Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10](C)(C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].CO.[CH3:17][Si:18]([O:28][CH3:29])([O:26][CH3:27])[O:19][Si:20]([CH3:25])(OC)[O:21][CH3:22]>C(O)(=O)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][SiH2:10][O:11][Si:20]([CH3:25])([O:21][CH3:22])[O:19][Si:18]([CH3:17])([O:28][CH3:29])[O:26][CH3:27])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CO[Si](C)(OC)O[Si](C)(OC)OC
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)OC
Solvent: CO
Solvent: CC(=O)O
Product: C=C(C)C(=O)OCCC[SiH2]O[Si](C)(OC)O[Si](C)(OC)OC
Reaction time: 1 h
Yield: 82 %

Procedure:
A flask was charged with 216 g of γ-methacryloxypropyldimethylmethoxysilane and 500 g of methanol. Under a nitrogen stream, the flask was cooled to 5° C., to which 18.0 g of 0.2N acetic acid was added dropwise over 15 minutes while the liquid temperature was maintained below 10° C. After the completion of dropwise addition, stirring continued for one hour at room temperature. Then, 2260 g of 1,3-dimethyl-1,1,3,3-tetramethoxydisiloxane was added. Stirring continued for 2 hours at room temperature and for a further 8 hours at 60° C. The methanol and volatile matter were removed from the reaction solution by heating in vacuum, obtaining 1-(γ-methacryloxypropyl)-3,5-dimethyl-3,5,5-trimethoxytrisiloxane (M-2) in a yield of 82%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(OC1C(C)=CC2C(=CC=CC=2)C=1C1C=CC([Cl:51])=CC=1Cl)(=O)=O>>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:51])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1C(OC(C)(C)C)C(=O)O

Procedure:
tert-butoxy-[1-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (33) was prepared in a similar manner as compound 3K in Example 1, except starting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonate instead of 3E. 1H-NMR: 400 MHz, (CD3CN) δ: 7.84 (d, 1H), 7.78 (s, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.47-7.54 (m, 2H), 7.37 (app dt, 1H), 7.16 (d, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.06 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Br:10]C1C(CBr)=NC=C(Br)C=1>>[Br:1][C:2]1[C:3]([CH2:9][Br:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: BrCc1ncc(Br)cc1Br
Reactant: Cc1nc(Cl)ccc1Br
Product: Clc1ccc(Br)c(CBr)n1
Yield: 45 %

Procedure:
Compound 55B (0.33 g, 45%) was prepared from 55A (0.53 g, 2.57 mmol) using a procedure similar to the synthesis of 52B. HPLC Rt=2.47 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27]1([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41]Br)=[C:37]([CH3:43])[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:36][C:37]=2[CH3:43])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Cc1cc(OCc2ccccc2)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(1.31 g, 5.87 mmol) in anhydrous THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (6 ml, 6 mmol) at ambient temperature under nitrogen. The yellow solution was stirred for 20 min. To the solution was added a solution of 4-(bromomethyl)-3-methylphenyl phenylmethyl ether (1.72 g, 5.91 mmol) in THF (13 ml). The mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (120 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the aqueous phase washed with ethyl acetate (30 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (3.10 g). The residue was loaded in DCM and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow gum (1.9 g); LCMS: (System 4) MH+=434, tRET=3.14 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]2[C:6]3[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=3[CH:8]=[CH:9]2)[S:21][CH:22]=1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2ccc(F)cc2F)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(F)cc3F)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]acetamide (111 mg, 0.330 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 60 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.21-7.27 (m, 1H), 7.36-7.42 (m, 2H), 7.52 (s, 1H), 8.03-8.10 (m, 1H), 12.70 (br s, 1H); APCI-MS (m/z) 432.20 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=O.[F:26][C:27]1[C:32]2[CH:33]=[CH:34][O:35][C:31]=2[C:30](B(O)O)=[CH:29][C:28]=1[F:39].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)CC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:30]2[C:31]3[O:35][CH:34]=[CH:33][C:32]=3[C:27]([F:26])=[C:28]([F:39])[CH:29]=2)[C:10]([CH3:22])([CH3:23])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cc(F)c(F)c2ccoc12
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(F)c3ccoc23)C(C)(C)C1
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
A solution of 0.483 gm (1.34 mMol) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine in 5 mL previously deoxygenated 9:1 toluene:n-propanol was placed under vacuum and pressurized with nitrogen three times to exclude oxygen. To this solution were added 0.008 gm (0.036 mMol) palladium acetate and 0.024 gm (0.092 mMol) triphenylphosphine and the resulting mixture was stirred for 15 minutes. Then 0.28 gm (1.41 mMol) 4,5-difluorobenzofur-7-ylboronic acid, 0.085 gm (2.0 mMol) lithium chloride, and 0.74 mL (1.48 mMol) of previously deoxygenated 2.0 M aqueous sodium carbonate were added to the reaction mixture. The mixture was deoxygenated by subjecting it three times to a vacuum/nitrogen cycle, was heated to reflux for 4 hours, and was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between water and diethyl ether. The aqueous phase was extracted well with diethyl ether and all of the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.374 gm (76.6%) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine as a crystalline white solid. A solution of 0.246 gm (0.68 mMol) 1-(tert-butoxycarbonyl)-3,3-dimethyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine in 3 mL 2 M hydrogen chloride in ethyl acetate was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to provide 0.202 gm of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[CH:29][CH:28]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(c1ccc(O)cc1)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1.23 ml (7.24 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.0 g (4.83 mmol) of 4-(4-morpholinyl-carbonyl)phenol and 2.02 ml (14.48 mmol) of triethylamine in 20 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 1.71 g (94.6% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16][O-:17].[Na+].[OH-].[Na+].O>CO>[CH3:16][O:17][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc(C(=O)O)cn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5-Chloropyrazine-2-carboxylic acid (5.0 g, 0.032 mol) was charged to a round-bottom flask equipped with a thermocouple, overhead stirrer and reflux condenser. Methanol (37.5 mL, 0.926 mol) was charged followed by conc. sulfuric acid (0.2 mL, 0.004 mol). The 3-neck flask was equipped with a heating mantle, and then the reaction mixture was heated to ca. 65.0° C. (T internal). The reaction mixture continued to stir at ca. 65.0° C. (T internal) for ca. 4 h. The reaction mixture cooled to ca. 25.8° C. (T internal). Methanol (12 mL, 0.31 mol) was charged and the slurry continued to stir at ca. 22.3° C. (T internal) for ca. 15 min then cooled to ca. 10.0° C. (T internal) under an atmosphere of nitrogen. 25% Sodium methoxide in methanol (1:3, Sodium methoxide:Methanol, 7.7 mL) was charged to flask while temperature remained below 30.0° C. (T internal). The reaction mixture was adjusted to 20.4° C. (T internal). After 30 min., sodium hydroxide (2.0 g, 0.04 mol) and water (37.5 mL, 2.08 mol) were combined to form a solution, and then the solution was charged to the reaction mixture. Water (50.0 mL, 2.78 mol) was charged and then the reaction mixture was heated to 40.0° C. (T internal) for ca. 60 mins. The heating mantle was removed, and then the reaction mixture cooled to ca. 25.4° C. (T internal). 38% aq. HCl Solution (38:62, hydrogen chloride:water, 4.0 mL) was added at a rate (ca. 5 min.) such that the temperature remained below 30.0° C. (T internal). The thick slurry was stirred for 1 h at ca. 21.4° C. (T internal), and then filtered over a sintered funnel. The solids were rinsed with water (10.0 mL, 0.555 mol) and dried under vacuum overnight to afford 5-methoxypyrazine-2-carboxylic acid (3.59 g). 1H NMR (500 MHz, DMSO) δ 13.24 (1H, br s), 8.79 (1H, d, J=1.2 Hz), 8.37 (1H, d, J=1.2 Hz), 3.98 (s, 3H); 13C NMR (125 MHz, DMSO) δ 165.36, 161.88, 143.88, 136.82, 135.55, 54.69.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][CH:6]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[F:22])[C:9]1=[O:23])[CH3:7]>C(Cl)Cl>[CH3:7][CH:6]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[F:22])[C:9]1=[O:23])[CH3:5]
Reactant: COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
A 1M methylene chloride solution of boron tribromide (41.6 ml, 0.0416 mole) was cooled to -20° C. While this temperature was maintained, a solution of 5.55 g (0.0208 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-methoxyphenyl)imidazolidin-2,4-dione in 25 mL of methylene chloride was added to the reaction during an eight minute period. The reaction mixture was allowed to warm to room temperature, where it was stirred for approximately 17 hours. At the end of this time the reaction was poured over ice, and the resulting two-phase mixture was filtered. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving a black solid as a residue. This solid was recrystallized from ethyl acetate/petroleum ether, to yield 3.25 g of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxyphenyl)imidazolidin-2,4-dione as a tan solid, m.p. 190°-192° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][OH:26])[CH2:30][CH2:31]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1
Solvent: C1COCCO1
Product: OCCN1CCN(c2nc(N3CCOCC3)c3ncnc(NCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 139°-141° C.) and N-hydroxyethyl-piperazine in dioxane at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To a solution of 3,5-Dimethoxy-benzaldehyde (9.5 g, 57.17 mmol) in pyridine (60 ml), malonic acid (9 g, 85.725 mmol) was added, and followed by piperidine (2 ml), the mixture was heated to 100° C. and stirred at this temperature for 6 hs under N2. Then most of pridine was removed, and the residue was poured into water (250 ml), acidified to PH=3 by aq.HCl, the precipitate was collected and dried to give product (10.9 g, 91.8%). LC-MS: m/e 207 (M−1)
Reaction SMILES: [CH:1]1[C@H:6]([NH2:7])[C@H:5]([OH:8])[C@@H:4]([OH:9])[C@H:3]([OH:10])[C:2]=1[CH2:11][OH:12].[CH2:13]1[O:19][C@@H:18]2[O:20][C@H:14]1[C@@H:15]([OH:23])[C@H:16]([OH:22])[C@H:17]2[OH:21]>Cl>[CH:1]1[C@H:6]([NH2:7])[C@H:5]([OH:8])[C@@H:4]([OH:9])[C@H:3]([OH:10])[C:2]=1[CH2:11][OH:12].[O:19]=[CH:13][C@@H:14]([C@H:15]([C@@H:16]([C@@H:17]([CH2:18][OH:8])[OH:21])[OH:22])[OH:23])[OH:20]
Reactant: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Agent: Cl
Agent: N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
1,6-anhydro-2-deoxy-2-[1D-(1N,2,4/3)-5-C-hydroxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 5) (152.5 mg, 0.47 mmol) was heated at 100° C. in 2N HCl solution for 4 days. Solvent was removed by co-evaporation with water and the residue was purified by chromatography on an latrobeads column (Iatron Laboratories, Japan) using chloroform:methanol:water, (65:38:3) as eluent to provide 2-deoxy-2-[ID-(1N,2,4/3)-(5-C-hydroxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-D-glucopyranose hydrochloride (compound 6) after lyophilization (116 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH2:26][C:27]([C:30](O)=[O:31])=[N:28][N:29]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[C:13]([C:12]1[C:11]([F:18])=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[NH:29][N:28]=3)=[O:31])[N:5]=2)=[CH:16][C:15]=1[F:17])#[N:14]
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Reactant: N#Cc1c(F)cc(-c2ccn(CCN)n2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(F)cc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1F
Yield: 18.5 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.3 g, 0.773 mmol), 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.161 g, 0.851 mmol), DIPEA (0.202 ml, 1.160 mmol), HOBt (0.157 g, 1.160 mmol) and EDCI (0.222 g, 1.160 mmol) using the method of Example 34(d) affording 0.06 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.70 (t, 2H), 4.39 (t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2)[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[NH:7][C:6](=[O:22])[O:12][C:5](=[O:13])[C:4]=12)[CH3:2]
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.114 mol) of 4-ethylisatin are suspended in 75 ml of 100 percent acetic acid, treated portionwise with 26 g (0.137 mol) of m-chloroperbenzoic acid, the temperature not rising above 50°, and then the mixture is stirred at this temperature for a further 15 minutes. The mixture is poured into ice-water and filtered. The crude product obtained is taken up in ethyl acetate and extracted cautiously with a mixture of 2 N sodium hydroxide and ice. The ethyl acetate phase is dried over magnesium sulphate and concentrated to give crude 6-ethylisatoic acid anhydride which melts at 202°-204° after recrystallization from ethyl acetate.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=[N:2][OH:3])[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of hydroxylamine hydrochloride (19 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (65 mg, 80%) was a white foam: EI-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202. found 451.1206.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:35])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:14]=2[CH:34]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:35][S:44]([C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)(=[O:46])=[O:45])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:14]=2[CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccc(OC)cc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccc(OC)cc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-(4-methoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[CH2:18]([O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH3:19].O1C2C=CC(O)=CC=2OC1.[CH:45]1[C:54]2[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=2[CH:48]=[CH:47][C:46]=1[OH:55]>>[CH2:18]([O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([OH:32])([C:47]2[C:46]([OH:55])=[CH:45][C:54]3[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=3[CH:48]=2)[C:24]1=[O:33])[CH3:19]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5,6,7,8-tetrahydronapthalen-2-ol, the title compound was obtained (81%): 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.54 (dd, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 4.45 (ABq, 2H), 4.21 (q, 2H), 4.18-4.14 (br, 1H), 2.73-2.47 (m, 4H), 1.77-1.63 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 364 (M−17), 404 (M+23)
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][NH:9][C:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.CO.[Ni](Br)Br>[C:15]([O:14][C:12]([N:11]=[C:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:28][CH:27]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N=C(NCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Br[Ni]Br
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To N-(4-nitrobenzyl)-N′,N″-bis(tert-butoxycarbonyl)guanidine (1.97 g, 4.99 mmol) dissolved in a mixed solvent of THF (25 ml) and methanol (25 ml) were added at 0° C. nickel bromide (109 mg, 0.50 mmol) and sodium borohydride (757 mg, 20.0 mmol) in the order, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with 1 N hydrochloric acid (40 ml) at 0° C., and the resulting mixture was stirred at the same temperature for 5 minutes. The resulting mixture was adjusted to about pH 8 by adding an aqueous saturated solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and was then concentrated under reduced pressure, diisopropyl ether was added to the residue, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain 4-[N′,N″-bis(tert-butoxycarbonyl)guanidinomethyl]aniline (1.21 g, 3.32 mmol, 66%).