Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1[C:16](F)=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10]>C1COCC1>[C:9]([C:11]1[C:16]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10]
Reactant: OCC(F)(F)F
Reactant: N#Cc1ncccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ncccc1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A stirred solution of 680 mg (6.80 mmol) of 2,2,2-trifluoroethanol in 25 mL of THF was added 273 mg (6.83 mmol) of sodium hydride (60% dispersion). After 30 min at room temperature, 822 mg (6.73 mmol) of 2-cyano-3-fluoropyridine in 5 mL THF was added via syringe. The reaction was quenched after 1 h, by the addition of 15% K2CO3 aqueous solution. Concentration gave an oil that was partitioned between water and EtOAc. The layers were separated, the aqueous phase was backwashed with EtOAc (2×), and the combined organic layers were dried (MgSO4) and concentrated to an orange oil. The resultant crude residue was chromatographed on SiO2 using 25:75 EtOAc-hexanes to afford the title compound as a yellow oil: 1H NMR (CDCl3) δ8.43 (d,1H, 4.6 Hz), 7.55 (dd, 1H, 4.6, 8.7 Hz), 7.42 (d, 1H, 8.7 Hz), 4.55 (q, 2H, 7.8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[C:32]([N+:40]([O-:42])=[O:41])=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[C:4]([O:30][C:31]1[C:32]([N+:40]([O-:42])=[O:41])=[C:33]3[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]3)[N:3]=[CH:2]2
Reactant: O=[N+]([O-])c1c(O)ccc2[nH]ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2cnc(Oc3ccc4[nH]ccc4c3[N+](=O)[O-])nc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (114 mg, 0.34 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (141 mg, 1.02 mmol), 5-hydroxy-4-nitroindole (60.5 mg, 0.34 mmol) and DMA (8.5 ml) for 5 minutes at ambient temperature. This mixture was then stirred at 90° C. for 4 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica column chromatography using gradient elution with dichloromethane/methanol (100/0 to 95/5) followed by dichloromethane/methanolic ammonia (7M) (95/5) to give a partially purified oil. This oil was further purified by silica column chromatography, gradient elution with ethyl acetate/methanolic ammonia (95/5 to 80/20) to give 6-methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (63 mg, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2].C(ON=O)(C)(C)C.[ClH:31].CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:31])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Br:21])[CH:15]=2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 50 °C

Procedure:
steps 4 and 5—A suspension of 44a (16.1 g, 37 mmol), Fe powder (8.2 g, 148 mmol, Fisher, electrolytically deposited), and NH4Cl (8.0 g, 148 mmol) in absolute ethanol (700 mL) and H2O (180 mL) was heated to reflux for 4 h. The solution was cooled to RT and filtered through CELITE®. The filter cake was washed with chloroform (2×150 mL). The filtrate was washed with aqueous NaHCO3, water, and brine and dried (K2CO3), filtered and the volatiles removed to afford 14.0 g of [4-amino-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44b). The aniline 44b (9.7 g, 24.1 mmol) was dissolved in anhydrous MeCN (100 mL) under nitrogen. This solution was added slowly to a mixture of tert-butyl-nitrite (7.1 mL, 60.3 mmol, assay 90%) and CuCl2 (6.5 g, 48.2 mmol) that had been prepared under nitrogen and warmed to 50° C. The reaction temperature was maintained at 50° C. for 15 min, cooled to 0° C. and poured into 5% aqueous HCl solution (80 mL) and Et2O (150 mL). The mixture was extracted with EtOAc (3×150 mL), the combined extracts were washed with brine and dried (MgSO4), filtered and the volatiles were removed. The residual oil was purified by flash SiO2 chromatography eluting with EtOAc/hexanes (0% to 10% EtOAc) to afford 6.25 g of [4-chloro-3-(3-bromo-5-chloro-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (44c) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.Cl.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[C:35]([F:41])[CH:34]=[CH:33][C:32]=1[CH2:42][NH2:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:30][C:31]1[C:36]([C:37]([F:39])([F:40])[F:38])=[C:35]([F:41])[CH:34]=[CH:33][C:32]=1[CH2:42][NH:43][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][C:9](=[O:10])[N:2]1[CH3:1]
Reactant: NCc1ccc(F)c(C(F)(F)F)c1Cl
Reactant: CN1C(=O)CC[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-methyl-5-oxoproline (0.057 g, 0.4 mmol, prepared in a manner analogous to that described above for example 51) dissolved in dichloromethane (4 ml) and treated with 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.104 g, 0.42 mmol). {[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]methyl}amine hydrochloride (0.105 g, 0.4 mmol, prepared as described below) was then added and the mixture was stirred at room temperature for 4 hrs. The mixture was treated with saturated aqueous sodium hydrogen carbonate (10 ml) and stirred for 5 minutes. The organic phase was separated using a hydrophobic frit and then washed with 2N aqueous hydrogen chloride (2×10 ml). Evaporation of the organic phase then gave pure N-{[2-chloro-4-fluoro-3-(trifluoromethyl)phenyl]methyl}-1-methyl-5-oxoprolinamide (0.106 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>[Fe].C1(C)C=CC=CC=1>[CH3:14][C:13]1[O:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2cc(C)oc12
Temperature: 70 °C
Yield: 76.6 %

Procedure:
A mixture of 2.02 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate, 4.75 g of iron powder and 40 ml of acetic acid is heated at 70° C. for 25 minutes. Toluene is added to the reaction mixture, and the mixture is filtered and washed with chloroform. The washings and the filtrate are combined and the mixture is evaporated under reduced pressure to remove solvent. 50 ml of toluene, 2.43 g of p-toluenesulfonic acid monohydrate and 1 ml of water are added to the residue. The mixture is refluxed for 50 minutes and further refluxed 20 minutes while removing water azeotropically. Ethyl acetate is added to the reaction mixture. The mixture is washed successively with water and an aqueous saturated sodium bicarbonate solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 1.24 g of methyl 2-methylbenzofuran-7-carboxylate as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(O)=O.C(Cl)(=O)C(C)(C)C.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][CH2:30]1.C(O)C.Cl>C(OCC)(=O)C.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)COC1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: NC(=O)O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Yield: 91.9 %

Procedure:
55.8 g (250 mmol) of (S)-2-benzyloxycarbonylaminopropionic acid (obtainable from the corresponding aminocarboxylic acid by protection of the amino function with a benzyloxycarbonyl derivative; Bodansky et al., 1 oc. cit.) were dissolved in 560 ml of ethyl acetate (Fluka) while stirring and under argon, cooled to 0 to 5° C. and treated with 31.0 ml (250 mmol) of pivaloyl chloride (Fluka). 35.0 ml of triethylamine (Fluka) were added dropwise to the light yellowish solution within 30 minutes, with the temperature being held at 0 to 5° C. A white suspension formed. The white precipitate was filtered off through a pre-cooled glass filter (G3) and the filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C., Fluka). To the combined filtrates, a clear, colourless liquid which contained the anhydride, were added 55.9 g (250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride (obtainable from the corresponding tert.-butyl compound (Alig et al., loc. cit.) by trans-esterification with ethanol/hydrochloric acid) and 66.6 g (250 mmol) of Na3PO4.3H2O. The white suspension was treated at 5 to 10° C. 500 ml of deionised water within 30 seconds under argon and while stirring vigorously, with the temperature rising to 20° C. The colourless two-phase system was stirred vigorously at 20 to 25° C. for one hour. Subsequently, the aqueous phase was separated and the organic phase was washed with 1M sodium bicarbonate solution and then with 1N aqueous ammonia solution. The organic phase was dried over about 50 g of sodium sulphate, filtered and the filter cake was washed with about 100 ml of ethyl acetate. The combined filtrates were evaporated in a rotary evaporator and the oily residue was taken up with 100 ml of ethanol. The clear solution was evaporated at 50°/20 mbar to give 90.2 g (92 wt. %) of ethyl (S)-[1-(2-benzyloxycarbonylaminopropionyl)-piperidin-4-yloxy]-acetate as a clear, colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][NH:30][CH3:31].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:29][N:30]([CH3:31])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: CNC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 85.7 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), dimethylamine hydrochloride (198 mg, 2.42 mmole), N-ethyldiisopropylamine (564 ul, 3.23 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4,1-trimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (138 mg, 85.7%) as a white solid. Mp.: 237-240° C. MS: m/z=399.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])[C:9](=[O:18])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:7]=1)=O)C.C([O-])(=O)C.[NH4+:27]>CO>[C:19]([N:8]1[C:9](=[O:18])[N:10]2[CH:11]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[NH:27][C:4](=[O:3])[C:6]2=[N:7]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1nn(C(C)(C)C)c(=O)n1CC(=O)C(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A solution of 8.60 g of the product of Step C and 21.30 g of ammonium acetate in MeOH was heated in a sealed system at 100° C. for 24 h. The solution was cooled to ambient temperature and concentrated to leave an oil that was partitioned between EtOAc and water. The aqueous layer was acidified to pH 5 with concentrated HCl and then extracted with EtOAc. The combined organic layers were washed with sat. sodium chloride, dried over sodium sulfate, filtered, and concentrated to provide 2,6-di-tert-butyl-2H,7H-[1,2,4]triazolo[4,3-a]pyrazine-3,8-dione as a white solid. MS (M+H+)=265.3.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(Cl)c3)nc2n(CCC)c1=O
Yield: 68 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.51 g (19.2 mmol) of 3-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 4.44 g (yield 67%) of Compound 38 as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[CH:4][N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOP(=O)(CCCCONc1ncnc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(CCCCOn1cnc2c(Cl)ncnc21)OCC
Temperature: 120 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Chloro-6-[[4-(diethoxyphosphoryl)butoxy]amino]-5-formamidopyrimidine (0.470 g, 1.24 mmol) was dissolved in diethoxymethyl acetate (4 ml) and the resulting solution was stirred at 120° C. for 2 hr. The reaction mixture was then allowed to cool and the solution evaporated to dryness. The residue was dissolved in methanol: conc. aq. NH3 solution (9:1, 5 ml) and stirred at 23° C. for 10 min. The solvents were evaporated under vacuum and the product was purified by column chromatography on silica gel (eluted with chloroform: ethanol, 98:2) to yield the title compound (0.360 g, 81%). 1H NMR: δH [(CD3)2SO] 1.34 (6H, t, J=7Hz, (OCH2CH3)2), 1.89 (6H, m, CH2CH2CH2P), 4.12 (4H, m, (OCH2CH3)2), 4.51 (2H, t, J= 6Hz, NOCH2), 8.28 (1H, s), 8.78 (1H, s). m/z (FAB positive ion) 363 (MH+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:27])=[C:6]([CH3:26])[C:7]([CH3:25])=[N:8]2.[H-].[Na+].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([C:35]([O:27][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:12]([O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[C:3]=3[C:2]([F:28])([F:1])[F:29])[N:8]=[C:7]([CH3:25])[C:6]=2[CH3:26])=[O:36])[CH2:34][CH2:33]1
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Reactant: O=C(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
5-Trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (30 mg) prepared in Synthesis Example 3 was dissolved in 1 mL of dimethylformamide. Under ice cooling, 4.3 mg of 60% sodium hydride was added to the solution, and the mixture was stirred for one hr. Thereafter, 10.4 mg of cyclopropanecarbonyl chloride was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to 5 mL of water, and the mixture was extracted with 5 mL of ethyl acetate. The ethyl acetate layer was washed with a saturated sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and was then concentrated under the reduced pressure. The crude product thus obtained was purified by chromatography on silica gel (Mega Bond Elut SI (Varian) 10 mL, solvent: n-hexane/ethyl acetate) to give 4-Cyclopropanecarbonyloxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline (13.8 mg, yield 39.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH2:10])=[O:4].[N:11]([O-])=O.[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1scnc1N
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1scnc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 4-aminothiazole-5-carboxylic acid methyl ester (15.3 g) in concentrated hydrochloric acid (90 ml) there was added dropwise an aqueous solution (10 ml) containing sodium nitrite (7.32 g) at 0-10° C. The mixture was then stirred at 0° C. for 30 minutes. To this mixture there was added dropwise a concentrated hydrochloric acid solution (100 ml) containing stannous chloride (73.2 g) at 0-10° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was filtered, and the filtrate was carefully added to a suspension of potassium carbonate and celite in ethyl acetate (3 liters) with stirring, with regular addition of potassium carbonate to prevent solution acidic. After adding the filtered substance to a solution of this mixture in ethyl acetate, it was rendered basic with a 5N aqueous sodium hydroxide solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A) was separated off. The remaining suspension was filtered through celite and the filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (500 ml) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layer, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (11.6 g) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OC[C:32]4(C=3C=C12)[C:40]1[C:35](=CC=[CH:38][CH:39]=1)N[C:33]4=[O:41].BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[O:41]1[CH2:38][CH2:39][CH:40]([CH2:35][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH2:32][CH2:33]1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CC2CCOCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (25%) as a white solid: mp 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.34-6.85 (m, 4H), 6.50 (s, 1H), 6.08 (s, 1H), 5.85 (ABq, 2H), 4.76 (ABq, 2H), 4.18-3.86 (m, 2H), 3.63 (ddd, 2H), 3.34 (t, 2H), 2.38-1.92 (m, 1H), 1.70-1.36 (m, 4H); MS (ES+) m/z 380.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][C:20]([CH3:27])=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:22]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:28]>C(O)=O>[CH2:23]([C:21]1[CH:22]=[C:18]([C:15]2[O:14][C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]([CH3:28])[CH:8]=3)=[N:17][N:16]=2)[S:19][C:20]=1[CH3:27])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)CCc1c(C)cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc1C
Solvent: O=CO
Product: Cc1cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid (763 mg, 3.59 mmol) in DCM (18 mL), DIPEA (542 mg, 4.20 mmol) is added followed by TBTU (1.27 g, 3.95 mmol). The mixture is stirred for 15 min before Intermediate C1 (1.0 g, 3.59 mmol) is added. Stirring is continued at rt for 16 h. The mixture is diluted with diethyl ether, washed with 1 N aq. NaOH solution, then 1 N aq. HCl solution followed by brine, dried over Na2SO4, and filtered. The solvent is evaporated to give 3-{4-[N′-(4-isobutyl-5-methyl-thiophene-2-carbonyl)-hydrazinocarbonyl]-2,6-dimethyl-phenyl}-propionic acid (1.66 g) as a colourless foam; LC-MS: tR=1.09 min, [M+1]=473.48. To a solution of this material in THF (15 mL) Burgess reagent (1.26 g, 5.27 mmol) is added. The mixture is heated to 110° C. for 3 min in a microwave oven. The mixture is cooled to rt, diluted with diethyl ether and washed with 1 N aq. NaOH. The organic extract is dried over Na2SO4, filtered and concentrated to give 3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionic acid methyl ester (1.26 g) as a yellow oil that slowly solidifies; LC-MS: tR=1.24 min, [M+1]=455.21. A suspension of this ester in formic acid (20 mL) is stirred at rt for 3 h. The formic acid is evaporated and the residue is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionic acid as a pale yellow solid; LC-MS: tR=1.07 min, [M+1]=399.16.
Reaction SMILES: [H-].[Na+].[Cl-].[PH4+].[C:5]([CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:6].[Cl-].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]=O)=[N:33][CH:34]=1.CO>O1CCCC1.CN(C)C=O>[Cl:28][C:29]1[CH:30]=[CH:31][C:32](/[CH:35]=[CH:7]/[C:5]#[N:6])=[N:33][CH:34]=1
Reactant: O=Cc1ccc(Cl)cn1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#C/C=C/c1ccc(Cl)cn1
Reaction time: 48 h
Yield: 55.2 %

Procedure:
To a suspension of 1.97 g, (0.045 mol) sodiumhydride (60% in oil) in 60 ml tetrahydrofurane and 60 ml dimethylformamide were added 15.25 g (0.045 mol) (cyanomethyl)triphenyl-phosphonium phosphonium chloride. After stirring for 1 hour at room temperature a solution of 6.39 g (0.045 mol) 5-chloro-2-pyridinecarboxaldehyde in 25 ml tetrahydrofurane were added and stirring was continued for 2 days. Then 15 ml methanol were added, the solvents were evaporated and the residue was chromatographed on aluminiumoxide with ethylacetate/hexane 3/7 to yield 4.09 g (55%) (E)-3-(5-chloro-pyridin-2-yl)-acrylonitrile as white solid. MS m/e (%): 164 (M30 , 100), 137 (17), 113 (45).