Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O[C:13]1[C:14]([Cl:21])=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].C(O)(=[O:24])C>O>[Cl:21][C:14]1[CH:13]=[C:19]([Cl:20])[C:18]([OH:24])=[CH:17][C:15]=1[N:16]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)c(O)c1Cl
Reactant: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 33.4 g. of 3,4,5,6-tetrahydrophthalic anhydride, 35.6 g. of 3-hydroxy-2,4-dichloroaniline and 130 ml. of glacial acetic acid was refluxed with stirring for 2 hours and the mixture was cooled to a room temperature and water was added to the mixture to precipitate a crystal. The crystal was separated by a filtration and recrystallized from benzene-n-hexane to obtain N-(2,4-dichloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 155°-157° C.: white crystal) (yield: 75%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19].[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>ClCCl>[ClH:15].[Cl:15][C:16]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:32][C:17]=1[C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19]
Reactant: O=CCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ccc1Cl

Procedure:
Sodium triacetoxyborohydride (4.10 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.46 g, Example 14b) and 3-aminopropanol (1.73 ml) in dichloromethane (200 ml). After 24 h the crude reaction mixture was purified by flash chromatography (eluting with 5-20% methanol/dichloromethane+1% ammonia) and the hydrochloride salt precipitated from ether/methanol 19:1, to afford the title compound as a white solid (1.60 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Brc1cccnc1
Reactant: COC(=O)c1nccnc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1nccnc1Nc1cccnc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Aminopyrazine-2-carboxylic acid methyl ester (0.8 g, 5.2 mmol) and 3-bromopyridine (1.2 g, 7.8 mmol) were dissolved in 20 mL dry toluene. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.6 g, 1.04 mmol), sodium tert.-butylate (0.75 g, 7.8 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (0.54 g, 0.52 mmol) were added and the reaction mixture was stirred under microwave irradiation for 60 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:2->0:100 gradient). The desired product was obtained as a brown solid (260 mg, 22%), MS: m/e=231.1 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:25])/[CH:17]=[CH:18]/[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:11]1)=[O:9])C.Cl.C(OCC)(=[O:37])C>>[F:29][C:28]([F:31])([F:30])[C:27]([OH:32])=[O:37].[NH:22]1[CH2:23][CH2:24][CH:19](/[CH:18]=[CH:17]/[C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][CH2:6][C@H:5]([NH:26][C:27](=[O:32])[C:28]([F:29])([F:30])[F:31])[C:4]([OH:33])=[O:3])=[O:9])[CH2:11]2)=[O:25])[CH2:20][CH2:21]1
Reactant: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1)NC(=O)C(F)(F)F
Reactant: CCOC(C)=O
Agent: Cl
Product: O=C(NC[C@H](NC(=O)C(F)(F)F)C(=O)O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a stirred solution of N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine ethyl ester (334 mg, 0.58 mmol) in ethyl acetate (1.5 ml) was added a solution of 4N-hydrogen chloride in ethyl acetate (1.0 ml, 4 mmol). After the solution was stirred for 2 hours at ambient temperature, the solvent was evaporated in vacuo. The residue was dissolved in 0.1M phosphate buffer (pH=7.3, 200 ml). To the solution was added Porcine liver esterase (0.5 ml), and the solution was stirred for 7 days at ambient temperature. Solvent was evaporated, and the residue was purified by HPLC to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2(S)-trifluoroacetylamino-β-alanine trifluoroacetate as a colorless oil (220 mg, 67.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)Cl.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:12][C@H:10]1[CH2:11][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a round-bottomed flask charged with tert-butyl(cis-3-hydroxycyclobutyl)carbamate (1.11 g, 5.93 mmol) and triethylamine (2.474 ml, 17.79 mmol) was added CH2Cl2 (12 ml). methanesulfonyl chloride (0.505 ml, 6.52 mmol) was added dropwise via syringe at −20° C. over 5 min. The reaction mixture was stirred at room temperature for 30 min, then diluted with water (15 mL) and extracted with CH2Cl2(2×). The organic extract was washed with saturated NH4Cl and dried over MgSO4. It was filtered and concentrated in vacuo to give cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (1.64 g, 6.1 mmol, 100% yield) as a off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.N1CCCC1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26]
Reactant: COc1ccc(C=O)cc1Br
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A mixture of 3-bromo-p-anisaldehyde (1 g, 4.65 mmol), pyrrolidine (1.9 ml, 23.2 mmol) and oxindole (0.62 g, 4.65 mmol) in dimethylformamide (7 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was cooled to room temperature and poured into 1N hydrochloric acid (100 ml). The precipitate which formed was filtered and washed with water. The precipitate was then dissolved in ethyl acetate (200 ml), the solution washed with brine, dried over magnesium sulfate and then concentrated. The solid obtained was chromatographed (silica, 30-40% ethyl acetate/hexanes) to give 0.63 g (42%) of 3-(3-bromo-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [C-:1]#[N:2].[K+].BrC[C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[CH3:17]S(C)=O>O>[CH3:16][C:15]1[CH:6]=[C:7]([CH2:17][C:1]#[N:2])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cc2ccccc2cc1CBr
Reactant: CS(C)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: Cc1cc(CC#N)c2ccccc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
KCN (1.81 g, 27.85 mmol) was added to a solution of 2-bromomethyl-3-methylnaphthalene (5.95 g, 25.32 mmol) in 150 mL of DMSO at room temperature. The resulting mixture was stirred 1 hour, diluted with water (175 mL) and stirred another 15 minutes. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the desired product (3.71 g g, 81%) of sufficient purity for use in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH2:42]O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(Cl)Cl>[Cl:30][C:27]1[S:26][C:25]([S:22]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:44])[CH:37]=3)[N:12]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Reactant: CN(C)CCOc1cccc(CO)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(OCCN(C)C)c1
Temperature: 65 °C
Yield: 70 %

Procedure:
A mixture of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (150 mg, 0.28 mmol), (3-{[2-(dimethylamino)ethyl]oxy}phenyl)methanol (73 mg, 0.37 mmol), triphenylphosphine (113 mg, 0.43 mmol) and di-tert-butyl azodicarboxylate (132 mg, 0.57 mmol) in THF (15 mL) was heated to 65° C. O/N. The mixture was evaporated under reduced pressure, the residue was dissolved in MeOH, and then loaded on a SCX-2 ion-exchange cartridge (20 g) and eluted with sequential solvents methanol, 2M ammonia in methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product. This was dissolved in DCM and purified by chromatography on silica (20 g cartridge) on Flashmaster using a 0-15% methanol (containing 1% Et3N)-dichloromethane over 20 min. The appropriate fraction was evaporated in vacuo to give the title product (140 mg, 70%) as a white foam. LCMS (System F) RT=1.27 min, ES+ve m/z 701/703 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9](=[C:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[C:10]#[N:11])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:20][C:21]1C=CC=C[C:22]=1[C:23](Cl)=O.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:20][C:21]1[CH:32]=[CH:31][C:30]([C:34]([N:13]2[CH2:14][CH2:15][CH2:16][C:12]2=[C:9]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:17])[C:10]#[N:11])=[O:33])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: C1CCOC1
Reactant: N#CC(C(=O)c1ccc(Cl)cc1)=C1CCCN1
Agent: [H-]
Agent: [Na+]
Product: N#CC(C(=O)c1ccc(Cl)cc1)=C1CCCN1C(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
At 0° C., 1 g of the 3-(4-chlorophenyl)-3-oxo-2-pyrrolidin-2-ylidene-propionitrile prepared according to Example 1 is dissolved in 10 ml of THF and admixed with 0.3 g of NaH (60% pure), and the mixture is heated to 20° C. for two hours. 0.8 g of chlorobenzoyl chloride in 10 ml of THF is then added, and the mixture is stirred at room temperature for another 24 hours. The reaction mixture is then poured into ice-water and extracted with ethyl acetate, the extract is dried over magnesium sulphate and the solvent is evaporated under reduced pressure. The residue was chromatographed over silica gel using n-hexane/acetone 7:3. After evaporation of the solvent, one of the main fractions gave 0.2 g (yield 14% of theory) of 2-[1-(4-chlorobenzoyl)pyrrolidin-2-ylidene]-3-(4-chlorophenyl)-3-oxo-propionitrile of melting point 218° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O1CCCC1>[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(S)cc2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Sc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
0.90 g (2.6 mmol) of 1-(4-mercaptophenyl)-4-methyl-2-(4-sulfamoylphenyl)-pyrrole (prepared as described in Example 129) was dissolved in 15 ml of tetrahydrofuran, and 0.27 ml (2.9 mmol) of acetic anhydride was added to the resulting solution. 0.53 ml (6.5 mmol) of pyridine was then added to the mixture, which was then stirred at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue. The resulting mixture was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.44 g (yield 43%) of the title compound as a white powder, melting at 149-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.N12CCCN=C1CCCCC2>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1
Reactant: O=C1CCc2c(cc(Br)nc2-c2ccc(F)cc2Cl)N1c1c(Cl)cccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-1,6-naphthyridin-2(1H)-one (2.33 g, 4.65 mmol) in 75 mL of CCl4 was added recrystallized N-bromosuccinimide (993 mg, 5.58 mmol) and 2,2′azobis(2-methylpropionitrile) (76.4 mg, 0.465 mmol). The resulting reaction mixture was evacuated and flushed with argon 3 times, then heated and maintained at reflux for 2.5 h. 1,8-diazabicyclo[5.4.0]undec-7-ene (695 μL, 4.65 mmol) was added and the reaction mixture was cooled to rt, washed with 140 mL of half-saturated aqueous NaHCO3, and the aqueous layer was back-extracted with 2×70 mL of ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash chromatography on Biotage 40M column, eluting with a gradient system of 90:10 hexanes-ethyl acetate to 80:20 hexanes-ethyl acetate to yield 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one as an off white solid. Mass spectrum (ESI) 497 (M+1). 1H NMR (500 MHz, CDCl3): δ 6.64 (s, 1H); 6.79 (d, J=10.1 Hz, 1H); 7.21 (m, 1H), 7.31 (m, 1H); 7.54 (m, 3H); 7.65 (m, 2H),
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=1[F:21])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CCCCNCc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
2-butylaminomethylbenzimidazole (2.6 g, 13 mmol) was dissolved in 30 mL toluene. Saturated NaHCO3 solution (30 mL) was added followed by 2,3-difluorobenzoyl chloride (1.3 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL ethyl acetate then washed 1×100 mL 1N NaOH followed by 1×100 mL H2O. The organic phase was dried over MgSO4, filtered, and then concentrated. The residue was purified by flash chromatography eluting with 1/1 ethyl acetate/hexane followed by ethyl acetate to afford 2.0 g N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:7][C:2]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Oc1ccc(C#N)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C#N)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-methyl-2-(5-cyano-2-pyridyloxy)propionate (12 mg) in tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (10 mg). After stirring at room temperature overnight, the reaction mixture was acidified with 1 N hydrochloric acid, and the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.23 (d, 1H), 7.96 (dd, 1H), 6.91 (d, 1H), 1.64 (s, 6H).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41]Br>O>[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41][O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH3:6]
Reactant: CCC(O)CC
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.90 ml of 3-pentanol was added 0.38 g of sodium hydride (55% dispersed material in mineral oil) under cooling in ice-bath, and the mixture was stirred at room temperature for 3 hours. Then, 0.99 g (1.75 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture, and the mixture was stirred at 45° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a slightly yellowish oil. (Yield: 65%)
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]([OH:30])[C:28]#[N:29])=[O:24])[C:12](=[O:38])[CH:11]1[CH:39]([CH3:41])[CH3:40])(=[O:9])[CH3:8].[C:42](OC(=O)C)(=[O:44])[CH3:43].CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OCC)(=O)C>[C:42]([O:30][CH:27]([C@@H:26]([NH:25][C:23]([CH2:22][N:13]1[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:10]([C:7](=[O:9])[CH3:8])[CH:11]([CH:39]([CH3:41])[CH3:40])[C:12]1=[O:38])=[O:24])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28]#[N:29])(=[O:44])[CH3:43]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C#N)C(=O)C1C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C#N)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reaction time: 6 h

Procedure:
Pyridine (0.15 ml) is added to a solution of (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile (291 mg, Compound No. 8-1) in methylene chloride (3 ml). The mixture is cooled with ice, acetic anhydride (115 μl) and dimethylaminopyridine (catalytic amount) are added to the mixture, and the whole is stirred for six hours. Ethyl acetate is added to the reaction mixture and the whole is washed with 1 N hydrochloric acid and saturated brine successively. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (317 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: CN(C)c1cnc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1cnc(N)cn1
Yield: 74.8 %

Procedure:
A solution of dimethyl-(6-nitro-pyrazin-3-yl)-amine (1.27 g, 7.55 mmol) in ethanol (90 mL) was treated with 10% palladium on activated carbon (0.40 g). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure overnight. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethanol. The filtrate was concentrated in vacuo, and the resulting black-orange solid was triturated with petroleum ether to afford N5,N5-dimethyl-pyrazine-2,5-diamine (0.78 g, 75%) as a black solid: mp 71.5–74.2° C.; EI-HRMS m/e calcd for C6H10N4 (M+) 138.0905, found 138.0903.