Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([NH2:11])[N:5]=1.FC(F)(F)S(O[CH2:18][CH3:19])(=O)=O.CO>CN(C=O)C>[CH2:18]([O:10][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([NH2:11])[CH:7]=1)[CH3:19]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: Nc1cc(O)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1cc(N)nc(N)n1
Reaction time: 0.5 h

Procedure:
174 mg of sodium hydride (60% in mineral oil, 4.36 mmol) are added in portions under an argon atmosphere to a vigorously stirred solution of 500 mg (3.96 mmol) of 2,6-diaminopyrimidin-4-ol in 10 ml of DMF. After 30 min, 700 μl (5.15 mmol) of ethyl trifluoromethanesulfonate are added dropwise, and the solution is stirred for a further 20 min. Methanol (1 ml) is then added to the reaction mixture, which is directly purified by preparative HPLC. Combining the product fractions and removing the solvent result in 370 mg (64% of theory) of the title compound as a white solid.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C[C:32]1[NH:36][CH:35]=[N:34][C:33]=1[CH2:37][CH2:38][C:39]([OH:41])=O.FC(F)(F)C(O)=O.[NH2:49][CH:50]([CH2:77][C:78]1[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][CH:79]=1)[C:51]([N:53]1[CH2:56][C:55]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[CH3:63])[CH2:54]1)=[O:52].[OH-].[Na+]>CN(C)C=O>[CH2:70]([O:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:55]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[CH3:63])[CH2:54][N:53]([C:51](=[O:52])[C@H:50]([NH:49][C:39](=[O:41])[CH2:38][CH2:37][C:33]2[N:34]=[CH:35][NH:36][CH:32]=2)[CH2:77][C:78]2[CH:79]=[CH:80][C:81]([O:84][CH3:85])=[CH:82][CH:83]=2)[CH2:56]1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: Cc1[nH]cnc1CCC(=O)O
Reactant: COc1ccc(CC(N)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@@H](NC(=O)CCc2c[nH]cn2)C(=O)N2CC(OCCCCOCc3ccccc3)(c3ccccc3C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
910 mg (2.83 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 0.8 ml (5.67 mmol) of triethylamine are added to a solution of 500 mg (1.89 mmol) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 5 ml of N,N-dimethylformamide. After 60 minutes, 1.4 g (1.89 mmol) of 2-amino-1-[-3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate dissolved in 5 ml of N,N-dimethylformamide are added. The reaction medium is stirred at room temperature for 72 hours, aqueous 1N sodium hydroxide solution is then added and the medium is extracted twice with 50 ml of a 2/8 heptane/ethyl acetate mixture. The organic phase is washed with aqueous 1N sodium hydroxide and then with aqueous 1N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel eluted with a 90/10 dichloromethane/methanol mixture. 1 g of N-[(R)-2-[3-(4-benzyloxybutoxy)-3-o-tolylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide is obtained in the form of a white solid, in a yield of 84%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[N:27]=[C:28]([CH3:32])[N:29]([CH3:31])[CH:30]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH2:35]1CCN2C(=NCCC2)C[CH2:36]1.C(I)C.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:35]([N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([O:8][Si:9]([CH2:14][CH3:15])([CH2:10][CH3:11])[CH2:12][CH3:13])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:33])[F:34])[CH2:21][CH2:20]1)[S:23]([C:26]1[N:27]=[C:28]([CH3:32])[N:29]([CH3:31])[CH:30]=1)(=[O:25])=[O:24])[CH3:36]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2cn(C)c(C)n2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN([C@H]1CC[C@H](C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)CC1)S(=O)(=O)c1cn(C)c(C)n1
Reaction time: 0.25 h

Procedure:
A solution of 150 mg (0.28 mmol) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid [4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide (example 9.1) in 1 mL of DMF was treated with 0.66 mL (0.44 mmol) of DBU, stirred for 15 min and treated with 0.9 mL (0.58 mmol) of ethyliodide. The mixture was stirred at 60° C. for 4 hrs and distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 150 mg (95%) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a light yellow liquid, MS: 566 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[Cl:19].ClC1C=CC=CC=1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[Cl:19].[C:27]1([O-:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [Br-]
Solvent: O
Solvent: Clc1ccccc1
Product: [O-]c1ccccc1
Temperature: 60 °C

Procedure:
29.75 g of 1-amino-2-chloro-4-hydroxyanthraquinone (titer 92%), 120 ml of chlorobenzene, 5 g of tetrabutylammonium bromide, 10.8 g of phenol and 6.48 g of potassium hydroxide are heated within 1 hour, with stirring, to boiling temperature (131°-133° C.), and then stirred for 5 hours at the boiling temperature. Reaction water occurring during the process is distilled off at the side, together with about 10 ml of chlorobenzene. The reaction mixture is subsequently cooled to 60° C., and 50 ml of methanol are added; the precipitate is filtered off, washed with methanol and water and then dried. The yield is 29.9 g of 1-amino-4-hydroxy-2-phenoxyanthraquinone (90.3% of theory). The product dyes polyester in exactly the same manner as the commercial product does, produced from 1-amino-2-chloro-4-hydroxyanthraquinone in phenol in the presence of phenolate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:24](F)=[C:23]3[C:18]([C:19](=[O:36])[C:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][N:22]3[C@@H:26]([CH3:30])[CH2:27][NH:28][CH3:29])=[CH:17][C:16]=2[F:37])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:24]3[N:28]([CH3:29])[CH2:27][C@H:26]([CH3:30])[N:22]4[CH:21]=[C:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19](=[O:36])[C:18]([C:23]=34)=[CH:17][C:16]=2[F:37])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn([C@@H](C)CNC)c2c(F)c(C3(NC(=O)OCc4ccccc4)CC3)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)N(C)C[C@@H]2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 240 mg of ethyl (S)-7-(1-benzyloxycarbonylaminocyclopropyl)-6,8-difluoro-1-[2-(N-methylamino)-1-methylethyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate. To the resulting solution was added 80 mg of potassium carbonate. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 3 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 120 mg (yield: 52.2%) of ethyl (S)-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-1,3-dimethyl-7-oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]-quinoxaline-6-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][N:10]=1.[F:18][C:19]([F:33])([F:32])[C:20](=[N:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[NH2:21].N1C=CC=CC=1>ClCCl.O1CCOCC1.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[N:23]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[N:22]=[C:20]([C:19]([F:18])([F:32])[F:33])[N:21]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reactant: COc1ccc(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(OC)nc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
Under ice-cooling, oxalyl chloride (0.206 mL, 2.4 mmol) and then cat. dimethylformamide were added to a suspension of 6-methoxynicotinic acid (367 mg, 2.4 mmol) in 3 mL of dichloromethane. The mixture was stirred at room temperature for 1.5 hour. The solvent was removed under reduced pressure and the residue was azeotropped with dioxane. A solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (466 mg, 2.0 mmol) and pyridine (0.194 mL, 2.4 mmol) in 5 mL of dioxane was added to a suspension of the residue in 1 mL of dioxane. The mixture was refluxed with stirring for 4 hours. After cooling, the solvent was removed under reduced pressure. The desired product was purified by silica gal column chromatogaraphy (hexane-ethyl acetate 4:1) to give 2-methoxy-5-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridine (90 mg, 14.9% yield).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:34])[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)[CH3:23])[C:16]=3[Cl:35])[C:7]2=[N:6][C:5]=1[CH3:36].[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C(Cl)Cl>[C:37]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]([N:22]([C:17]1[C:16]([Cl:35])=[C:15]([C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:14][O:13][C:12]1[C:7]2[N:8]([C:4]([Br:3])=[C:5]([CH3:36])[N:6]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:23])=[O:34])=[O:33])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@@H]4CCCN4)c3Cl)cccn2c1Br
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@H]1C(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-(L-prolylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine dihydrochloride (40 mg), acetic anhydride (0.01 ml), pyridine (0.03 ml) and methylene chloride (2 ml) was stirred for 2 hours at ambient temperature. The mixture was washed with water twice, dried over magnesium sulfate, and concentrated in vacuo to give 8-[3-[N-(acetyl-L-prolylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (31 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8](=[O:25])[C:9]2[C:10]([N:24]=1)=[N:11][C:12]1[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH2:22]C)[CH:13]=1)=[O:5])C.COC1C=C(C([N+]([O-])=O)=CC=1OCC)C=O>>[CH3:20][O:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:21][CH3:22])[N:11]=[C:10]1[N:24]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8](=[O:25])[C:9]1=[CH:18]2
Reactant: CCOC(=O)c1nc2nc3cc(OCC)c(OC)cc3cc2c(=O)[nH]1
Agent: CCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Product: COc1cc2cc3c(=O)[nH]c(C(=O)O)nc3nc2cc1OC

Procedure:
Ethyl-7-methoxy-8-ethoxypyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate is similarly prepared according to procedures A-C, beginning with 3-methoxy-4-ethoxy-6-nitrobenzaldehyde. It melts at 264°-265° C. (dec.)
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+:13].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>O>[K+:13].[K+:13].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([S:14]([OH:16])(=[O:18])=[O:15])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccc(O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(S(=O)(=O)O)cc(O)c1O
Temperature: 20 °C

Procedure:
2,3-Dihydroxybenzoic acid (15.4g, 0.1 moles) was dissolved in small portions at 5° C. in 80 ml of sulfuric acid containing 30% sulfur trioxide. The mixture was allowed to warm to 20° C. over 1 h and was then poured slowly into 1L of vigorously stirred ice water. The pH was adjusted to 4.5 with 30% potassium hydroxide and the solid formed was removed by filtration. The filtrate was diluted with a 1.5 fold volume of methanol and filtered again. This filtrate was evaporated to 200 ml and the pH was adjusted to 6.0 with potassium hydroxide. Acetone (500 ml) was added and the resulting white precipitate was filtered and dried to give 18 g of crude product. Chromatography of this solid on HP20 in water gave 12.8 g of pure title compound after lyophilization.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:27]>[C].[Pd].C(O)C.O>[ClH:27].[N:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCNCC1

Procedure:
26.4 Grams of 6-[(4-benzyl-1-piperazinyl)carbonyl]carbostyril was suspended in 800 ml of a mixed solvent of ethanol-water and the pH of the suspension was adjusted to about pH 1 by adding concentrated hydrochloric acid. To this mixture was added 2.6 g of 5% palladium-carbon and catalytic reduction was conducted under a normal pressure at 45°-65° C. After the reaction was completed, the catalyst was removed by filtration and the solvent was removed by distillation under a reduced pressure. The residue obtained was crystallized by adding acetone and the crude crystals thus obtained were recrystallized from ethanol-water to obtain 19.9 g of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride. Colorless granular crystals. Melting point: over 300° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C:29](=[O:33])[NH:30]2)=[CH:26][CH:25]=1.N1CCCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2/[CH:21]=[C:28]2\[C:29](=[O:33])[NH:30][C:31]3[C:27]\2=[CH:26][CH:25]=[C:24]([Cl:23])[CH:32]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C=O)CC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 92.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-(4-chloro-2-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (8 g, 25 mmol) was reacted with 6-chlorooxindole (4.1 g, 25 mmol) and pyrrolidine (1.8 g, 25 mmol) in methanol (50 mL) to give the title compound as a yellow solid (11 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[PH:9](=[O:12])([OH:11])[OH:10].[CH2:13]([C:15](CC)([CH:17]([O:42][CH3:43])[C:18]1[N:22]=[CH:21][N:20]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:56])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[PH:9](=[O:10])([OH:12])[OH:11].[F:56][CH2:13][CH2:15][CH:17]([O:42][CH3:43])[C:18]1[N:22]=[CH:21][N:20]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(C)(CC)C(OC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)[N-]C(C)C
Agent: O=[PH](O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(CCF)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of lithium diisopropylamide (1.75 ml, 1.5M in cyclohexane) was added dropwise, with stirring, to a solution of diethyl 3-methoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.65 g, prepared as described in Example 25) in dry tetrahydrofuran (15 ml), under nitrogen and with temperature maintained below -60° C. After a further twenty minutes, a solution of N-fluorobenzenesulphonimide (0.51 g) in tetrahydrofuran (15 ml) was added dropwise to the stirred reaction mixture at below -60° C. The mixture was stirred for a further two hours at -78° C., allowed to warm to room temperature and to stand overnight. It was then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl (1RS,3RS; 1RS,3SR)-1-fluoro-3-methoxy-3(1-trityl-1,2,4--triazol-3-yl)propane phosphonate (0.21 g) as an oily mixture of diastereoisomers in a ratio of 3:1 or 1:3. NMR (CDCl3): δ1.3(6H,2t), 2.5-2.7(2H,m), 3.3(3H,2xs), 4.2(4H,m), 4.6-4.8(2H,m), 7.1-7.3(15H,m), 8.0(1H,2xs). M/S: M+ 537. The structures were confirmed by 19F and 13C NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(F)ccc2C1=O
Yield: 68 %

Procedure:
A solution of 20.0 g of 5-fluoro-1-indanone, 27.5 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxy-propane was boiled under reflux for 63 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 18.6 g (68%) of (RS)-2-(2-buten-1-yl)-5-fluoro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.CI>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16]([CH3:1])([CH3:20])[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C(=O)O)c1cccc(Br)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCc1ccccc1
Product: CC(C)(C(=O)O)c1cccc(Br)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of lithium diisopropylamide in tetrahydrofuran/n-heptane/ethylbenzene (1.8 M, 17 mL) at 0° C. is added a solution of 2-(3-bromo-phenyl)-propionic acid (3 g, 13.9 mmol) in tetrahydrofuran (5 mL) dropwise during 15 minutes. The mixture is stirred for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in tetrahydrofuran (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2 N HCl, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2 N HCl, extracted three times with 2 N NaOH (50 mL). The combined NaOH layers are acidified with 6 N HCl to pH=1 and extracted three times with ether (75 mL). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91%), which is used without further purification. LC/MS: 243 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:39][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:41]3)[O:35][N:34]=2)=[CH:27][C:26]=1[NH:25][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:13]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: Cc1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(C)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (24j) (35 mg, 0.196 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (17 uL, 0.206 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (28 mg, 0.098 mmol) in anhydrous pyridine (1.5 mL) was stirred at room temperature for 2 hours. The solvent was concentrated and the crude product was purified by silica chromatography to give methyl 3-(3-(4-methyl-3-(6-methylimidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F62). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.36 (s, 1H), 8.67 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.85 (dd, J=2.0, 8.0 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.57 (dd, J=1.2, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.24 (m, 1H), 4.22-4.17 (m, 2H), 3.59 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H). MS m/z 447.17 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[N:18][CH:19]=2)=[O:13])[CH2:10][CH2:9]1.C(N(C(C)C)C(C)C)C.Cl[C:45]1[N:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][N:46]=1>CN(C)C=O>[CH:8]1([N:11]([CH:29]2[CH2:30][CH2:31][N:32]([C:45]3[N:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][N:46]=3)[CH2:33][CH2:34]2)[C:12]([C:14]2[CH:19]=[N:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[N:16][CH:15]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4ncc(CC)cn4)CC3)cn2)cn1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide trifluoroacetic acid salt (48 mg), ethyldiisopropylamine (52 μL), and 2-chloro-5-ethylpyrimidine (14 mg) in N,N-dimethylformamide (2.0 mL) is stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture is purified by HPLC (H2O/MeOH/TFA) to give the title compound. LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=474 [M+H]+.