Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.O.[OH-].[Li+]>C1COCC1.O.CO>[C:39]([O:38][C:36]([N:32]1[CH2:33][CH2:34][CH2:35][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:6]4[C:5]([CH2:4][C:3]([OH:43])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=3)=[CH:25][CH:26]=2)[CH2:31]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I148) (0.030 g, 0.050 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) was added lithium hydroxide monohydrate (0.020 g, 0.48 mmol). The reaction mixture was stirred at room temperature for 17 hours then the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) then the solvent removed in vacuo to give the title compound (I149) (0.029 g, 99%) as a white solid. LCMS Method C: rt 5.50 min, m/z=586.1 [M+H]+, 584.2 [M−H]+.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15](CON4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1>C(O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:9]=2[CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nncn1-2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reated at 65° C. with 8-bromo-1-[(phthalimidooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-(aminooxy)methyl]-8-bromo-6-(2pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[C:9]([C:17]3C=CC(CN4CCC(C5N=C(C6C=CC=CN=6)NN=5)CC4)=[CH:19][CH:18]=3)=[N:10][C:11]3[N:12]([N:14]=[CH:15][CH:16]=3)[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=O>C(Cl)(Cl)Cl>[Cl:1][C:16]1[CH:15]=[N:14][N:12]2[CH:13]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([C:17]3[CH:43]=[CH:44][C:45]([CH:46]=[O:47])=[CH:19][CH:18]=3)=[N:10][C:11]=12
Reactant: c1ccc(-c2cn3nccc3nc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3c(Cl)cnn3cc2-c2ccccc2)cc1

Procedure:
0.4 g 6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 19) and 0.19 g N-chlorosuccinimide are refluxed in 10 ml chloroform for 5 d. The solvent is removed by distillation and the crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 2-chloro-5-trifluoromethyl-benzoic acid (2.8 g, 12.5 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 7 ml, 14 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, methanol (10 ml) was added. After stirring for 20 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide methyl 2-chloro-5-trifluoromethyl-benzoate (2.6 g, 87% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:6]2[N:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]=1.[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]([N:7]2[C:8](=[O:9])[C:3]([CH2:2][N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH3:24])=[N:4][C:5]3[CH:23]=[CH:22][CH:21]=[N:20][C:6]2=3)[CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(=O)c(Cn3ccnc3C)nc3cccnc32)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
A mixture of 2-bromomethyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.22 g) and 2-methylimidazole (1.35 g) in N,N-dimethylformamide (10 ml) was stirred at 80° C. for 1 hour. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 4-(3-methoxycarbonylphenyl)-2-[(2-methylimidazol-1-yl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (154 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22](C(OC(C)(C)C)=O)[C@@H:21]([CH3:30])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:30][C@H:21]1[CH2:20][N:16]2[C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=[C:15]2[NH:22]1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1cc(F)c(F)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,4,5-trifluorophenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Yield: 36.9 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-benzimidazole-2-carboxamide (1.50 g, 2.78 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.42 g, 5.56 mmol,), sodium carbonate (1.17 g, 11.12 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) at 80° C. for 18 hours. Additional 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.90 mmol,), sodium carbonate (0.508 g, 4.80 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) was added and the mixture was heated for another 24 hours. Additional tetrakis triphenylphosphine palladium (0) (0.32 g, 0.27 mmol) was added and the mixture was heated for another 24 hours after which time all starting material was consumed. The solvent was removed in vacuo and the residue was triturated with water (30 mL) for 3 hours. The solid was collected by filtration and dried in vacuo. The crude product was suspended in acetone (60 mL) and water (8 mL) and reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.52 mmol) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solvent was removed an the residue was partitioned between dichloromethane (20 mL) and water (40 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (0.48 g, 31%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.19 (s, 1H), 9.64 (d, 1H), 8.52 (dd, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H), 7.75-7.82 (m, 2H), 7.47 (t, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.93 (dd, 1H), 4.25 (s, 3H), 4.04 (s, 3H), 1.86 (s, 3H); RP-HPLC (Conditions g) Rt 12.21 min.; MS: MH+ 468.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25]N=[C:23](OC)[CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:29][C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.BrCCC1C=CC(Cl)=CC=1>>[Cl:29][C:30]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:11]3[S:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=4)[N:12]=3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Agent: Clc1ccc(CCBr)cc1
Product: Clc1ccc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)cc1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and 1-(2-bromoethyl)-4-chlorobenzene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2cc(F)ccc12
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cnc(F)c2cc(F)ccc12
Temperature: 145 °C
Yield: 49.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (3.7 g, 17.48 mmol) in DMSO was added cesium fluoride (10.26 g, 69.9 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (1.7 g, 49%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.47 (m, 1H), 7.46 (s, 1H), 4.04 (s, 3H); 19F NMR: δ ppm 109.65 (1 F), −78.53 (1 F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: [CH:1]1([C@H:7]([OH:10])[C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O.CCCCCC>[Si:20]([O:10][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]#[CH:9])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H](O)C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-cyclohexylprop-1-yn-3-ol, prepared as shown in Preparation 3 or 4, (2.76 g, 0.02 mol), in 10 ml N,N dimethylformamide (DMF), cooled to 0° C., was added imidazole (2.1 g), followed by tert-butyldimethylchlorosilane (3.1 g, 0.02 mol). The mixture was stirred for 3 h. Water (80 ml) and hexane (80 ml) were added; the organic layer was separated and combined with 2×80 ml of hexane extractions of the aqueous layer. The solvent was removed (in vacuo), after drying over sodium sulfate, to give a crude residue (4.3 g) which was chromatographed on silica gel (80 g), eluting with ethyl acetate-hexane (2:1, v/v) to afford (S)-3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-yne.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C:55]([CH3:58])([OH:57])[CH3:56]>CN(C=O)C>[OH:57][C:55]([CH3:58])([CH3:56])[CH2:54][NH:53][C:18]([C:14]1[S:13][C:12]([CH2:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NCC(C)(C)O)s1
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (80 mg, 0.26 mmol) in DMF (4 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (92 mg, 0.29 mmol), N,N-diisopropyl ethyl amine (168 mg, 1.3 mmol) and 1-amino-2-methyl-propan-2-ol (25 mg, 0.29 mmol). The resulting reaction mixture was stirred for 15 h and then evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (55 mg, 56%) as a colourless oil MS: m/e=380.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.[Zn](C)[CH3:30]>C1COCC1.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: C[Zn]C
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1 (94 mg, 0.237 mmol) and PdCl2(dppf) (18 mg, 0.047 mmol) in THF (1 ml) at room temperature was added ZnMe2 in toluene (1.2 M, 0.4 mL). The reaction mixture was stirred at 50° C. for 2 h. A second portion of ZnMe2 (0.6 mL) and PdCl2(dppf) (18 mg) was added. The reaction was heated at 50° C. for 3 h, cooled and quenched by sat. aqueous NaHCO3. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. Purification by reverse-phase HPLC (C-18 column, 5-90% MeCN in H2O with both containing 0.05% TFA) provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.0 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.13 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.60 (d, J=7.6, 1H), 7.30 (dd, J=2.4, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 4.45 (s, 2H), 3.92-3.84 (m, 1H), 3.61-3.57 (m, 1H), 2.51 (s, 3H), 2.17-2.12 (m, 2H), 1.82-1.79 (m, 2H), 1.54-1.23 (m, 4H). HRMS (ES) [M+1]+ calcd for C23H25N3O2: 376.2020, Found: 376.2010.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([C:30](O)=O)[N:21]=2)=[CH:16][CH:15]=1>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([C:30]2[O:11][N:10]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=3)[N:9]=2)[N:23]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Nc1cc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)ccn1

Procedure:
The title compound was prepared from 2-amino-N-hydroxy-pyridine-4-carboxamidine (example C.5) (0.11 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.13 g, 57%). MS (ISP) 453.1 [(M+H)+]; mp 223.5° C.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([N:30]=[C:31]=[S:32])[CH2:28][CH3:29]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[S:32])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CCCN=C=S
Solvent: ClCCl
Product: CCCNC(=S)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (100 mg, 0.294 mmol) in dichloromethane (15 mL) was added propyl isothiocyanate (0.038 mL, 0.323 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The solvent was removed under reduced pressure and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 15 to 20% EtOAc:Hexane to get 1-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-3-propylthiourea (255) (64 mg 49%). 1H NMR (300 MHz, CDCl3) ppm 7.08-7.34 (m, 10H) 6.39 (s, 2H) 4.11 (t, J=6 Hz, 2H) 3.32-3.46 (m, 2H) 3.16-3.23 (m, 4H) 2.25-2.30 (m, 2H) 2.13-2.17 (m, 2H) 1.32-1.39 (m, 2H, 0.73 (t, J=6 Hz, 3H)
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[CH3:77][O:78][C:79](=[O:91])[C:80]([C:83]1[CH:88]=[CH:87][C:86]([NH2:89])=[C:85]([F:90])[CH:84]=1)([CH3:82])[CH3:81]>CN(C)C1C=CN=CC=1>[CH3:77][O:78][C:79](=[O:91])[C:80]([C:83]1[CH:88]=[CH:87][C:86]([NH:89][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:85]([F:90])[CH:84]=1)([CH3:82])[CH3:81]
Reactant: COC(=O)C(C)(C)c1ccc(N)c(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: COC(=O)C(C)(C)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c), 2-(4-amino-3-fluoro-phenyl)-2-methyl-propionic acid methyl ester and using 4-(dimethylamino)pyridine as a base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15](=[O:29])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:20][CH:19]=1.C1C=CC2[N:38]([OH:39])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:15](=[O:29])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([NH:38][OH:39])=[O:28])=[CH:22][CH:23]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Cl)c(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid (compound from STEP A, 205 mg), HOBT (134 mg, 0.99 mmol), EDC (190 mg, 0.99 mmol), TEA (0.138 ml, 0.99 mmol) and NH2OTHP (70 mg, 0.60 mmol) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with AcOEt twice. The organic phases were washed with water, brine and then dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 3 h. The precipitate was filtered and rinsed with DCM and Et2O to give 124 mg of (E)-3-(4-{(E)-3-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide hydrochloride.
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[C:14]([C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:14]([C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:1])[N:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
They were added to a solution of 16.8 grams of diethyl malonate in 75 ml. of dioxane with stirring and under a nitrogen atmosphere 3.3 grams of sodium hydride (80%) and then stirring continued for 15 minutes more. Then there were added in portions 26.3 grams of 2-benzoyl-3-nitro-6-chloropyridine and then stirring was continued at 70° C. for two hours more. The precipitated deeply colored sodium salt of the dicarbethoxymethyl compound was filtered off with suction. Five grams of this compound were boiled under reflux in a mixture of 25 ml. of concentrated hydrochloric acid and 25 ml. of methanol for 90 minutes, the solution filtered hot and the filtrate treated with water to the point of turbidity. The desired product crystallized out.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5].[C:21](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([N:11]([CH3:21])[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 78 h
Yield: 65.1 %

Procedure:
[2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-carbamic acid, ethyl ester (22 g, 75.1 mmol), sodium carbonate (16.0 g, 0.112 mol) and methyl iodide (13 g, 0.122 mol) were added to 100 ml of dry DMF and the mixture stirred at ambient temperature for 78 hours. The reaction was quenched with 1 liter of H2O and extracted with five 200 ml portions of diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and evaporated to give 15 g of solid. This solid was purified by HPLC (silica gel, DCM) to give 13.1 g (57%) of crystals, m.p. 54°-56°.