Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2cc(C)nc(C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
2,6-Dimethyl-4-chloro-pyrimidine (1.0 g) in ethanol (10 ml) was added slowly to a solution of ethyl isonipecotate (1.1 g) and triethylamine (2.0 ml) in ethanol (20 ml). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water, washed with water (2×50 ml), dried and evaporated to give 1-(2,6-dimethylpyrimidin-4-yl)-4-(ethoxycarbonyl)piperidine as an oil (1.71 g); NMR (CDCl3): 1.25 (t, 3H), 1.65-1.80 (m, 4H), 1.95-2.00 (m, 2H), 2.55 (s, 3H), 2.45 (s, 3H), 2.50-2.60 (m, 1H), 3.00 (dt, 2H), 4.15 (q, 2H), 4.35 (d, 2H), 6.2 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1>CCO.[NH4+].[Cl-].CCOC(C)=O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cn2cc(N)cn2)cc1
Temperature: 105 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (1031 mg, 4.42 mmol) in EtOH (25 mL) and sat. aq. NH4Cl (15 mL) in a sealed tube (125 mL) was treated with iron (1234 mg, 22.10 mmol, Aldrich, St. Louis, Mo.). The mixture was stirred at 105° C. for 1 h, then cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and filtered through a plug of Celite® (diatomaceous earth). The filtrate was separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was filtered through a plug of silica gel (eluting with DCM:EtOAc: MeOH=25:25:1) to give 1-(4-methoxybenzyl)-1H-pyrazol-4-amine (560 mg, 2.76 mmol, 62.3% yield) as a brown solid. m/z (ESI, positive ion) 204 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[C:20]3[N:19]=[CH:18][N:17]([CH3:21])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[C:20]2[N:19]=[CH:18][N:17]([CH3:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:9])[NH2:10]
Reactant: Cn1cnc2c(Nc3cc(Cl)nnc3C(N)=O)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)cccc21
Temperature: 120 °C
Yield: 32 %

Procedure:
A solution of 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (260 mg, 859 μmol) in N-methyl-2-pyrrolidinone (3.0 mL) was treated with tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (368 mg, 1.72 mmol), and the mixture was heated to 120° C. for 72 h. The solvent was evaporated under high vacuum and the residue was purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 5% of a 9:1 MeOH: NH4OH solution in CH2Cl2, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (132 mg, 32%) as a light brown foam. 1H NMR (CHLOROFORM-d) δ: 11.05 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.77 (s, 1H), 7.39 (br. s., 1H), 6.96-7.30 (m, 3H), 6.40 (br. s., 1H), 6.10-6.33 (m, 2H), 3.78 (br. s., 4H), 3.52 (br. s., 1H), 0.95-1.70 (m, 17H); LC-MS 481.0 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27]C(OC)=O)[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O.Cl>CO>[ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (259 mg, 0.54 mmol), (prepared as described for the starting material in Example 12), in methanol (15 ml) containing 1M sodium hydroxide (1.6 ml) was stirred at ambient temperature for 1 hour. After addition of water (15 ml), concentrated hydrochloric acid (1 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. After evaporation of methanol, the precipitate was filtered, washed with water and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (192 mg, 80%). m.p. 294-298° C. 1H NMR Spectrum: (DMSOd6) 2.2(s, 3H); 4.05(s, 3H); 5.35(s, 2H); 6.9(d, 1H); 7.12(d, 1H) 7.35-7.5(m, 4H); 7.55-7.6(m, 2H); 8.25(s, 1H); 8.8(s, 1H); 9.7(s, 1H); 11.35(s, 1H) MS-ESI: 406 [MH]+
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:25][CH2:24][C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: NCc1ccncc1
Reactant: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCn1c(=S)nc(NCc2ccncc2)c2[nH]c(C3CC3)nc21

Procedure:
5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxanthine and 21.3 ml (200 mmoles) of 95% 4-picolylamine were heated under argon to 150-5° C. After 14 hours the cooled solution was poured into 100 ml of water, acidified with 19 ml of 10N HCl and 1N HCl to pH 6, where an orange colored gum was formed. With sodium bicarbonate the mixture was neutralized to pH 7. With time the gum crystallized and the solid is collected and washed. The residue was suspended in acetone and the crystals collected: 3.92 (57.6%) of crude product. The filtrate was evaporated to dryness, dissolved in 40 ml of 0.5N NaOH, extracted 4 times with methylene-chloride, and acidified again with 5N HCl to pH 6. Again the gum crystallized over 48 hours and the mixture was neutralized to pH 7 with bicarbonate and the solid collected: 1.75 g (25.7%) of crude product. Both parts were dissolved in 30 ml of methylenechloride and filtered through 30 g of silicagel in a column. 150 mg (2.8%) of starting material was recovered first, then 5.04 g (74.0%) of product was recovered with 5% of methanol, which was dissolved in 32 ml of 1N HCl, treated with 250 mg of charcoal, filtered, and neutralized with 7.5 ml of 2N NaOH and sodium bicarbonate solution to pH 7-8. The water phase was decanted from the gum and the latter washed with water and crystallized from acetone: 4.08 g (59.9%) of thioisoguanine with mp 204-210° C. with decomposition.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)C3CCCCC3)CN2C1=O
Yield: 26.7 %

Procedure:
Prepared by way of method I of example 27 using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (50 mg, 0.088 mmol) and cyclohexanecarbonyl chloride (35 μL, 0.26 mmol). The final trituration (diethyl ether/petroleum ether) and filtration gave 16 mg (27%) of 18-cyclohexanecarbonyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 96.1% pure (HPLC), MS m/z 679 (M−H)−, HRMS: calcd. 679.3013 and found 679.3007 (M−H)−, mp 128-130° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:25])(=O)=O.[OH-].[K+]>C(#N)C>[F:20][C:11]1[C:10]([N:9]([CH3:25])[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (8.75 g, 32.0 mmol) was dissolved in acetonitrile (200 ml). Dimethyl sulfate (4.3 g, 34.1 mmol) and potassium hydroxide (2.63 g, 39.8 mmol) were sequentially added thereto, and the reaction mixture was agitated for 30 minutes at 60° C. The mixture was cooled to room temperature, and then was concentrated. Ethyl acetate was added to the concentration residue, and the mixture was washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and the filtrate was concentrated under reduced pressure. n-hexane was added to the concentration residue, as a result of which 8.00 g (yield: 87%) of the indicated compound was obtained.
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][N:14]=[N+:15]=[N-:16])[CH3:10]
Reactant: CCOC(OCC)C1CN1C(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@@H](CN=[N+]=[N-])NC(C)=O
Temperature: 75 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture containing 3.26 g of 124 and 15 g of sodium azide in 140 ml of DMF was added 140 ml of ZnCl2 (1.0M solution in Et2O), The mixture was stirred at 75° C. for 3 days and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc=3:2) to yield 2.52 g of 125 (62%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26].C(OCC)C>CN(C)C=O>[C:1]1([S:7]([CH2:10][C:11]2([C:14]([O:17][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([CH3:15])[CH3:16])[CH2:13][CH2:12]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C1(CS(=O)(=O)c2ccccc2)CC1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)C1(CS(=O)(=O)c2ccccc2)CC1
Yield: 126.3 %

Procedure:
To a stirred and ice-cooled solution of 8 (4.05 g, 15.9 mmol) and imidazole (2.16 g, 31.7 mmol) in N,N-dimethylformamide was added chlorotriethylsilane (4 mL, 23.8 mmol), and the mixtrue was stirred at ambient temperature overnight. To the mixture was added ice and diethyl ether and the mixture was stirred at ambient temperature for 20 min. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 7.40 g of an oily material, which was purified by column chromatography (silica gel 70 g, 4-12% ethyl acetate in n-hexane) to give 5.89 g (quantitative) of 9, as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ: 0.55 (6H, q, J=7.9 Hz), 0.80(2H, dd, J=6.8 and 4.2 Hz), 0.91(9H, t, J=7.9 Hz), 0.92(2 H), 1.20 (6H, s), 3.39(2H, s), 7.55(2H, t, J=7.4 Hz), 7.64(1H, t, J=7.4 Hz), 7.89(2H, d, J=7.4 Hz)
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[F:19][C:18]1[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccnc1OCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(COc2ncccc2F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 2-(4-bromo-benzyloxy)-3-fluoro-pyridine (2.03 g, 7.20 mmol) described in Manufacturing Example 149-1-1 was added n-Butyl lithium (5.04 mL, 1.6 M hexane solution, 7.92 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78° C. Then, N,N-dimethylformamide (725 μL, 9.36 mmol) was added to the reaction mixture at −78° C., which was stirred for 1 hour and 10 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (887 mg, 53%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:34]([OH:36])=[O:35])[CH2:30][C:27]2([CH2:29][CH2:28]2)[C@@H:26]2[C@H:24]1[C@H:25]2[C:31]([OH:33])=[O:32])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:34]([O:36][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:35])[CH2:30][C:27]2([CH2:29][CH2:28]2)[C@@H:26]2[C@H:24]1[C@H:25]2[C:31]([O:33][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:32])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2)CC2(CC2)[C@H]2[C@H](C(=O)OCc3ccccc3)[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Add cesium carbonate (0.24 g, 730.7 μmol) and benzyl bromide (87.16 μL, 730.7 μmol) to a solution of (1S,2S,5R,6S)-2-(tert-butoxycarbonylamino)spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (0.09 g, 292.29 μmol) in N,N-dimethylformamide (2 mL). Stir at room temperature for 1.5 hours under nitrogen. Quench with water and extract with ethyl acetate. Separate the layers and filter the organics through a hydrophobic frit before concentrating to dryness to yield the crude product (134 mg). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (1:99 to 25:75) to give a clear oil. Purify further by flash chromatography eluting with ethyl acetate:iso-hexane (1:99 10:90) to yield the title product (105 mg, 68%) as a clear oil. MS (m/z): 514 (M+23).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[O:32][CH3:33])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](F)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C(C2C(=O)CCCC=2O)NC(NC2C=C(C(F)(F)[F:54])C=C(F)C=2)=O)=CC=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:25]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]=2[O:32][CH3:33])[NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[C:18]([F:54])[CH:19]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: COC1=C(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1
Product: COC1=C(C(NC(=O)Nc2cc(F)cc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-methoxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 46), using 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)urea (intermediate 45, 378 mg, 0.85 mmol) as starting material. Yield: 367 mg; ESI mass spectrum [M+H]+=462; Retention time HPLC: 1.11 min (Z018_S04).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:14]O>>[CH:5]1([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)CC1CCCC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCCC1
Reaction time: 20 h

Procedure:
Thionyl chloride (7.0 ml) was slowly added to a solution of cyclopentylacetic acid (8.0 ml) in dry methanol (60 ml) and the mixture was stirred at 23° for 20 h. The mixture was concentrated in vacuo; then, the residue was taken up in DCM (100 ml), washed with a 5% sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried and concentrated in vacuo to give the title compound (6.47 g) as a yellow oil, which was not purified further. T.l.c. CH-EA (1:1), Rf =0.79. 1H-NMR: 3.70(s); 2.35(s); 2.4-2.15(m); 1.8(m); 1.7-1.5(m); 1.2(m).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(Nc2ccccn2)c(N)cn1
Reactant: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cn1)nnn2-c1ccccn1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 6-methyl-N4-(pyridin-2-yl)pyridine-3,4-diamine (550 mg, 2.7 mmol) in THF (30 mL) was added acetic acid (0.17 mL, 6.49 mmol) and tert-butyl nitrite (0.54 mL, 4.12 mmol). The reaction was then heated to reflux and stirred overnight. The reaction was concentrated and the residue was purified by chromatography on silica gel (0-10% [2M NH3 in MeOH]CH2Cl2) to give the desired product as a yellow gum (408 mg, 70%). MS (ESI) mass calcd. C11H9N5, 211.09. m/z found, 212.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.44 (d, J=0.9, 1H), 8.67-8.62 (m, 1H), 8.37 (s, 1H), 8.31-8.23 m, 1H), 8.01-7.96 (m, 1H), 7.41-7.35 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[N:9]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:25])=[O:17])[N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Compound 25 of the present invention may be prepared according to Scheme A as follows. A slurry of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (Compound A1, 15.0 g; 52.8 mmol) and 100 μL of dimethylformamide catalyst in 250 mL of anhydrous dichloromethane is allowed to cool to 0° C. Oxalyl chloride (9.2 mL, 105.5 mmol, 2.0 eq.) is added to this slurry over 3 minutes. The reaction mixture is then allowed to warm to room temperature, and is stirred for 16 h. The resultant yellow solution is concentrated in vacuo, azeotroped several times with anhydrous dichloromethane (2×50 mL) and dried under high vacuum for 2 hrs to give 15.5 g of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl chloride (Compound A2) as a white solid (97%): 1H NMR (CDCl3) δ 7.23-7.38 (m, 2H), 7.58-7.71 (m, 2H), 8.22-8.29 (m, 2H), 8.50 (d, J=7.8 Hz, 1H), 8.91 (t, J=1.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10](OS(C(F)(F)F)(=O)=O)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([N:31]=[N+:32]=[N-:33])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(COCc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O

Procedure:
2-Benzyloxymethyl-2-(trifluoromethylsulfonyloxy) -1-phthalimido-ethane (8.5 g, 19.1 mmol) and sodium azide (2.5 g, 38.2 mmol) were stirred in dimethylformamide (80 ml) at 60° C. for 6 hours under nitrogen. TLC in several systems was inconclusive because the Rf of the product was identical to the Rf of the starting material. A small sample was worked up and IR indicated full conversion to the azide. The reaction mixture was transferred to a 1 l extraction funnel and distributed between ethyl acetate (350 ml) and water (130 ml). The aqueous phase was extracted with ethyl acetate (80 ml); the combined organic phases were washed with water (2×120 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to a pale brown oil. Crystallisation was initiated by adding ether (7 ml). Crystals were collected on a glass sinter, washed with cold ether and dried under vacuum for 28 hours. Yield: 4.5 g (70%). The mother liquors were concentrated, diluted with ether and seeded with crystals from the first crop--yielding another 1 g. Total yield: 5.5 g (85%). The structure was confirmed by NMR and IR.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH:21]=[O:22]
Reactant: O=CCCc1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: O=CC(Cl)Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Proline (410 mg, 3.5 mmol) was added to a solution of 3-quinolin-6-ylpropanal (3.27 g, 17.6 mmol) in chloroform (39 mL) at 0° C. followed by addition of N-chlorosuccinimide (2.48 g, 18.5 mmol) and the reaction mixture was slowly warmed to ambient temperature and stirred for 1 h, monitoring by LCMS. The solvent was concentrated under reduced pressure and the residue was purified on a silica gel column with ethyl acetate in hexane (0-50%) to give the desired product. (95%) LCMS: (M+H+H2O)=237.9/239.9.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:13]1=[O:21]
Reactant: Cc1cccc2c1CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cccc2c1CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 44.8 %

Procedure:
A mixture of 0.5 g 4-methyl-1-indanone, 1.37 g oxindole and 3 ml piperidine in 5 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate and concentrated. The resulting solid was precipitated from ethyl acetate/hexanes (2×) followed by methylene chloride/hexanes to afford 400 mg of 3-(4-methyl-indan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.