Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].O.[NH2:12][NH2:13]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[N:12][NH2:13])[NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C#N)ccc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(C(N)=NN)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A 500-mL, three-neck, round-bottom flask was equipped with 5-bromo-6-methylpicolinonitrile (101.5 g, 0.515 mol), ethanol (122 mL) and hydrazine hydrate (50 mL, 1.03 mol). The resulting very thick mixture was allowed to stir at ambient temperature for 24 h. More ethanol (50 mL) was added and the mixture was allowed to stir over the weekend. The mixture was filtered and washed with cold ethanol (100 mL) and cold hexanes (50 mL). The solids were dried in a vacuum oven to afford the product (110 g, 93% yield) as an off-white solid.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:20][C:19]=3[C:29]([F:32])([F:31])[F:30])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:20][C:19]=3[C:29]([F:30])([F:32])[F:31])(=[O:16])=[O:17])[CH2:12][N:11]2[C:33](=[O:35])[CH3:34])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4ccnc4)cc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccc(-n3ccnc3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(4-imidazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment D10 was acylated with acetic anhydride in analogy to experiment L29 to give (2S,4R)-1-acetyl-4-(4-imidazol-1-yl-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22](Br)[CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:7]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:9]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:7]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(-c3ccccc3)cc12
Yield: 32.6 %

Procedure:
To (3,5-Bis-difluoromethoxy-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-1519, 29.0 mg, 0.067 mmol) in acetonitrile (4.0 mL) were added phenylboronic acid (12.2 mg, 0.10 mmol), Tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 8.65E-6 mol) and 1.0 M potassium carbonate in water (1.5 mL). The reaction was microwaved (300 watts) at 160° C. for 7 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated, and purified with silica gel column chromatography to give the compound as a white solid (P-1521, 9.4 mg, 33%). MS (ESI) [M+H+]+=431.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br
Reaction time: 5 h

Procedure:
A stirred solution of 25.5 g (0.1 mole) of 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (prepared as disclosed by Krapcho et al, J. Med. Chem., 6, 544, (1963)) in 250 ml of dimethylformamide is treated with a solution of 35 g (0.2 mole) of N-bromosuccinimide in 100 ml of dimethylformamide. The mixture is stirred at 105°-110° for 5 hours, cooled, and poured into 1.8 liters of cold H2O to precipitate a solid. After cooling overnight, the latter is filtered, washed with H2O, and air-dried; wt. 29.6 g (89%); m.p. 190°-192°; s. 180°. Following crystallization from a mixture of 30 ml of hot dimethylformamide and 60 ml of MeCN, the colorless solid weighs 17.8 g (53%); m.p. 240°-242° (dec.).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][C:17]1[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:5]3[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:15][CH:14]=2)[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 3-{4-[(4-hydroxycycloheptyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.10 g) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.11 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.051 g, 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH:12]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2cccnc2)ccn1
Temperature: 150 °C
Yield: 93 %

Procedure:
4-Chloro-2-pyridine carbonitrile (1.0 g, 7.2 mmol, 1.0 eq), 3-hydroxypyridine (686 mg, 7.21 mmol, 1.00 eq) and K2CO3 (1.2 g, 8.7 mmol, 1.2 eq) were dissolved in DMF (10 mL) and heated in a microwave for 15 minutes at 150° C. The reaction was cooled, diluted with EtOAc and washed with H2O (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.32 g (93%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=5.8 Hz, 1H), 8.56 (m, 2H), 7.79 (d, J=2.4 Hz, 1H), 7.75 (dt, J=8.4, 1.4 Hz, 1H), 7.55 (dd, J=8.3, 4.7 Hz, 1H), 7.27 (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]+: 198.0.
Reaction SMILES: [C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40][C:41]#[N:42])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40][C:41]#[N:42])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(CC#N)C2c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC#N)C2c1ccc2c(c1)OCO2
Yield: 87.7 %

Procedure:
1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-propoxyindane (240 mg, 0.42 mmol) was stirred in methylene chloride (3 ml) with TFA (0.8 ml) under argon at room temperature for 1 h then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the product as an oil (190 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][CH:10]([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([NH:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][CH:10]([F:12])[F:11])=[CH:8][C:2]=1[F:1])=[O:20])=[O:17]
Reactant: Nc1ccc(SC(F)F)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(SC(F)F)cc1F
Reaction time: 0.5 h
Yield: 77 %

Procedure:
In 15 ml of toluene was dissolved 1.0 g of 2-fluoro-4-difluoromethylthioaniline, and 1.0 g of 2,6-difluorobenzoyl isocyanate was added dropwise to the solution at room temperature (20° to 25° C.). After the reaction was allowed to proceed at the same temperature for 30 minutes, the crystals, which separated out, were recovered by filtration and washed with toluene to give 1.5 g of N-(2,6-difluorobenzoyl)-N'-(2-fluoro-4-difluoromethylthiophenyl)urea (Compound No. 55). Recrystallization from acetone gave crystals having a melting point of 172°-173° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>CC(O)=O>[Br:17][C:9]1[C:10](=[O:14])[NH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]ccc(OCc2ccc(F)cc2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
To an ice-cold solution of 4-(4-fluorobenzyloxy)pyridine-2(1H)-one (3.1 g, 14 mmol) in AcOH (26 mL) was added a solution of bromine (0.79 mL, 15 mmol) in AcOH (51 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and purification by flash column chromatography (silica, 1:1 Et2O/hexanes) to afford 3-bromo-4-(4-fluorobenzyloxy)-1H-pyridin-2-one as an orange solid (0.78 g, 48%): MS APCI m/z 298 [M+H]+.
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(C[CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)CC1>>[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 21 analogously to the method described in example 1.
Reaction SMILES: C1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=1.[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[S:11][CH:12]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Brc1csc(C2OCCO2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A benzene (55 mL) solution of 4-bromo-2-thiophene carboxaldehyde (9.76 g 51.09 mmol), ethylene glycol (8.55 mL, 153.26 mmol) and p-toluenesulfonic acid monohydrate (0.972 g, 5.11 mmol) was refluxed with azeotropic removal of H2O for 6 h and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and the organics washed with sat'd NaHCO3, brine and then dried (MgSO4), filtered and concentrated. Chromatography on silica gel using 95:5 Hexanes:EtOAc eluted the product to provide the title compound upon concentration as a yellow oil (10.76 g 90% yield): 1H NMR (CDCl3, 400 MHz) δ 7.22 (s, 1H), 7.08 (s, 1H), 6.07 (s, 1H), 4.14–4.00 (m, 4H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.[Cl-].[Na+].O>[Cl:7][C:8]1[N:9]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[C:10]2[C:15]([C:16]=1[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 60 °C
Yield: 3.7 %

Procedure:
Cs2CO3 (996 mg, 3.06 mmol) was added to a solution of 2-chloro-1H-indole-3-carbaldehyde (0.5 g, 2.78 mmol) and benzene sulfonyl chloride (0.39 mL, 3.06 mmol) in DMF (5 mL) and the mixture heated to 60° C. After 3 h the mixture was diluted with brine and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford 2-chloro-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (33 mg, 5%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.[C:13]1([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]([NH:4][CH2:3][CH2:2][O:1][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: O=C(NCCO)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCc1ccccc1)OCCNC(=O)c1cccnc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N-(2-Hydroxy-ethyl)-nicotinamide (3.3 g, 20.0 mmol, 1.0 eq.) was dissolved in DCM (100 mL) and pyridine (20 mL). The light yellow solution was cooled to 2° C. A solution of 4-phenylbutanoylchloride (3.65 g of 20 mmol, 1.0 eq.) in DCM (25 mL) was slowly added. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (75 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL) and of brine (50 mL). The organic layer was dried over Na2SO4, filtrated and evaporated under reduced pressure. The yellow, oily residue was dried at high vacuum at room temperature to give 6.2 g (100%) of the product as yellow oil. The crude product was purified by flash chromatography over silica gel with ethyl acetate to yield the pure 4-phenyl-butyric acid 2-[(pyridine-3-carbonyl)amino]-ethyl ester 5.6 g (89%) as a light yellow oil. 1H NMR (CDCl3) δ=1.87-1.95 (m, 2H), 2.29-2.34 (m, 2H), 2.58-2.63 (m, 2H), 3.67-3.72 (m, 2H), 4.25-4.29 (m, 2H), 7.11-7.41 (m, 7H), 8.08-8.12 (m, 1H), 8.65-8.67 (q, 1H), 8.99-9.00 (d, 1H). 13C NMR (CDCl3) δ=26.3, 33.4, 35.0, 39.6, 62.9, 123.5, 126.0, 128.4, 128.4, 130.0, 135.2, 141.1, 148.1, 152.1, 165.8, 173.9. MS (ESI) m/z=313.2 (100) [M+H+]. DC (silica gel/ethyl acetate): RF=0.32.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](#[N:14])/[CH:10]=[CH:11]/[C:12]#[N:13]>>[C:1]1([NH:7][NH:8][CH:11]([CH2:10][C:9]#[N:14])[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: N#C/C=C/C#N
Product: N#CCC(C#N)NNc1ccccc1
Temperature: 77.5 °C
Yield: 44.5 %

Procedure:
A mixture of phenylhydrazine (4.29 g) and fumaronitrile (3.1 g), where the phenylhydrazine served as a solvent, was heated at 75-80° C. for 20 hours. Purification by flash chromatography on silica gel and crystallization from dichloromethane/hexane gave the title compound (3.29 g, 45%), m.p. 97-98° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[CH3:12])[CH2:3]1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[CH2:3]2
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (52 mg, 0.20 mmol) and triethylamine (1 mL, 7.7 mmol) in methylene chloride (10 mL) was added a solution of 4-chlorobenzoyl chloride (50 mg, 0.29 mmol) in methylene chloride (10 mL) and the reaction was stirred at 0° C. for 30 min. The stirring was continued for another 2 h at ambient temperature and then the solvent was evaporated in vacuo. The remains were purified on a silica gel column using ethyl acetate containing triethylamine (7.5%) as the eluent to give 50 mg (63% yield) of the title compound as white crystals: mp 210-212° C.; EIMS (70 eV) m/z (relative intensity) 397 (28, M+).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH:38]5[S:42][C:41](=[O:43])[NH:40][C:39]5=[O:44])=[CH:33][CH:32]=4)[CH:28]=[CH:29][CH:30]=3)[CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.S(=O)(=O)(O)O>CO>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH:38]5[S:42][C:41](=[O:43])[NH:40][C:39]5=[O:44])=[CH:33][CH:32]=4)[CH:28]=[CH:29][CH:30]=3)[CH3:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(-c2ccc(C(=O)N(C)Cc3cccc(-c4ccc(CC5SC(=O)NC5=O)cc4)c3)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
1.6 g of 4′-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide, 100 ml of methanol and 1 ml of 98% sulphuric acid are introduced, in order, into a 250 ml three-necked flask. The mixture is stirred at room temperature for 18 hours. The reaction medium is concentrated. It is taken up in ethyl acetate and it is washed twice with water. The organic phase is dried over magnesium sulphate. After filtration and evaporation, the product obtained is recrystallized from an acetone/dichloromethane mixture. After filtration and drying, 1.34 g (99%) of 4′-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbiphenyl-4-carboxamide are obtained in the form of a white powder having a melting point of 211-213° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22]Br)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCC(CBr)OC(=O)c1ccccc1)c1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCC(Cn1ccc2ncnc(Cl)c21)OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), 3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N-dimethylformamide (6.5 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (401 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc(NC2CCCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(C)N(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9 g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me3SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me3SiCl was evaporated under reduced to yield 4-bromo-N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:16][C:15](=[O:17])[N:14]([CH3:18])[CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[C:19](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[CH3:18][N:14]1[C:15](=[O:17])[CH2:16][CH:12]([C:10]([NH:9][CH2:8][C:3]2[C:2]([CH3:19])=[N:7][CH:6]=[CH:5][N:4]=2)=[O:11])[CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC(C(=O)NCc2nccnc2Cl)CC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Product: Cc1nccnc1CNC(=O)C1CC(=O)N(C)C1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
To a stirred suspension of N-((3-chloropyrazin-2-yl)methyl)-1-methyl-5-oxopyrrolidine-3-carboxamide (700 mg, 2.61 mmol) and potassium carbonate (540 mg, 3.91 mmol) in 1,4-dioxan (10 ml) under a nitrogen atmosphere was added trimethylboroxine (981 mg, 7.82 mmol) and 1,1′-bis-(diphenylphosphino)-ferrocene) palladium dichloride (214 mg, 0.261 mmol). The reaction was heated at 100° C. for one hour. Then the reaction mixture was filtered over celite and the celite was rinsed three times with ethyl acetate. Subsequently, the combined filtrates were concentrated in vacuo and the crude product was purified by column chromatography (silica gel; dichloromethane/methanol 96/5) to give 1-methyl-N-((3-methylpyrazin-2-yl)methyl)-5-oxopyrrolidine-3-carboxamide (440 mg).