Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:39])([P:36](=[O:38])=[O:37])[N:3]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH2:25][CH2:26][NH:27][C:28]2[C:33](Cl)=[CH:32][N:31]=N[C:29]=2Cl)[CH:18]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[CH3:40]P(C)(C(=O)N(C1C=C(C)C=C(OCCNC2C(Cl)=C(Cl)N=NC=2)C=1)S(C1C=CC=CC=1OCCC)(=O)=O)=O>>[CH3:39][C:2]([CH3:1])([P:36](=[O:38])=[O:37])[N:3]([C:17]1[CH:18]=[C:19]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:29]=[CH:40][N:31]=[CH:32][CH:33]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1ccccc1S(=O)(=O)N(C(=O)P(C)(C)=O)c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1
Reactant: CCCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2c(Cl)cnnc2Cl)c1)C(C)(C)P(=O)=O
Product: CCCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2ccncc2)c1)C(C)(C)P(=O)=O

Procedure:
was produced analogously to example 5 in a 33% yield. Oil. MS (m/e)=532. For this 2-propyloxy-benzene-sulfonyl chloride was used in step 5c) instead of 2-methoxy-benzenesulfonyl chloride and one obtained N-(3cyanomethoxy-5-methyl-phenyl)-2-propyloxy-benzene-sulfonamide (Fp. 154°-155° C.) in a 57% yield, which was reacted to N-(dimethyloxo-phosphinyl-methyl)-N-(3-cyanomethoxy-5-methyl-phenyl)-2-propyloxy-benzene-sulfonamide (60% yield, Fp. 143°-145° C.) analogously to example 5d), which was reacted analogously to example 5e) to form N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-propyloxy-benzene-sulfonamide (86% yield, oil, MS (m/e)=454), which was reacted analogously to example 5f) to form a mixture of N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-propyloxy-benzenesulfonamide and N-(dimethyloxo-phosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methyl-phenyl}-2-propyloxy-benzene-sulfonamide (quant., oil, MS (m/e)=601) from which the title compound was obtained by catalytic hydrogenation analogously to example 5g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=[C:15]([CH:23]=[O:24])C=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:15][CH:23]=[O:24])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1cnc2ccccc2c1
Product: O=CC=Cc1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 7 by substituting 6-trifluoromethyl-3-pyridinecarboxaldehyde for the 3-quinolinecarboxaldehyde of Reference Example 7. MS 202 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:18][CH:19]([CH3:22])[CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:22])[CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)CI
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCN(CC(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 68.7 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (2.09 g, 8.44 mmol), 2-methyl-iodopropane (2.1 g, 11.39 mmol), and potassium carbonate (4.7 g, 34 mmol) in acetonitrile (80 mL) was heated in a pressure vessel at 80° C. for 24 hours. The reaction was cooled and the acetonitrile was removed under reduced pressure. The solids were dissolved in methylene chloride/water. The organic layer was dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The resultant residue was purified by chromatography on SiO2 (10% MeOH/CH2CL2 with 0.2% NH3) to give 1-[3-(methyloxy)-4-nitrophenyl]-4-(2-methylpropyl)piperazine as a pale yellow solid (1.70 g, 5.8 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (d, J=6.59 Hz, 6 H), 1.80 (ddd, J=13.69, 7.05, 6.91 Hz, 1 H), 2.13 (d, J=6.04 Hz, 2 H), 2.52 (s, 4 H), 3.38 (s, 4 H), 3.93 (s, 3 H), 6.29 (d, J=2.38 Hz, 1 H), 6.40 (dd, J=9.43, 2.47 Hz, 1 H), 7.98 (d, J=9.52 Hz, 1 H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([C:40]4C=CC=CC=4)=[C:28]([OH:46])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[Cl:39])[C:29]([CH3:40])=[C:28]([O:46][CH3:3])[C:27]3=[O:47])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2c(F)ccc(F)c2Cl)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1=C(C)C(c2c(F)ccc(F)c2Cl)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2-chloro-3,6-difluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.103 g, 0.25 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.013 g (13.3%); MS m/z: 390.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.78, 1.81 (2s, 3H), 3.94, 3.95 (2s, 3H), 6.34-6.35 (m, 1H), 7.11-7.17 (m, 1H), 7.25-7.29 (m, 1H), 7.35-7.40 (m, 1H), 7.52-7.54 (m, 1H), 7.67 (s, 1H), 8.35 (s, 1H); HPLC (METHOD [A]): rt 12.59 min (95%)
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:48][C:49]4[NH:54][CH2:53][CH2:52][O:51][C:50]=4[N:55]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[C:56]1([C:47]2[C:46]([C:43]3[CH:42]=[CH:41][C:40]([C:36]4([NH2:35])[CH2:39][CH2:38][CH2:37]4)=[CH:45][CH:44]=3)=[N:55][C:50]3[O:51][CH2:52][CH2:53][NH:54][C:49]=3[CH:48]=2)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Yield: 139.9 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.03 mmol) was reacted to afford the title compound (15 mg, quantitative). LCMS (Method A): RT=3.80 min, M-NH2=341. 1H NMR (500 MHz, MeOD): 7.31 (4H, s), 7.22-7.21 (3H, m), 7.12-7.11 (2H, m), 7.01 (1H, s), 4.45 (2H, t), 3.45 (2H, t), 2.75-2.70 (m, 2H), 2.56-2.50 (m, 2H), 2.24-2.15 (m, 1H), 1.97-1.88 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(C=O)c1
Yield: 92.5 %

Procedure:
3-Hydroxybenzaldehyde (900 mg, 7.37 mmol) is treated with 2.16 g (11.05 mmol) of ethyl 4-bromobutyrate, 3.06 g (22.11 mmol) of potassium carbonate, and a catalytic amount (110 mg 0.74 mmol) of sodium iodide under the same conditions as in Preparation 3 to give a yellow oil. Purification by flash chromatography using hexane/ethyl acetate (10:1) gives 1.61 g of 4-(3-formylphenoxy)butanoic acid, ethyl ester as a light yellow oil. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1700, 1600, 1580 cm-1 ; MS (CI low res) m/e 237 (M+H), 191, 115.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=[S:18]>>[OH:4][CH2:3][CH:2]([NH:1][C:17]([NH:16][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[S:18])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=1
Reactant: NC(CO)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethoxy)phenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.58 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.37-7.26 (m, 3H), 7.21 (d, J=8.6 Hz, 2H), 6.76 (dd, J=11.6, 8.6 Hz, 4H), 6.64-6.56 (m, 3H), 6.43 (d, J=7.9 Hz, 1H), 5.13 (s, 1H), 3.45 (dd, J=11.2, 4.0 Hz, 1H), 3.33 (dd, J=11.2, 4.5 Hz, 1H); ESIMS m/z 568 ([M+H]+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]#[N:11].[C-]#N.[Na+]>>[C:1]([C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#N
Reactant: O=C(Cl)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Product: N#CC(=O)c1ccccc1

Procedure:
Process as claimed in claim 1 wherein benzoyl chloride is heated in the presence of hydrocyanic acid anhydrous pyridine and sodium cyanide, to form benzoyl cyanide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15]C)=O)[NH:6]2.[CH3:17][C:18](C)([O-])C.[K+].C(OC)(=O)C=C>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:13](=[O:15])[CH2:18][CH2:17][N:6]3[C:7]=2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc2c(Br)cc(OC)cc2[nH]1
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CC(=O)OC
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2cc3n(c2c1)CCC3=O
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of the ester from Step 3 (0.5 g, 1.76 mmol) in toluene (7 mL) and THF (1 mL) at RT was added 1M potassium t-butoxide (1.76 mL, 1.76 mmol). After 15 minutes, methyl acrylate (0.32 mL, 3.5 mmol) was added, and the mixture was brought to reflux for 1.5 hours. The reaction was quenched by the addition of saturated NH4Cl solution, and the product was extracted with EtOAc/THF. The organic layer was washed with H2O and brine, dried (MgSO4), filtered, and evaporated. The intermediate was suspended in EtOH (10 mL), and concentrated HCl (2 mL) was added. After heating to reflux for 2 hours, the mixture was cooled and diluted with H2O (30 mL). The product was extracted with CH2Cl2 and the organic phase was washed with H2O before drying (MgSO4). Following filtration and removal of solvent under vacuum, the product was stirred with 1:2 EtOAc:hexane to give a tan-coloured solid (0.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C([O-])=O.[Na+]>O.O1CCCC1.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([OH:14])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2ccc(Br)cc2n1
Agent: Cl[Ru]Cl
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: O=C[O-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)c1ccc2ccc(Br)cc2n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Dichloro (p-cymene) ruthenium(II) dimer (61 mg, 0.100 mmol) and (1R,2R)-(−)—N-p-tosyl-1,2-diphenylethylenediamine (88 mg, 0.012 mmol) was suspended in degassed water (40 mL) and the mixture was degassed with nitrogen for 5 min. The mixture was stirred at 70° C. under nitrogen for 90 min. The resulting turbid orange mixture was allowed to cool to room temperature. 1-(7-Bromo-quinolin-2-yl)-ethanone (5.00 g, 20 mmol) in degassed tetrahydrofuran (40 mL) was added followed by sodium formate (6.8 g, 100 mmol) and the reaction mixture was degassed with nitrogen for 5 min. The reaction mixture was vigorously stirred at 40° C. for 4 h and allowed to cool. It was then diluted with ethyl acetate and water and the organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in iso-hexanes to afford the title compound (4.96 g, 98%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.59 (d, J=6.7 Hz, 3H), 4.85 (d, J=4.5 Hz, 1H), 5.04-5.07 (m, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.64 (dd, J=8.7, 1.6 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H). LCMS (m/z) 252.1/254.1 [M+H], Tr=1.74 min.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[C:7]([CH:11]=O)=[CH:6][N:5]=1.O>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]2[NH:1][N:2]=[CH:11][C:7]2=[CH:6][N:5]=1
Reactant: NN
Reactant: O=Cc1cnc(Cl)nc1Cl
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncc2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of hydrazine (Aldrich, 64 mg, 2 mmol) in THF (5 mL), 2,4-Dichloro-pyrimidine-5-carbaldehyde (Example 17, 176 mg, 1 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc. The extract was dried with sodium sulfate and the solvent was removed to give an orange solid. 128 mg, 82%. MS (M+H)+, 155.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[C:20](=[O:42])[NH:21][C:22](=[O:41])[C:23]=2[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[CH:25]=2)=[CH:11]1>CN(C=O)C>[NH:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:35][CH2:34][CH2:33][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:23]2[C:22](=[O:41])[NH:21][C:20](=[O:42])[C:19]=2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH3:9])[CH:11]=2)=[CH:25]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: Sc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(CCCSc4ncc[nH]4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
7 mg of a 80% dispersion of sodium hydride in mineral oil was added to a cooled solution of 23 mg of 2-mercaptoimidazole in 10 ml of DMF. The mixture was stirred for 0.5 hour while cooling. 100 mg of the product of Example 58 were added and the mixture was stirred for 2 hours while cooling. The mixture was then allowed to warm to room temperature and was stirred overnight. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 20 mg of 3-[1-[3-(2-imidazolylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 130°-132° C.
Reaction SMILES: [CH2:1]([C:3]1[S:39][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].C(OCC)(=O)C.O>C(Cl)Cl>[CH2:1]([C:3]1[S:39][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(O)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
To a solution of 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in methylene chloride (6 mL) was added tribromide boron (5.6 mL, 1.0M methylene chloride solution), and the mixture was stirred at room temperature for 24 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.49 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1cccc(F)c1
Product: COc1cc(Nc2cccc(Nc3cccc(F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-fluoroaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=24%). MS ISP (m/e): 390.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.10 (s very broad, 2H), 7.70-7.50 (m, 2H), 7.45 (t, 2H), 7.39 (s, 1H), 7.30-7.10 (m, 4H), 7.02 (s, 1H), 6.63 (t broad, 1H), 6.30 (t, 2H), 3.62 (s, 3H), 2.14 (s broad, 3H).
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(C(C)C)CC)(C)C.C[Si]([N:31]=[C:32]=[S:33])(C)C>ClCCl.CN(C1C=CN=CC=1)C.CC(O)=O.CCOC(C)=O>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH:5]2[NH:6][C:32](=[S:33])[NH:31][C:4]2=[O:17])=[CH:9]1
Reactant: C[Si](C)(C)N=C=S
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=S)NC1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.257 mg, 0.001 mol.) in dichloromethane (10 mL) was added DMAP (5.0 mg), diisopropylethylamine (10 eq.) and then trimethylsilylisothiocyanate (1.3 gm, 0.01 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was dissolved in AcOH (10 mL) and refluxed for 6 h. The reaction mixture was concentrated and dried under vacuum. The solid obtained was suspended in EtOAc, filtered, washed with EtOAc, and dried under vacuum to give 893-18 (230 mg, 94%): mp 206-210° C., 1H NMR (500 MHz, DMSO-d6): 3.00-yield 34%, 1H NMR (500 MHz, CDCl3): 3.24-3.33 (m, 2H), 4.23-4.26 (m, 1H), 7.01(dd, J=8.0 and 7.0 Hz, 1H), 7.09 (dd, J=8.0 and 7.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 8.50 (s, 2H), 11.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH:9][C:10](=[O:23])[C:11]2[C:12](=[CH:16][C:17]([C:20](=O)[NH2:21])=[CH:18][CH:19]=2)[C:13](N)=[O:14])[CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:11]3[C:10]2=[O:23])[CH:3]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc(C(N)=O)cc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C#N)cc2C1=O

Procedure:
The mixture of 0.3 g of N-(4-amino-o-tolyl)-4-carbamoylphthalamide, 2 ml of dioxane and 5 ml of phosphorus oxychloride is refluxed for 1 hour and evaporated. The residue is taken up in methylene chloride, the solution washed with cold aqueous sodium carbonate, dryed and evaporated, to yield the N-(4-amino-o-tolyl)-4-cyanophthalimide, which is identical with that obtained according to Example 20.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[CH2:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH3:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][C:41]([CH2:39][CH3:40])=[CH:42][CH:43]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(CC)cc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and 4-ethylbenzoylchloride. Yield: 64% of theory, C36H37N7O4 (631.7); Rf value: 0.78 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=632; (M+H+Na)++=327.8; (M+Na)+=654.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1>[C].[Pd].CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Into a 10-mL round-bottom flask purged and maintained with an atmosphere of hydrogen, was placed a solution of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-[[(3R)-1-[(tert-butoxy)carbonyl]piperidin-3-yl]amino]-6-oxo-1,6-dihydropyrimidin-2-yl]piperidine-1-carboxylate (644 mg, 1.00 mmol, 1.00 equiv), Palladium carbon (64.4 mg) and methanol (20 mL). The resulting mixture was stirred overnight at room temperature. Filtration and evaporation gave 480 mg (94%) of the title compound as a light yellow solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 511.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C1(SC2C=CC=CC=2)C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: N#C/C=C/c1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 68.1 %

Procedure:
A solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (32 mg, 0.069 mmol), diphenylsulfide (1.145 μl, 6.87 μmol) and Pd/C (7.31 mg, 6.87 μmol) in methanol (5 ml) and ethyl acetate (5 ml) was stirred under hydrogen gas (45 psi pressure) overnight. The palladium was filtered off, the solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(2-cyanoethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (22 mg, 0.047 mmol, 69% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (s, 1H), 7.15-7.40 (m, 2H), 7.04 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 4.61 (s, 2H), 2.87 (t, 2H), 2.69 (t, 2H). LC-MS (ES+) m/z 467.02, [M+H].