H](COC1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5]C(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52](OC)=[CH:51][CH:50]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[ClH:1].[OH:31][CH:32]([CH2:47][O:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([C:4]#[N:5])[CH:54]=1)[CH2:33][NH:34][C:35]([CH3:46])([CH3:45])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M−15, 0.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclopentylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown solid (95%). MS (Turbo Spray): m/z=496.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[CH:66][CH:65]=1>>[CH2:74]([O:73][C:71](=[O:72])[CH2:70][C:67]1[CH:66]=[CH:65][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:69][CH:68]=1)[CH3:75]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 35.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (120 mg, 0.257 mmol), was reacted with diisopropylethylamine (207 mg, 1.60 mmol), diphenylphosphinic chloride (146 mg, 0.618 mmol), then reacted with ethyl 2-(4-aminophenyl)acetate (56 mg, 0.315 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (57 mg, 47%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)[NH2:3].C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:35])[C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=O)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=2)[N:2]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[N:3]=1)=[O:35])[CH3:20]
Reactant: COc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(C)c2)n(-c2ccc(OC)nc2)n1

Procedure:
5-Hydrazino-2-methoxypyridine hydrochloride (0.380 g) obtained from Referential Example 1 and triethylamine (0.30 mL) were added to a solution of the above-obtained 4-(3-methylphenyl)-2,4-dioxobutanoic acid ethyl ester (1.014 g) dissolved in ethanol (20 mL) at room temperature. The resultant mixture was refluxed under heat for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure, and the residue was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate: 20%), to thereby give the title compound as an oily substance (0.451 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][CH2:6][C:7]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:16]([SiH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:13]1[O:14][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15]
Reactant: CC[SiH](CC)CC
Reactant: COC(=O)C=CCC1(C=O)CCCCC1
Agent: Cl[Rh]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)OC1C(C(=O)OC)CCC12CCCCC2
Temperature: 55 °C
Reaction time: 27 h

Procedure:
To a solution of 4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester (3.7 g) obtained in Step 1 and tris(triphenylphosphine) rhodium(I) chloride (163 mg) in toluene (80 mL) was added dropwise triethylsilane (5.9 mL) under argon atmosphere over 10 minutes, followed by stirring the reaction mixture at 55° C. for 27 hours. After cooling down to room temperature and adding aqueous sodium bicarbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=20:1) to give 1-triethylsiloxy-spiro[4.5]decane-2-carboxylic acid methyl ester (5.0 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=O)C.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:29]1[CH:30]=[CH:31][O:27][CH:28]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: OB(O)c1ccoc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Product: O[C@@H]1[C@@H](O)[C@H](Oc2ccccc2-c2ccoc2)SC[C@H]1O
Yield: 57 %

Procedure:
By carrying out the operation analogously to example 29, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3-furanboronic acid, the expected compound is obtained in the form of white flakes with a yield of 57%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[C:23]([CH3:28])([CH3:27])[N:22]=3)[C:9]=2[CH2:29][CH3:30])=[CH:4][CH:3]=1.[CH3:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH3:31])[C:24](=[O:26])[C:23]([CH3:27])([CH3:28])[N:22]=3)[C:9]=2[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CI
Product: CCc1c(C2=NC(C)(C)C(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 28 was synthesized from compound 24 (101 mg, 0.22 mmol) and methyl iodide (2 g, 14.08 mmol) as a white solid (70 mg, 68%) in a manner similar to that described in Example 57. 1H NMR (400 MHz, CDCl3) δ 7.42 (br s, 1H), 7.29 (d, 2H), 7.24 (d, 1H), 7.19 (d, 1H), 7.07 (d, 2H), 3.21 (s, 3H), 2.62 (q, 2H), 1.85 (s, 6H), 1.11 (t, 3H); ESMS m/z: 475.1 (M+1).