Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH3:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([C:2]2[O:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CN[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1nc2ccc(Cl)cc2o1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g (2.6 mmol) 2,6-dichloro benzoxazole, 0.68 g (3.58 mmol) ((R)-1-benzyl-pyrrolidin-3-yl)-methyl-amine and 0.4 g (4 mmol) NEt3 in 12 mL DCM was stirred over night at room temperature. DCM was added and the mixture was washed with NaHCO3 aq., dried with MgSO4 and evaporated to dryness to yield the title compound as yellow oil which was used in the consecutive step without further purification. (MH+) 342.1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].O.C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
5 g of 5-nitro-1H-indole-2-carboxylic acid ethyl ester is introduced into 170 ml of methanol and 0.5 ml of water, mixed with 6.73 g of ammonium formate and with 50 mg of palladium on carbon (10%) and refluxed for 1 hour at 90° C. Then, it is suctioned off on Celite and rewashed with warm methanol. After the solvent is removed, the residue is mixed with 100 ml of water, stirred for 10 minutes, and the precipitated solid is suctioned off on a G4 frit. The thus obtained solid is dried in a vacuum. In this way, 4.12 g of the title compound is obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:6]([F:15])[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].[CH3:19][Li]>CCOCC.O>[F:15][C:6]1[C:5]([F:16])=[C:4]([F:17])[C:3]([F:18])=[C:2]([CH3:19])[C:7]=1[C:8]1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=1
Reactant: CC1(C)COC(c2c(F)c(F)c(F)c(F)c2F)=N1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: Cc1c(F)c(F)c(F)c(F)c1C1=NC(C)(C)CO1
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 21.2 g (80.0 mmol) of 2-(pentafluorophenyl)-4,4-dimethyl-2-oxazoline (Bull. Chem. Soc. Jpn., 57, 225 (1984)) in 300 ml of dry ether was cooled to -20° C. under argon and treated with 60 ml of 1.6M methyl lithium (96.0 mmol). The solution was stirred at -20° C. for two hours, then stirred at room temperature overnight. The mixture was diluted with water, and the organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=2)=[CH:31][CH:30]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)CCNc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine (0.052 g, 0.181 mmol), potassium carbonate (0.062 g, 0.452 mmol) and 4-chlorophenacyl bromide (0.047 g, 0.199 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as hygroscopic solid of undefined melting point. 1H-NMR (400 MHz, d6-DMSO): 8.14 (d, 2H); 7.87 (m, 2H); 7.41 (m, 2H); 7.32 (d, 2H); 7.29 (t, 1H); 6.37 (s, 2H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([F:19])=[CH:12][C:5]=1[O:6][CH2:7][C:8](OC)=[O:9])([O-])=O>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:16][C:14]1[C:13]([F:19])=[CH:12][C:5]2[O:6][CH2:7][C:8](=[O:9])[NH:1][C:4]=2[CH:15]=1
Reactant: COC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc2c(cc1F)OCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
To a suspension of 12.2 g (0.22 mol) of iron powder in 100 ml of 5% aqueous acetic acid was added dropwise a solution of 10.0 g (36.5 mmol) of methyl 2,4-dinitro-5-fluorophenoxyacetate in 100 ml of EtOAc and 100 ml of glacial acetic acid. The reaction mixture was stirred at room temperature for 18 hours. The iron was removed by suction filtration through a small pad of Celite® and the filter pad was rinsed with 50 ml of EtOAc. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with EtOAc (3×50 ml) and the combined organic phases were washed with sodium bicarbonate (2×50 ml), dried over Na2SO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 3.9 g (60% yield) of 6-amino-7-fluoro-2H-1,4-benzoxazin-3(4H)-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20]C4C=CC=CC=4)=[N:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:5]=[C:4]([O:29]C)[N:3]=1.N>Cl>[Cl:1][C:2]1[NH:3][C:4](=[O:29])[CH:5]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:20])[NH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:7]=1
Reactant: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Agent: Cl
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1cc(Cl)[nH]c(=O)c1
Yield: 59.9 %

Procedure:
A mixture of 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (400 mg, 0.95 mmol) and 2M hydrochloric acid (20 ml) was heated at reflux for 3 hours. The mixture was allowed to cool and adjusted to pH6-7 with aqueous ammonia solution. The resulting precipitate was collected by filtration washed with water and dried to give crude 7-((6-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (190 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].O.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:9]=1
Reactant: COCOc1cc(Br)c(OCOC)c(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCOc1cc(Br)c(OCOC)c(CO)c1
Yield: 99.1 %

Procedure:
Treat a solution of 3-bromo-2,5-bis-methoxymethoxy benzaldehyde (9.40 g, 30.6 mmol) in EtOH (200 mL) with sodium borohydride (1.16 g, 30.6 mmol). Stir the reaction for 2 hours at ambient temperature and pour into H2O (200 mL) and saturated NaHCO3 (100 mL). Extract the H2O with EtOAc (3×100 mL) and wash the combined extracts with H2O (100 mL) and brine (50 mL) then dry (MgSO4) and filter. Concentrate the filtrate to afford the title product (9.31 g, 99%) as an oil. 1H NMR (CDCl3) δ 3.20 (t, J=6.9 Hz, 1H), 3.47 (s, 3H), 3.64 (s, 3H), 4.60 (d, J=6.9 Hz, 2H), 5.08 (s, 2H), 5.13 (s, 2H), 7.02 (d, J=2.9 Hz, 1H), 7.23 (d, J=2.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (80 mg, 0.160 mmol), 5-(tributylstannyl)-3-vinylisothiazole (96 mg, 0.240 mmol), and tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.080 mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and were concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid, which was used without further purification (81.3 mg, 88%). ESI-MS m/z [M+H]+ calc'd for C28H36FN5O5S, 574. found, 574.
Reaction SMILES: C(OC(=O)C[O:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[C:9]([F:15])[N:8]=1)C.[OH-].[Na+]>[Ni].O>[F:15][C:9]1[N:8]=[C:7]([OH:6])[C:12]([Cl:13])=[CH:11][C:10]=1[Cl:14]
Reactant: CCOC(=O)COc1nc(F)c(Cl)cc1Cl
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(F)c(Cl)cc1Cl

Procedure:
To a 500 milliliter nickel lined reaction bomb was added 10 grams (0.05 mole) of 3,5-dichloro-2,6-difluoropyridine (prepared as above, Example I), 4.4 grams (0.11 mole) of sodium hydroxide and 65 milliliters of water. The bomb was sealed and the reaction carried out at 125° C. for 21/2 hours. At the completion of the reaction, the bomb was opened and the contents, which consisted of a crystalline meterial and a dark liquid, were removed. The mixture was heated until the crystals went into solution. Activated charcoal was added and the mixture filtered through diatomaceous earth. The solution was acidified, cooled and filtered to recover the crude 6-fluoro-3,5-dichloro-2-pyridinol product as a solid. The product was purified by recrystallization from hot benzene and recovered as white crystals melting at 136°-140° C. The product was recovered in a yield of 3.2 grams (31.7 percent). The structure of the product was analyzed by infrared. Upon elemental analysis, the product was found to have carbon, hydrogen, chlorine, fluorine and nitrogen contents of 33.6, 1.3, 37.2, 10.7 and 7.7 percent, respectively, as compared with the theoretical contents of 33.0, 1.1, 38.9, 10.5 and 7.7 percent, respectively, calculated for the above named compound.
Reaction SMILES: [C:1]([C:4]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([N:8](CC)CC)=[O:7])(=O)[CH3:2].[NH2:19]N>O>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]2[C:4]=1[C:1]([CH3:2])=[N:19][NH:8][C:6]2=[O:7]
Reactant: CCN(CC)C(=O)c1cccc(OC)c1C(C)=O
Reactant: NN
Solvent: O
Product: COc1cccc2c(=O)[nH]nc(C)c12
Yield: 64 %

Procedure:
To 0.37 g (1.48 mmol) of 2-acetyl-3-methoxy-N,N-diethylbenzamide* in 5 ml of water was added 5 ml of anhydrous hydrazine. This was heated at reflux for four hours, cooled and the resulting solid filtered and washed with water to provide 0.18 g (64%) of the desired product; mp 257°-260°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[C:25](=[O:28])(O)[O-:26].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:12]([O:26][C:25](=[O:28])[NH:21][C:17]1[S:18][CH2:19][CH2:20][C@@:13]2([N:16]=1)[C:12]1[CH:11]=[C:10]([O:22][CH3:23])[CH:9]=[C:8]([F:24])[C:7]=1[O:6][C:5]1[C:14]2=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:11])[CH3:7]
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(Br)ccc1O2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (400 mg, 0.977 mmol) was dissolved in dioxane (48870. Saturated aqueous sodium bicarbonate solution (5 mL) was added, followed by addition of Boc-anhydride (681 μl, 2.93 mmol). The reaction mixture was stirred at room temperature for 2 hrs. Then it was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with MgSO4, filtered, and concentrated. The material was purified through column chromatography eluting with a gradient of 45% to 60% to 75% EtOAc in Hexane to afford (S)-tert-butyl(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)carbamate (490 mg, 0.962 mmol, 98% yield) as a yellow solid.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5](OCC)=[O:6])#[N:3].S(O)(O)(=O)=O.[C:15]([NH2:20])(=[NH:19])[CH:16]([CH3:18])[CH3:17]>C(O)C>[NH2:3][C:2]1[N:19]=[C:15]([CH:16]([CH3:18])[CH3:17])[NH:20][C:5](=[O:6])[CH:4]=1
Reactant: CC(C)C(=N)N
Reactant: CCOC(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: CC(C)c1nc(N)cc(=O)[nH]1
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (1.15 g.) in dry ethanol (20 ml.) was added ethyl cyanoacetate (1.8 ml.) followed after 15 minutes by isobutyramidine sulphate (2.25 g.). The mixture was refluxed for 20 hours, evaporated to dryness, the residue triturated with water (30 ml.) and the pH adjusted to 6 by the addition of hydrochloric acid. After cooling to 0° C, 4-amino-2-isopropylpyrimid-6-one (1.7 g.), m.p. 248°-250° C, was filtered off and recrystallised from ethanol to give 4-amino-2-isopropylpyrimid-6-one (0.95 g.), m.p. 254° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1>[F:37][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccccc2c2cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (3.23 g, 9.3 mmol) in dry THF (50 ml) was added n-BuLi (1.6 M, 8.7 ml, 13.9 mmol) at −78° C. The resulting mixture was stirred for 50 min at −78° C. and then added with N-fluorobenzenesulfonimide (5.6 g, 18.6 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h before quenched with ammonia chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to give compound 5 in 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=7.6 Hz, 1H), 7.73 (dd, J=2.4 Hz, J=8.8 Hz 1H), 7.50-7.44 (m, 2H), 7.39 (dd, J=4.4 Hz, J=8.8 Hz, 1H), 7.25-7.17 (m, 2H), 4.49 (t, J=6.4 Hz, 2H), 3.86 (t, J=6.4 Hz, 2H), 3.52-3.50 (m, 2H), 3.43-3.41 (m, 2H), 3.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.6, 156.2, 141.4, 137.1, 126.3, 123.4, 123.3, 122.6, 122.6, 120.6, 119.1, 113.6, 113.3, 109.7, 109.6, 109.2, 106.1, 105.9, 72.1, 71.0, 69.4, 59.2, 43.4. HRMS (MALDI-TOF) m/z Calcd for C17H18FNO2 287.1316. Found 287.1314[M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[C:16]([OH:17])[C:11]=3[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([O:17][C:16]1[C:11]2[CH2:10][O:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[CH3:18])=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)O
Reactant: Cc1ncc2c(c1O)CO[C@H]2c1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)Oc1c(C)ncc2c1CO[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-ol (346 mg, 1.32 mmol), 1-[(Z)-butoxy-NNO-azoxy]-L-proline (306 mg, 1.32 mmol), and triethylamine (369 mL, 2.65 mmol) in CH2Cl2 (10 mL) was added BOP-Cl (438 mg, 1.72 mmol). After stirring at rt over night, the mixture was purified by flash chromatography (Biotage 40+M) using 40-50% EtOAc/hexane gradient, affording the title compound: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m, 2H), 6.19 (s, 1H), 5.21 (dd, J=2.4, 14.1 Hz, 1H), 5.07 (dd, J=1.9, 14.2 Hz, 1H), 4.78 (dd, J=4.5, 14.1 Hz, 1H), 4.20 (t, 6.7 Hz, 2H), 3.93-3.88 (m, 1H), 3.73-3.68 (m, 1H), 2.54-2.48 (m, 1H), 2.47 (s, 3H), 2.26-2.15 (m, 3H), 1.76-1.70 (m, 2H), 1.45-1.38 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:27]([CH3:33])[CH2:28][C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:27]([CH3:33])[CH2:28][C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1)[CH:2]=[CH2:3]
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Reactant: C=CCOc1ccccc1OCC1CO1
Product: C=CCOc1ccccc1OCC(O)CNCCOc1cccc(C2=NNC(=O)CC2C)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)=[O:2].[CH3:21][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)[CH3:21]
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A suspension of 150 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 ml of tetrahydrofuran is cooled to 5° C. 1.9 ml of a 3M solution of methylmagnesium chloride in tetrahydrofuran are added dropwise. The reaction mixture is stirred at 5° C. for 4 hours, then treated with 20 ml of a saturated ammonium chloride solution, stirred and then diluted with 30 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with a saturated sodium chloride solution, dried and concentrated to dryness under reduced pressure. After chromatographing on silica, elution being carried out with dichloromethane and then with mixtures of dichloromethane and ethyl acetate (85/15, then 60/40), the fractions comprising the expected product are combined and evaporated to dryness under reduced pressure to give 59 mg of 6-[(RS)-1-hydroxyethyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].[BH3-]C#[N:19].[Na+].O>CO>[NH2:19][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [BH3-]C#N
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC(N)CC(=O)OC
Yield: 44.8 %

Procedure:
Dimethyl 3-ketoglutarate (13 g) in methanol (50 ml) was treated with ammonium formate (5 g) and NaCNBH3 (2 g). 10 ml of H2O was added and the excess solvent removed under reduced pressure. The semi-solid was dissolved in 5% aqueous HCl (250 ml), and washed with CH2Cl2 (2×50 ml). The aqueous layer was made basic (pH>9) with K2CO3 and the product was extracted using CH2Cl2 (2×75 ml). The organic layers were combined and dried with Na2SO4. The excess solvent was removed to give 2.5 g of the dimethyl (±)3-aminoglutarate. This was dissolved in methanol (50 ml) and treated with 4N HCl/Dioxane (10 ml). The excess solvent was removed under reduced pressure to give a 2.7 g of dimethyl (±)3-aminoglutarate hydrochloride. MS and 1H-NMR were consistent with the desired product.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[C:12]([CH3:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[C:12]([CH3:29])=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(O[C@H]2CCCC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (175.6 mg, 0.29 mmol) prepared in Example 66a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (122 mg, 93%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]([NH2:22])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCOCC(=O)O)cc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(CCOCC(N)=O)cc1

Procedure:
The subtitle compound (0.77 g) was prepared according to the procedure in example 1 part b using 2-[2-(4-methylphenyl)ethoxy]acetic acid (1.1 g). oxalyl chloride (1.44 g), concentrated ammonium hydroxide (20 ml), and toluene (40 ml).