Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].CN(C)[CH:26]=[O:27]>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH2:1][O:2][CH2:3][CH2:4][O:27][CH3:26])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1cc(O)ccc1C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved in 65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to the solution was added 1.9 g of 60% sodium hydride with stirring in an ice bath. After removing from the ice bath, the mixture was stirred at a room temperature for 30 minutes, and after addition of 5.4 g of methoxyethoxymethyl chloride with ice cooling, stirred for 15 hours allowing to warm to a room temperature. The reaction mixture was poured on ice, saturated with sodium chloride and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain 13.85 g of the title compound in a colorless amorphous form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:16]([CH3:24])[C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:21]([C:17]1[N:16]([CH3:24])[C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:25])=[N:19][C:18]=1[CH3:20])=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)n(C)c1C(=O)O
Reactant: NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)n(C)c1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,4-dimethyl-1H-imidazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 62% yield: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 10H), 7.19 (d, J=7.7 Hz, 1H), 6.17 (t, J=5.6 Hz, 1H), 6.09 (dd, J=7.7, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 4.62 (d, J=5.6 Hz, 2H), 3.67 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 163.3, 160.9, 141.5, 138.0, 137.8, 136.8, 134.7, 128.84, 128.8, 128.6, 127.7, 127.7, 127.6, 123.5, 102.8, 97.8, 70.6, 43.6, 32.7, 15.2; MS (ES+) m/z 429.3 (M+1).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])([CH3:3])[CH3:2].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C1CCN2C(=NCCC2)CC1>O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:16][CH2:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:10]
Reactant: CC(C)NCc1cccc(C#N)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-[(isopropylamino)methyl]benzonitrile (5.7 g, 32.7 mmol), tert-butyl acrylate (4.78 ml, 32.7 mmol) and DBU (5.0 ml, 32.7 mmol) was heated neat at 80° C. for 24 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. After purification by chromatography (silica, pet ether/EtOAc), the title compound was obtained as a colorless oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.73 (s, 1H,), 7.67 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 3.56 (s, 2H), 2.75 (m, 1H), 2.62 (t, J=6.5 Hz, 2H), 2.25 (t, J=6.4 Hz, 2H), 1.39 (s, 9H), 0.83 (d, J=8.8 Hz, 6H).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:20]1[OH:21]
Reactant: O=C(Cc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1O
Yield: 36 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-(phenylacetylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (97 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-3-(phenylacetylamino-1,3-dideoxy-β-D-ribofuranuronic acid (340 mg) prepared in Example 17 with n-butylamine according to a similar manner to that of Example 23, mp. 159°-165° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:7](N(OC)C)=[O:8])[CH3:2].[CH3:22][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH3:22])[CH:13]=[C:14]([S:16]([F:21])([F:17])([F:18])([F:19])[F:20])[CH:15]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Solvent: C1CCOC1
Product: CCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Ethoxy-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (2.6 g) was dissolved in THF (60 ml). After cooling to 0° C., methylmagnesium bromide (6.46 ml, 3 M in ether) was added dropwise. Thereafter, the cooling bath was removed and stirring was continued at RT. After 1 h, the mixture was acidified with 1N hydrochloric acid, admixed with water and extracted by shaking twice with EA. The EA phases were dried over magnesium sulfate, filtered and concentrated. 2.25 g of the title compound were obtained.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:48]=[CH:47][C:11]2[N:12]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:13]([NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][C:30]=5[O:31][CH3:32])[CH:23]=4)[N:18](COCC[Si](C)(C)C)[N:17]=3)=[N:14][C:10]=2[CH:9]=1)(C)(C)C.Cl>C(O)C>[CH:41]1([N:12]2[C:11]3[CH:47]=[CH:48][C:8]([CH2:7][OH:6])=[CH:9][C:10]=3[N:14]=[C:13]2[NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][C:30]=4[O:31][CH3:32])[CH:23]=3)[NH:18][N:17]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3n1C1CCCCC1)nn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1ccncc1-c1ccc2[nH]nc(Nc3nc4cc(CO)ccc4n3C3CCCCC3)c2c1
Temperature: 100 °C

Procedure:
A mixture of [5-(tert-Butyl-dimethyl-silanyloxymethyl)-1-cyclohexyl-1H-benzoimidazol-2-yl]-[5-(4-methoxy-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-amine (from Step 6) and 12 M HCl (2.0 mL) in ethanol (6.0 mL) was heated at 100° C. for 1 hr. The mixture was evaporated to dryness and then purified twice by preparative HPLC to yield 4.1 mg of the title compound as the TFA salt.
Reaction SMILES: [OH2:1].O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:17][CH2:16]3)[C:11]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1.[OH-].[Na+:35]>CO>[OH2:25].[OH2:1].[Na+:35].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])[CH2:17][CH2:16]3)[C:11]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])CCC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 194.4 %

Procedure:
A slurry of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H- pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate (150 mg, 0.31 mmol) from above in methanol (10 mL) was treated with a solution of sodium hydroxide (12 mg, 0.31 mmol) in methanol (2 mL). The reaction was stirred at room temperature for 15 minutes until dissolution was completed. The solvent was removed in vacuo. The residue was treated with tetrahydrofuran and filtered and air dried to give 150 mg (97%) of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid monosodium salt dihydrate as a solid. Anal. Calc'd. for C22H21ClN5O3Na.2H2O: C, 53.07; H, 5.06; N, 14.07. Found: C, 52.81; H, 5.11; N, 13.90.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH:29]([CH2:40][CH:37]2[CH2:39][CH2:38]2)[C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=CC1CC1
Reactant: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 25 h
Yield: 99.4 %

Procedure:
Sodium triacetoxyborohydride (1.80 g, 8.49 mmol) is added to a stirred solution of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.71 g, 5.25 mmol), cyclopropanecarboxaldehyde (0.44 ml, 5.89 mmol), acetic acid (0.32 ml, 5.59 mmol), and 1,2-dichloroethane (35 ml). The reaction is stirred for 25 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 40% ethyl acetate/hexanes to yield (1.98 g, 99%) of 4-{[cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=380.3 (M+1); 1H NMR (CDCl3): δ=4.18 (2H, brs), 3.74 (2H, s), 2.86-2.78 (1H, m), 2.70-2.60 (5H, m), 2.41 (2H, d), 2.32 (3H, s), 1.81-1.70 (2H, m), 1.50-1.39 (11H, m), 0.87-0.80 (1H, m), 0.53-0.46 (2H, m), 0.12-0.06 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][OH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(F)cc1F
Product: CC(C)N1c2cc(OCc3ccc(F)cc3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,4-difluorophenyl)methanol.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[N:16]1([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CO
Product: OC(COc1cccc2ccccc12)CN1CCCC1

Procedure:
A solution of 1,2-epoxy-3-(1-naphthyloxy)propane (62.0 g) and the amine of formula NHR3R3, pyrrolidine (23.5 g), in methanol (250 ml) is heated at reflux for two hours. The reaction mixture is concentrated to dryness. The oily residue is crystallized from chloroform and diethyl ether by the addition of hexane to give the title compound, mp 68-70° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC>[C:24]1([C:22]#[C:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CC2=CCCCC2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (106 mg, 85%); 1H NMR δ (CDCl3): 7.68 (s, 1H), 7.6-7.7.49 (m, 2H), 7.46-7.37 (m, 1H), 6.28 (m, 1H), 2.31-2.12 (m, 4H), 1.73-1.57 (m, 4H); LCMS m/z: 250.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23]([CH3:33])=[CH:24][C:25](=[O:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[CH:27]1([CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:19]([CH3:20])[NH:22][C:23]=2[CH3:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(N)=CC(=O)CC1CCCC1
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CC2CCCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 38 mg (0.227 mmol) of 4-amino-1-cyclopentylpent-3-en-2-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 43 mg (55% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].[CH2:7]([O:23][C:24](Cl)=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)Cl>[CH2:7]([O:23][C:24]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: C=C(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(CO)COC(=O)OCCCCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 2.5 h

Procedure:
2-Methylenepropane-1,3-diol (5.0 g), hexadecyloxycarbonylchloride (17.4 g) and pyridine (4.4 g) was dissolved in methylene chloride (60 ml). The mixture was stirred for 2.5 hours at 22° C. The mixture was purified through a column of silica gel 60 (70-230 mesh, 30 g), eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®-System 500A using a PrepPAK®-500-SILICA cartridge with ether/chloroform/pentane 1:1:3 as eluent.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:7][C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([F:1])[CH:9]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Reactant: COc1cc(C=O)cc(F)c1O
Product: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(F)c1O
Yield: 57 %

Procedure:
The reaction was effected in the same manner as in Example 1 with 5-fluorovanillin (410 mg, 2.41 mmol) and N-(3-chlorophenyl) cyanoacetamide (469 mg, 2.41 mmol) to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-fluoro-4-hydroxy-5-methoxyphenyl) propenamide (476 mg, 57% in yield) as yellow powders.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cl:30][CH2:31][C:32](Cl)=[O:33]>CCOCC>[Cl:30][CH2:31][C:32]([NH:28][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[N:18]([CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]2=[O:29])=[O:33]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: CCOCC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Yield: 96 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione (2.0 g, 4.8 mmol) and chloroacetyl chloride (2 mL, 25 mmol) was heated to reflux for 30 minutes. The solvent was removed in vacuo to give a solid. The solid was stirred in ether (40 mL) for 1 hour to give a suspension. The suspension was filtered and washed with ether to give 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (2.28 g, 96% yield); mp, 166-168° C.; 1H NMR (CDCl3) δ 1.48 (t, J=6.9 Hz, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.13 (q, J=7.0 Hz, 2H, CH2), 4.24 (s, 2H, CH2), 4.57 (dd, J=10.5, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.5, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.57 (d, J=7.2 Hz, 1H, Ar), 7.70 (t, J=7.6 Hz, 1H, Ar), 8.77 (d, J=8.3 Hz, 1H, Ar), 10.53 (s, 1H, NH); 13C NMR (CDCl3) δ 14.60, 41.52, 42.67, 48.72, 54.51, 55.88, 64.48, 111.46, 112.44, 116.37, 119.06, 120.38, 124.74, 129.17, 131.22, 136.04, 136.29, 148.58, 149.75, 165.21, 167.25, 169.01; Anal Calcd for C22H23N2O7ClS+0.1H2O: C, 53.19; H, 4.71; N, 5.50; H2O, 0.36. Found: C, 52.89; H, 4.52; N, 5.50; H2O, 0.17.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:37])[NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29](=[O:36])[NH:30][C:31]5[NH:32][CH:33]=[CH:34][N:35]=5)[C:22]=4[N:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:32]1[CH:33]=[CH:34][N:35]=[C:31]1[NH:30][C:29]([C:28]1[C:22]2[N:21]=[C:20]([NH:19][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:37])[NH:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ccc2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2

Procedure:
49.8 mg (0.10 mmol) of 6-[4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-ylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in 2 mL of 4 N HCl in dioxane was stirred at r.t. for 2 h. Evaporation of solvents in vacuo gave 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide in quantitative yield. LCMS: 402 (M+1)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCOCC1>[Cl:10][C:11]1[N:16]=[C:15]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.46 g (19.0 mmol) Diisopropylethylamine are added slowly to a solution of 3.36 g (17.3 mmol) 2,4-dichloro-5-nitropyrimidine and 2.13 g (17.3 mmol) p-anisidine in 30 ml dioxane. The mixture is stirred for 3 hours at room temperature. Then it is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethyl acetate/cyclohexane as eluent giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine as orange crystals; HPLC/MS (B): 2.24 min, [M+H] 281;
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:50][CH3:51])[C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:43]=3)=[O:37])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C>C(Cl)Cl>[CH2:50]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:35][C:36]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:43]=3)=[O:37])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH3:51]
Reactant: CCN(C(=O)OC(C)(C)C)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1cccc(-c2ccc(C(=O)O)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a methylene chloride (2.0 mL) solution of the obtained tert-butyl 4-(3-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.15 g) at room temperature, followed by stirring at the same temperature for 7 hours and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (3 mL) and dioxane (1 mL) were added to the obtained residue. The pH was adjusted to 13.0 with a 2 mol/L aqueous solution of sodium hydroxide, then to a pH of 4.6 with a 10% aqueous solution of citric acid. The solid substance was collected by filtration to obtain 0.10 g of 4-(3-(ethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a light yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:24])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)[CH2:9]1)C1C=CC=CC=1.C(O)C.[ClH:28]>O.[OH-].[Pd+2].[OH-]>[ClH:28].[ClH:28].[ClH:28].[CH3:24][N:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][CH:22]=[CH:23][C:16]=12
Reactant: CN(c1ccnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(c1ccnc2[nH]ccc12)C1CCCNC1
Reaction time: 60 h

Procedure:
A degassed mixture of N-(1-benzylpiperidin-3-yl)-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (0.17 g, 0.00053 mol) and palladium hydroxide (0.15 g, 0.00011 mol) in ethanol (3.5 mL, 0.060 mol) and 3.0 M of hydrogen chloride in water (0.40 mL) was stirred under an atmosphere of hydrogen over 2.5 days. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated under vacuum to give 92 mg of orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH2:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16]>>[OH:16][CH2:15][C:14]([NH:13][S:8]([C:6]1[CH:5]=[N:4][C:3]([Cl:12])=[C:2]([Br:1])[CH:7]=1)(=[O:10])=[O:9])([CH2:17][OH:18])[CH3:19]
Reactant: CC(N)(CO)CO
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Yield: 83.4 %

Procedure:
Prepared by general procedure III from 3-bromo-2-chloropyridine-5-sulphonylchloride (580 mg, 2 mmol) and 2-amino-2-methyl-1,3-propanediol (231 mg, 2 mmol) to give 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (600 mg, 83%) as a yellow solid. MS (ISN) 357 [(M−H)−], 359.0 [(M+2−H)−], 361.0 [(M+4−H)−].