Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.C(N(CC)CC)C.[Br:14][CH:15]([CH3:19])[C:16](Br)=[O:17]>C(Cl)(Cl)Cl>[Br:14][CH:15]([CH3:19])[C:16]([NH:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1)=[O:17]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1ccon1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)Nc1ccon1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−40° C.) stirring solution of 3-aminoisoxazole (0.88 ml, 11.9 mmol) and triethylamine (1.99 ml, 14.3 mmol) in chloroform (6 ml) is added slowly, 2-bromopropionyl bromide (1.37 ml, 13.1 mmol) in chloroform (6 ml). The reaction mixture is stirred at −40° C. for 30 minutes, and then allowed to warm to room temperature. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with saturated sodium hydrogen carbonate, dried over Na2SO4 and the solvent removed in vacuo to afford the titled compound as a yellow oil.
Reaction SMILES: C([O:8][P:9]([O:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]3[CH:33]=[N:34][C:35]([NH:47][C:48](=[O:52])[NH:49][CH2:50][CH3:51])=[CH:36][C:37]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=3)=[CH:29][N:30]=2)[C:25](=[O:53])[C:24]([C:54]([OH:56])=[O:55])=[CH:23]1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.C[Si](Br)(C)C.O>ClCCl.CO>[CH2:50]([NH:49][C:48]([NH:47][C:35]1[N:34]=[CH:33][C:32]([C:28]2[CH:27]=[C:26]3[C:31](=[N:30][CH:29]=2)[N:22]([CH2:21][CH2:20][O:19][P:9]([OH:11])([OH:10])=[O:8])[CH:23]=[C:24]([C:54]([OH:56])=[O:55])[C:25]3=[O:53])=[C:37]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[N:42]=2)[CH:36]=1)=[O:52])[CH3:51]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn1
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCOP(=O)(O)O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
1-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Example 13, 220 mg, 0.27 mmol) was dissolved in dry dichloromethane (30 mL), the reaction mixture was cooled to 0° C. Trimethylsilyl bromide (83.31 mg, 0.54 mmol) was added and the mixture was stirred for 2 h at room temperature. A solid formed on the walls of round bottom flask. The solvent was decanted and the solid was washed with ethyl acetate (20 mL) to give crude compound. The crude compound was dissolved in methanol (20 mL) and water (50 mL) was added to precipitate a solid compound which was filtered and dried to give crude compound. The crude compound was purified preparative HPLC to afford 45 mg (25.9%) of 6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1-[2-(phosphonooxy)ethyl]-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=CC(S(O)(=O)=O)=CC=2O)[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[N:21]1C(F)=NC(F)=NC=1F.NC1C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+]>O.Cl>[NH2:21][C:5]1[CH:6]=[CH:11][CH:2]=[CH:3][C:4]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Fc1nc(F)nc(F)n1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: Cl
Agent: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Solvent: O
Product: Nc1ccccc1S(=O)(=O)O
Reaction time: 1 h

Procedure:
12.8 g of 1-amino-8-hydroxynaphthalene-3,6-disulphonic acid in 200 ml of water are subjected to a condensation reaction with 3.8 ml of cyanuric fluoride at pH 4.0-4.5 and at 0°-5° as described in Example 3. 7.0 g of 4-aminobenzenesulphonic acid are added to the resulting solution and the pH value in the reaction mixture is kept at 5.5-6.0. The mixture is subsequently stirred at 0°-5° for one hour. A diazonium salt suspension which has been obtained from 7.0 g of 2-aminobenzenesulphonic acid in 100 ml of water and 20 ml of concentrated hydrochloric acid with 20 ml of 2N sodium nitrite solution at 0°-5° is then allowed to run in and the pH value is kept at 7.0-7.5 and the temperature at 0°-10° for the coupling. Finally, the temperature is increased to 20° in the course of 1 hour. After the coupling has ended, the dyestuff is salted out by adding 100 g of sodium chloride, filtered off and washed with 20% strength sodium chloride solution until the runnings are almost colourless. The dyestuff, which, in the form of the free acid, corresponds to the formula ##STR25## is dried at 40° in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.Cl[C:15]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[F:24][C:22]1[C:21]([F:25])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:7][C:5]2[N:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:23]=1
Reactant: Cc1cc(N)n(-c2ccncc2)n1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2ccncc2)n1
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-ylamine (5.80 g, 33.3 mmol), 2-chloro-4,5-difluorobenzoic acid (5.78 g, 30.0 mmol), copper acetate (II) (0.545 g, 3.00 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux under an argon atmosphere for 2 hours. The solution was allowed to cool to room temperature and poured into water. The solution was made weakly acidic by the addition of 1N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give crude 4,5-difluoro-2-[[3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (6.44 g, 65% yield). A solution of the compound (5.50 g, 16.7 mmol) in phosphorous oxychloride (10 mL, 107 mmol) was heated under reflux for 3 hours. The solution was allowed to cool to room temperature, and the resulting residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform to 1% methanol/chloroform) to give the title compound (0.88 g, 16% yield).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:39])[CH:13]([N:15]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH3:14])=[CH:8][CH:7]=1)(=O)=O.O.[OH-].[K+].Cl>CC(C)=O>[CH2:32]([N:15]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1)[CH:13]([CH3:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C(=O)c1ccc(OS(C)(=O)=O)cc1)N(CCc1ccc(OCc2ccccc2)cc1)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C(=O)c1ccc(O)cc1)N(CCc1ccc(OCc2ccccc2)cc1)Cc1ccccc1
Temperature: 59 °C
Yield: 96.7 %

Procedure:
50 g of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B), 100 ml of water, 355 ml of acetone and 18.4 g of potassium hydroxide are introduced into a one liter glass reactor at room temperature. The mixture is heated to reflux temperature (about 59° C.) and kept at such a temperature for two hours. Subsequently, the mixture is cooled down to 45-50° C. and 30% hydrochloric acid is added until a pH of around 7 is obtained. The lower phase is separated and the organic phase is diluted with 100 ml of water. A suspension is obtained that is cooled down to 0° C. The solid is isolated through filtration and washed and then vacuum dried at 40° C. 41.4 g of 2-{Benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C) as a white solid, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[CH3:24].[C:25](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:25])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[CH3:24]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(4-Chloro-6-fluoro-3-methyl-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.1 g) was dissolved in dimethylformamide (100 ml) and potassium carbonate (5.7 g, 41.3 mmol) and dimethylsulfate (11.9 g, 55.1 mmol) were added. Solution was stirred at ambient temperature for 14 hr, water was added and product extracted with ethyl acetate. The title compound was separated by column chromatography on silica gel (eluent, hexane-ethyl aceatate, 9:1; 8.5 g).
Reaction SMILES: [OH:1][C:2]([CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([CH3:7])[C:3]([F:6])([F:5])[F:4].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[OH:1][C:2]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([CH3:7])[C:3]([F:5])([F:6])[F:4]
Reactant: CC(O)(C1CCC(O)CC1)C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(O)(C1CCC(=O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.8 g (0.089 mol) of 4-(2-hydroxy-1,1,1-trifluoro-2-propyl)cyclohexanol were placed in a mixture of 350 ml of acetone and 20 ml of water, and 50 ml of Jones' reagent were added dropwise at from 10° to 15° C. The mixture was subsequently stirred at room temperature for 1 hour, 10 ml of isopropanol were added, and after a further 30 minutes the mixture was neutralized with 40 g of sodium bicarbonate. It was then filtered, the filtrate was concentrated and the residue was taken up with water/diethyl ether. After drying and concentration of the organic phase, 11.1 g (59.6% of theory) remained of a colorless product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:39][NH2:40])[C:32]2[O:37][CH2:36][O:35][CH2:34][C:33]=2[CH:38]=1>>[F:28][C:29]1[CH:30]=[C:31]([CH2:39][NH:40][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[C:32]2[O:37][CH2:36][O:35][CH2:34][C:33]=2[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCc1cc(F)cc2c1OCOC2
Product: Fc1cc(CNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c2c(c1)COCO2

Procedure:
Intermediate 7 was coupled with C-(6-fluoro-4H-benzo[1,3]dioxin-8-yl)-methylamine following procedure F and the resulting intermediate 4eprotected following procedure G. LC-MS showed the product had the expected M+H+ of 436. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.6 (s, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.8 (t, 1H) 7.4 (d, 1H), 7.2 (d, 1H), 7.1 (d, 2H), 6.6 (d, 2H), 3.4 (d, 2H), 2.8 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH:15]([C:21]([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.N1CCCCC1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCS(=O)(=O)c1ccc(OC)cc1)C(=O)[O-]
Agent: C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCS(=O)(=O)c1ccc(OC)cc1)C(=O)OCC

Procedure:
A mixture of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid, monoethyl ester (1.1 g, 3.2 mmol), paraformaldehyde (0.11 g, 3.5 mmol), piperidine (0.03 mL, 0.32 mmol), and pyridine (20 mL) is refluxed for three hours. The mixture is transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine, and the organic phase is concentrated in vacuo to yield the title compound as a clear, colorless oil.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[N:54]=[N:55][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:71])([F:70])[F:69])=[CH:63][CH:62]=4)=[CH:57][CH:58]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([O:42]C)=[O:41]>>[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[N:54]=[N:55][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:69])([F:70])[F:71])=[CH:63][CH:62]=4)=[CH:57][CH:58]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([OH:42])=[O:41]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)nn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)nn3)cc2C1=O
Yield: 76 %

Procedure:
The compound of example 502 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 501.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].[C:7](Cl)(C1C=CC=CC=1)([C:14]1C=CC=CC=1)[C:8]1C=CC=C[CH:9]=1.P(=O)([O-])[O-].C([NH+](CC)CC)C.CNC.N=C=N.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O.CO.C(N(CC)CC)C>[PH:3](=[O:4])([OH:6])[OH:5].[NH+:1]1[CH:2]=[CH:9][CH:8]=[CH:7][CH:14]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCP(=O)(O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[NH+](CC)CC
Agent: CNC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[PH](O)O

Procedure:
Aminomethylphosphonic acid (Aldrich Chem. Co.) is reacted with trityl chloride in the presence of triethylamine. The dianionic phosphonate product, where the counter ions are triethylammonium, is mixed with an excess of reagent suitable for adding the desired pendant X moiety (e.g., addition of methanol gives X=methoxy, and addition of dimethylamine gives X=N(CH3)2) and then a carbodiimide, such as dicyclohexylcarboiimide (DCC), is added. The resultant monoanionic product is shaken with a mixture of water and chloroform containing pyridinium hydrochloride. This procedure gives a monoionic phosphonic acid having a pyridinium counter ion. This product is added to chloroform containing N4-Benzoylcytidine-2',3'-phenylboronate and DCC is added. The product is dried and chromatographed on silica using methanol/chloroform mixtures. The pure product is next treated with 1,3-dihydroxypropane to give Structure 2 of FIG. 12, and a portion is further treated with acetic acid in trifluoroethanol.
Reaction SMILES: [CH3:1][C@H:2]([CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:3][CH2:4][O:5][C@@H:6]([CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:7][OH:8].ClC(Cl)(Cl)C(=N)O[C@H:51]1[O:76][C@H:75]([CH2:77][O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C@@H:66]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C@H:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:52]1[O:53][C:54](=[O:56])[CH3:55].C([Si](OS(C(F)(F)F)(=O)=O)(CC)CC)C>C(Cl)Cl>[C:54]([O:53][C@H:52]1[C@@H:57]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@H:66]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C@@H:75]([CH2:77][O:78][CH2:79][C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[O:76][C@@H:51]1[O:8][CH2:7][CH:6]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:56])[CH3:55]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@H](C)CCOC[C@@H](CO)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OCC(COCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a mixture of (2R)-2,3-Bis[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyloxy]propan-1-ol (archaeol) (720 mg; 1.1 mmol), 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl trichloroacetimidate (1.4 g; 2.2 mmol) and molecular sieves 4A° (3 g) was added CH2Cl2 (15 ml). After stirring at R.T. under an argon atmosphere for 1 h, triethylsilyltrifluoromethanesulfonate (25 μL; 0.11 mmol) was added and the stirring continued for 40 min. The reaction was quenched with diisopropylethylamine (100 μL). The whole reaction was adsorbed on silica gel and then purified by silica gel chromatography eluting with hexanes:ethyl acetate 9:1 to yield pure product as a viscous oil (0.58 g; 47%) plus some mixed fractions.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=O)[N:4]=[C:3]1[CH3:27].F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)[N:46]1[CH2:51][CH2:50]OC[CH2:47]1)C(OCC)=O)#N.C(N(CC)C(C)C)(C)C.N1CCC1>CN(C=O)C>[CH3:22][N:12]1[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([CH3:27])=[N:4][C:5]=1[C:24]([N:46]1[CH2:47][CH2:50][CH2:51]1)=[O:26])=[O:23]
Reactant: Cc1nc(C(=O)O)c(C(=O)NCCc2nc(-c3ccccc3)cn2C)n1C
Reactant: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC2)c(C(=O)NCCc2nc(-c3ccccc3)cn2C)n1C
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-dimethyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylic acid (30 mg, 81.7 μmol) in DMF (1 mL) were added under nitrogen atmosphere at 0-5° C. (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU; 38.5 mg, 89.8 μmol) and N,N-diisopropylethylamine (14.3 μL, 81.7 μmol). After stirring for 5 min, azetidine (6.18 μL, 89.8 μmol) and N,N-diisopropylethylamine (14.3 μL, 81.7 μmol) were added, the ice bath was removed after additional 10 min and the reaction mixture was stirred at RT for 2 h. The product was obtained after purification by preparative HPLC using an acetonitrile/water (containing 0.1% formic acid) gradient as colorless waxy solid (1.9 mg, 4.67 μmol, 5.72%). MS: M=407.4 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C@@H:11]([NH:21]C(=O)OC(C)(C)C)[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[NH2:21][C@H:11]([C:4]1[N:3]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:2](=[O:1])[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=1)[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 83.2 %

Procedure:
(S)-tert-Butyl (1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-phenoxypropyl)carbamate (8 mg, 0.02 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 109 μl, 0.43 mmol) according to the method described in Preparation 1 to obtain 6 mg (87% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[CH2:23][CH2:24]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: CCC(O)CN1CCC(CN)CC1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(O)CC)CC3)c2n1

Procedure:
The tilte compound (free base) was prepared according to the procedure described in the step 5 of Example 1 from 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxilic acid (Example 4, Step 2) and 1-[4-(aminomethyl)piperidin-1-yl]butan-2-ol (Example 13, Step 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(/C(=C/C=C/C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
As in Example 115, (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (3.2 g) and 4-nitrophenol (1.73 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (2.35 g) and the mixture was stirred at room temperature for 1.5 hours. The usual work up furnished 4.2 g of crude product which was crystallized from 2-propanol to give 3.5 g of (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 101°-103° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]>COCCOC.CC(=O)OCC>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:23])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCc2ccccc2)nc(-c2ccncc2)nc1OCCO
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (644 mg, 60% in mineral oil) in DME (15 ml) was added ethylene glycol (15 ml). After evolution of gas had ceased, 2-phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (800 mg) was added and the resulting solution was stirred at 90° C. for 16 h. A further portion of NaH (322 mg) was added and stirring was continued at 90° C. for 4 d. The mixture was diluted with EA (200 ml) and washed once with 10% aq. citric acid and 3 times with water. The organic phase was evaporated and the residue was suspended in diethyl ether. The solid material was collected, washed with diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (513 mg) as a beige solid. LC-MS: tR=4.05 min, [M+1]+=523.10, [M−1]−=521.24.