Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11](N)=[C:10]([CH3:13])[CH:9]=[CH:8][N:7]=1.N([O-])=[O:15].[Na+]>OS(O)(=O)=O.O>[OH:15][C:11]1[C:6]([CH:2]=[O:1])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:13]
Reactant: Cc1ccnc(C2OCCO2)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(C=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1,3-dioxolanyl)-4-methyl-3-aminopyridine (0.60 g, 3.3 mmol) in 15 mL of 10% H2SO4 at 0° C. (ice bath) with stirring was added dropwise a solution of NaNO2 (0.38 g, 5.5 mmol) in 3 mL of water. The mixture was stirred at 0° C. for 15 min and then heated in a steam-bath for 30 min. The resulting solution was evaporated at room temperature under reduced pressure to yield 3-hydroxy-4-methyl-2-formylpyridine as a syrup, which was dissolved in 15 mL of water, decolorized with charcoal and filtered. To the filtrate was added a solution of thiosemicarbazide (0.31 g, 3.3 mmol) in 5 mL of 5% HCl. The mixture was refluxed for 30 min, cooled and the yellow precipitate was filtered, washed with water, and recrystallized from aqueous ethanol solution (1:1, v/v) containing 5% conc. HCl to afford 0.21 g (30%) of product: the mp and all spectroscopic data were identical with those obtained in Example XLIII.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH2:15][C:16]([C:18]([F:21])([F:20])[F:19])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.1 g, 0.73 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-4,4,4-trifluoroacetoacetate (0.216 g, 1.17 mmol) and sodium carbonate (0.140 g, 1.32 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]([CH2:36][CH:37]=[CH2:38])[CH:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1.[CH3:39]I>O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]([CH2:36][CH:37]=[CH2:38])[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)([CH3:39])[C:21](=[O:25])[O:22]2)=[CH:17][CH:16]=1
Reactant: C=CCC1c2ccc(OCOC)cc2OC(=O)C1c1ccc(OCOC)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1c2ccc(OCOC)cc2OC(=O)C1(C)c1ccc(OCOC)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A 1M solution of lithium hexamethyl-disilazide in tetrahydrofuran (170 ml) was added dropwise to a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one (32.70 g) in anhydrous tetrahydrofuran (400 ml) at −73° C. over 15 minutes under nitrogen atmosphere, followed by stirring for 30 minutes at −10° C. The reaction mixture was cooled to −75° C. and methyl iodide (10.6 ml) was added dropwise thereto over 10 minutes, followed by stirring for 10 minutes at −75° C., for 1 hour at −10° C. and then for 1 hour at 0° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was washed twice with water and dried over sodium sulfate. After concentration under reduced pressure, the resulting oil was purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=9/1) to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(2-propenyl)chroman-2-one (30.74 g, Yield 90.8%) as a yellow oil.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(C(OCC)=O)[C:6]([O:8][CH2:9]C)=[O:7])(=O)C>Cl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[CH2:17][CH2:16][CH:5]([C:6]([O:8][CH3:9])=[O:7])[N:4]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(CCC(=O)c1ccc(F)cc1)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: COC(=O)C1CCC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
A stirred solution of diethyl acetamido[2-(4-fluorobenzoyl)-ethyl]malonate (5.72 g, 15.6 mmol) in conc. hydrochloric acid (45 ml) was heated under reflux conditions for 15 h, filtered and evaporated. Subsequently hydrochloric acid in MeOH (3N, 30 ml) was added and the solution stirred at room temperature for 20 h. The reaction mixture was evaporated, sat. NaHCO3 solution was added (50 ml) and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated to give methyl (RS)-2-(4-fluorophenyl)-1-pyrroline-5-carboxylate (2.3 g, yield 67%) as a pale brown oil, MS: m/e=221 (M+).
Reaction SMILES: [OH-].[Na+].Cl.[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:36][CH2:37][CH3:38])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6]>CO>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:36][CH2:37][CH3:38])[N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:12]=1[C:13]([OH:15])=[O:14])([CH3:7])[CH3:6]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 55.4 %

Procedure:
3.65 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.31 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate hydrochloride [prepared as described in Example 18(b)] in 6 ml of methanol, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to remove the methanol. The concentrate was diluted with water and its pH was adjusted to a value of 3 by the addition of dilute hydrochloric acid, after which it was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was triturated with diisopropyl ether, to give 0.15 g of the title compound, melting at 166°-169° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:28])[CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
Compound 117 was prepared according to General Method 5 (EXAMPLE 2) from (±)-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (18 mg, 0.05 mmol), 37% aqueous formaldehyde (0.01 mL, 0.3 mmol, 5 eq), sodium cyanoborohydride (16 mg, 0.3 mmol, 5 eq) in 1 mL acetic acid (0.05 M) stirred at rt for 12 h to afford 7 mg of (3R/S)-3,4-dihydro-8-isopropoxy-4-methyl-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (7 mg, 0.02 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of a 1:1 acetic acid:concentrated HCl (5 mM) and heated at 90° C. for 6 h to afford 5 mg (83%) of Compound 117 after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 10.83 (bs, 1H), 7.11 (s, 1H), 6.99 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.28 (dd, J=10.7, 2.2, 1H), 4.07 (dd, J=10.7, 2.4, 1H), 3.24 (m, 1H), 2.97 (s, 3H), 1.48 (m, 4H), 0.96 (t, J=7.3, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:27].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:27][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:41])([F:40])[F:42]
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (100 mg, 0.27 mmol) in anhydrous DMF (15 mL) under a N2 atmosphere containing, at 0° C., sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol) was added. The mixture was allowed to stir at 0° C. for 30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O (1×15 mL), brine (1×15 mL), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to yield {4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone as off-white crystals.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[F:23][C:10]([F:9])([F:22])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8])(=[O:20])=[O:19]
Reactant: Cc1n[nH]c(=O)n1N
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Solvent: c1ccncc1
Product: Cc1n[nH]c(=O)n1NS(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: -10 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
10.0 g (0.088 mol) of 4-amino-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are dissolved in 50 ml of dry pyridine, the mixture is cooled to -10° C., and 32.7 g (0.12 mol) of 2-trifluoromethoxy-benzenesulphonyl chloride are added. The reaction mixture is allowed to reach room temperature (approximately 20° C.) and stirred for approximately 12 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride and shaken with 1N hydrochloric acid and then with water. The organic phase is dried with sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate under a water pump vacuum. 23.1 g (80% of theory) of 4-(2-trifluoromethoxy-phenylsulphonylamino)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as an oily residue.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[C:12]=2[N+:16]([O-])=O)[CH2:7]1)(=[O:4])[CH2:2][CH3:3]>CO>[C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[C:12]=2[NH2:16])[CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)NC1CCc2c(ccc(OC)c2[N+](=O)[O-])C1
Solvent: CO
Product: CCC(=O)NC1CCc2c(ccc(OC)c2N)C1

Procedure:
1.8 g of the isomer nitrated in the 5-position, prepared as described in (b) above, in suspension in 50 ml of methanol, are hydrogenated under the conditions of Example 1(d). After the catalyst has been filtered off and the solvent has been evaporated off, 1.4 g of a product, melting at 141° C., are collected.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15]([NH2:17])=[O:16])=[CH:6][CH:5]=1.BrC[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[NH2:17])=[CH:13][C:12]=1[C:11](=[O:23])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:25])[F:1])=[CH:5][CH:6]=1)[CH3:32]
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamide and ethyl bromoacetate by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCOCC1>[CH2:16]([NH:19][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2)[CH:17]=[CH2:18]
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Reactant: C=CCN
Solvent: C1COCCO1
Product: C=CCNCC(O)COc1cccc2c1CC(=O)N2

Procedure:
3 g of 4-(2,3-epoxypropoxy)oxindole, 30 cc of allylamine and 70 cc of dioxane are heated to the boil for 16 hours. The mixture is evaporated to dryness at reduced pressure and the crude title compound is recrystallized from ethanol/ethyl acetate. M.P. 124°-127° .
Reaction SMILES: O[C:2]1[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)=[N:4][CH:5]=[CH:6]C=1.Cl.ClCC1N=C(C)[S:24]C=1.[OH-].[Na+]>>[CH3:6][C:5]1[S:24][CH:2]=[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)[N:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccn(Cc2csc(C)n2)n1

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 41, replacing the benzyl halide by 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE). 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE) was also liberated using NaOH (1N, aq) at room temperature. 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.37 (s, 1H), 7.62-7.63 (m, 1H), 7.25 (s, 1H), 6.43-6.44 (m, 1H), 5.20 (s, 2H), 2.59 (s, 3H), 1.93 (s, 3H). [ES+MS] m/z 237 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-]>CO>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]([CH3:11])(=[O:14])=[O:13])=[N:1]2)=[N:4][CH:5]=1
Reactant: COC(=O)CC(=O)c1ccccc1S(C)(=O)=O
Reactant: Nc1cc(F)cnc1C=O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 100 °C

Procedure:
A mixture of 3-amino-5-fluoropicolinaldehyde (930 mg, 6.63 mmol), methyl 3-(2-(methylsulfonyl)phenyl)-3-oxopropanoate (1.7 g, 6.63 mmol) and cerium chloride heptahydrate (435 mg, 1.32 mmol) was heated to 100° C. for 3 h. The residue was dissolved in MeOH and purified by column chromatography on neutral alumina using 0-30% EtOAc in hexane to give methyl 7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate: LC-MS (ESI) m/z 361.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>O1CCCC1>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
4-Nitrophenol (4.01 g), 2-(tert-butoxycarbonylamino)ethanol (4.65 g) and triphenylphosphine (7.55 g) were dissolved into tetrahydrofuran (50 ml) and the solution was ice cooled. Azo dicarboxylic acid diethyl (5.52 g) dissolved in tetrahydrofuran (5 ml) was added drop-wise into the ice-cooled solution. After being stirred for one hour at room temperature, the reaction mixture was concentrated under vacuum. Residue was dissolved into ethyl acetate (50 ml). Hexane (400 ml) was added to the ethyl acetate solution and insoluble matter formed was removed from solution by filtration. Filtrate was concentrated under vacuum to small volume. Concentrate was purified by silica-gel column chromatography using ethyl acetate:hexane (1:1) as the solvent system to obtain N-(tert-butoxycarbonyl)-2-(4-nitrophenoxy)ethylamine (5.91 g) as color-less oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4](Cl)[N:3]=1.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[C:5]([NH2:9])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(N[C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-diamino-4,6-dichloropyrimidine (10.5 g, 58.6 mmol), trans-4-aminocyclohexanol (6.75 g, 58.6 mmol, 1 equiv.), sodium bicarbonate (17.2 g, 205 mmol, 3.5 equiv.) and 1-butanol (210 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by LCMS), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Water (150 mL) was added to the residue with stirring at room temperature for 30 min, and the dark red solid filtered under vacuo to give, after drying, 10 g (66% yield) of the desired product. 1H NMR (300 MHz, d6-DMSO) δ, ppm: 6.14 (d, 1H), 5.57 (s, 2H), 4.54 (d, 1H), 3.90 (s, 2H), 3.81-3.76 (m, 1H), 3.40-3.32 (m, 1H), 1.86-1.82 (m, 4H), 1.28-1.20 (m, 4H); MS (EI) m/z 258.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[CH:8]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[CH:28][N+:25]([O-:27])=[O:26])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
80.9 g of 1-(4-chlorobenzyl)-3-formylindole, prepared in Example 5, 18 g of ammonium acetate and 300 ml of nitromethane are refluxed for 30 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32]C)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.CC1N=C(NC)N=C(C(O)=O)C=1.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH3:34][C:15]1[CH:16]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH3:32])[N:25]=3)[O:21][N:20]=2)[CH:18]=[C:3]([CH3:1])[C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: CNc1nc(C)cc(C(=O)O)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{2,6-Dimethyl-4-[5-(6-methyl-2-methylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-methylamino-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.85 min; [M+H]+=443.21.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[CH:11]=[O:12].[C:13](=O)(O)[O-].[K+].BrC[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]=1[C:32]([O:34][CH3:35])=[O:33].O>CN(C)C=O>[Br:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH3:10])[N:4]([CH2:13][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[C:21]([C:32]([O:34][CH3:35])=[O:33])=[CH:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][CH:30]=2)[C:3]=1[CH:11]=[O:12]
Reactant: O=C([O-])O
Reactant: COC(=O)c1c(CBr)cccc1-c1ccccc1
Reactant: CCCCc1nc(C=O)c(Br)[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 0.08 h

Procedure:
3.7 g of the product of Step B were introduced into 50 ml of dimethylformamide and 2.46 g of potassium bicarbonate were added with stirring. Then, the mixture stood for about 5 minutes and 5.86 g of methyl bromomethyl-(1,1'-biphenyl)-2-carboxylate (prepared according to EP 0,253,310) in 55 ml of dimethylformamide were added. The mixture stood for 3 days at ambient temperature and the reaction medium was hydrolyzed with 100 ml of water, then extracted with ethyl acetate. The extracts were washed with water saturated with sodium chloride, dried, filtered and evaporated. After chromatography, (eluant: ethyl acetate 5-methylene chloride 95), 6.36 g of the expected product were recovered.