Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.O.NN>C(O)C.C(Cl)Cl>[NH2:3][O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(OCCON)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 4-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}piperidine-1-carboxylate 70 (0.57 g, 1.46 mmol) in a mixture of ethanol (1 mL) and DCM (6 mL) was added hydrazine hydrate (0.086 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h. Precipitate was filtered off. The filtrate was evaporated and the residue was subjected to chromatography to give 71 (0.327 g, 86%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of 6-bromopyridin-3-ol (5.00 g, 28.8 mmol) in DMF (50 mL) were added potassium carbonate (7.96 g, 55.6 mmol) and (bromomethyl)cyclopropane (4.18 mL, 43.1 mmol), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give the title compound (6.32 g, yield 96%) as an oil.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH3:28][CH2:29][Mg+].[Br-]>C1COCC1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]4([OH:27])[CH2:29][CH2:28]4)=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[CH2:17][CH2:18]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC[Mg+]
Reactant: COC(=O)c1ccc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3ccc(C4(O)CC4)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 4-[6-(1-tert-butoxycarbonylamino-cyclopropyl)-pyridin-3-yl]-benzoic acid methyl ester (0.68 g, 1.8 mmol) in THF (20 mL) was added Ti(Oi-Pr)4 (0.54 mL, 1.8 mmol). To this mixture was slowly added EtMgBr (3M in Et2O, 1.2 mL, 3.7 mmol) over 30 minutes. The reaction was allowed to stir at room temperature for 1 h. Ti(Oi-Pr)4 (1.1 mL, 3.2 mmol) and EtMgBr (3M in Et2O, 1.2 mL, 3.7 mmol) were again added to the solution and the reaction stirred for 30 minutes. The mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and the residue purified by reverse phase HPLC to give (1-{5-[4-(1-hydroxy-cyclopropyl)-phenyl]-pyridin-2-yl}-cyclopropyl)-carbamic acid tert-butyl ester (0.05 g, 1.4 mmol) as a brown solid, m/z 367.7 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N+:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)#[C-:35]>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][CH:36]([N+:34]#[C-:35])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: [C-]#[N+]C1CCNCC1
Product: [C-]#[N+]C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-isocyano-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-Isocyano-piperidine following General Procedure B.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][N:14](C)C=O>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
20 g of polifungin and 6 g of glucose were dissolved in 100 ml of dimethyl formamide and then the further procedure was carried out as in the Example IV till the moment of washing with water of precipitated N-glycosyl polifungin. The washed precipitate was suspended in 1200 ml of methanol of the temperature of 50° C., then was stirred and 7 g of N-methylglucamine, dissolved in 70 ml of water, were added. After dissolving the solution was filtered, 800 ml of n-amyl alcohol were added and the whole was concentrated under the reduced pressure at the temperature of 40° C. till the moment of removal of methanol and water. The resulting precipitate was filtered and washed with acetone. The precipitate was dried at a room temperature under the reduced pressure. 16.3 g of N-methylglucamine salt of N-glycosyl polifungin of biological activity of 1980 U/mg, E1 cm1% =572 at 304 nm were obtained. Original antibiotic exhibited E1 cm1% =720 at 304 nm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCc1ccc2ncnc(Cl)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 4-chloroquinazoline-6yl methanol (3.5 g, 0.018 mol) in dry CH2Cl2 (100 mL) was added Dess-Martin periodinane (8.4 g, 0.019 mol) and stirred at RT for 30 min. The reaction mixture was washed with 10% aqueous NaHCO3 (75 mL), water, brine and dried. The solvent was removed under vacuum to give 4-chloroquinazoline-6-carboxaldehyde (3 g, 88%) as pale yellow solid.
Reaction SMILES: COC1C=CC(S([N:12]2[CH2:17][CH:16]=[CH:15][C@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:13]2[C:24]([OH:26])=O)(=O)=O)=CC=1.Cl.C([NH:35]O)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(OCC)(=O)C>[C:18]1([CH:14]2[CH:15]=[CH:16][CH2:17][NH:12][CH:13]2[C:24]([NH2:35])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=C[C@H](c3ccccc3)[C@@H]2C(=O)O)cc1
Reactant: ONCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)C1NCC=CC1c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylic acid (65 mg, 0.17 mmol) (from Example 20), is added benzylhydroxylamine hydrochloride (32 mg, 0.20 mmol), dicyclohexylcarbodiimide (41 mg, 0.20 mmol) and dimethylaminopyridine (27 mg, 0.22 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and filtered through Celite™ and evaporated. The crude product is purified by chromatography elution with 1:1 hexane-ethyl acetate to provide (+)-(2R*-3R*)-N-benzyloxy-1-4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:7]=O)[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][C:35]#[N:36])=[CH:33][C:28]=2[O:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32](/[C:34](=[CH:7]/[C:6]3[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)/[C:35]#[N:36])=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CCOc1cc(C=O)ccc1OCCCCCCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: CCOc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Yield: 96 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{3-ethoxy-4-[(11-hydroxyundecyl)oxy]phenyl}prop-2-enenitrile is prepared from 3-ethoxy-4-[(11-hydroxyundecyl)oxy]benzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 96% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([CH:20]=C)=[CH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.C[OH:28]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([CH2:20][OH:28])=[CH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: C=Cc1cnc2c(c1)CN(C(=O)c1ccc(F)cc1)CC2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2ncc(CO)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluorophenyl)(3-vinyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (50 mg, 0.2 mmol; prepared as described above) was dissolved in CH2Cl2:MeOH (9:1, 15 mL) and cooled in a dry ice/acetone bath. Ozone was bubbled through the solution for 3 min and the reaction was allowed to warm to RT as then purged with an air inlet for 5 min. Sodium borohydride (65 mg, 1.7 mmol) in MeOH (10 mL) was added and the reaction allowed to stir for 1 h. The reaction mixture was concentrated, partitioned between water and EtOAc, and the water layer extracted with CH2Cl2:butanol (9:1). The volatiles were removed under reduced pressure to give 40 mg of crude product. The crude (4-fluorophenyl)(3-(hydroxymethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone was used in the next step without further purification. LC-MS (M+H)=287.2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][CH:14]([CH3:24])[CH2:13][C@H:2]1[C:3](=[O:11])[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)C[C@@H]1Oc2ccccc2NC1=O
Yield: 77.9 %

Procedure:
4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.01 g, 15.0 mmol) and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM24-21) (3.92 g, 78%). 1H NMR (CDCl3) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[N:31]=[CH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[CH2:13][CH2:14]2)=[N:7][C:2]([NH:34][C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)=[N:3][CH:4]=1
Reactant: Cn1cnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of tert-butyl 3-[(2,5-dichloropyrimidin-4-yl)amino]-9-azaspiro[5.5]undecane-9-carboxylate (500 mg, 1.204 mmol), 1-methylimidazol-4-amine (176.1 mg, 1.813 mmol) and cesium carbonate (1.19 g, 3.65 mmol) in anhydrous dioxane (10 mL) were added BINAP (148.6 mg, 0.2386 mmol) and Pd(OAc)2 (54.1 mg, 0.241 mmol). The reaction was under an inert atmosphere and stirred at 150° C. under microwave irradiation for 2 h. The reaction solution was concentrated in vacuo and the residue was purified by silica gel column chromatography with (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (292 mg, 50.97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:13][C:14]([Cl:16])=[CH2:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([CH:15]=[C:14]([Cl:16])[Cl:13])=[O:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)cc1Cl
Temperature: 0 °C
Yield: 96.7 %

Procedure:
136.5 g (0.6 mole) of 2,4-dichloro-5-fluorobenzoyl chloride and 97 g (1 mole) of 1,1-dichloroethylene are successively added dropwise to a suspension of 84 g of anhydrous aluminum chloride in 300 ml of methylene chloride, while cooling with ice and stirring, during which the temperature should not exceed 30° C. The mixture is stirred at room temperature for 3 hours and poured onto a mixture of about 600 g of ice and 60 ml of concentrated hydrochloric acid, the organic phase is separated off and the aqueous phase is subsequently extracted three times with 100 ml of methylene chloride. The methylene chloride solution is washed with 100 ml of water and dried with sodium sulphate and the solvent is distilled off in vacuo. The residue (218.8 g) is heated at 130°-140° C. with 0.34 g of triphenylphosphine until the initially vigorous evolution of HCl has ended (about 3/4 hour). Distillation under a fine vacuum gives 167.1 g (96.4%) of 2,2-dichlorovinyl 2,4-dichloro-5-fluorophenyl ketone of boiling point 121°-123° C./0.13 mbar, melting point 64°-65° C.
Reaction SMILES: FC1C=CC(S(N(S(C2C=CC(N3CC[C@@H](O)C3=O)=CC=2)(=O)=O)C2SC=CN=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:59]=[C:60]([CH:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:61]=[C:62]([Cl:64])[CH:63]=1>>[Cl:64][C:62]1[CH:61]=[C:60]([C@H:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:59]=[C:58]([Cl:57])[CH:63]=1
Reactant: Clc1cc(Cl)cc(C2CNCCO2)c1
Agent: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)cc([C@@H]2CNCCO2)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Synthesized according to General procedure 31, Method A. A stirring suspension of ((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.00 mmol), N,N-diisopropylethylamine (465 μL, 3.00 mmol), and CH2Cl 2 (5.0 mL), under N2, was cooled to −20° C. Triflic anhydride (220 μL, 1.3 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (R)-2-(3,5-dichlorophenyl)morpholine (248 mg, 1.00 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×25 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (1.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (174 μL, 2.0 mmol) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours. The solution was allowed to warm to room temperature and concentrated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired lactam as a white solid (420 mg, 0.76 mmol, 76% yield). 1H-NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.84-7.77 (m, 4H), 7.54-7.50 (m, 1H), 7.44 (d, J=1.8 Hz, 2H), 7.24 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.57 (dd, J=1.7, 9.8 Hz, 1H), 3.97-3.91 (m, 1H), 3.79-3.62 (m, 4H), 3.21-3.17 (m, 1H), 2.95-2.86 (m, 2H), 2.69-2.66 (m, 1H), 2.22-2.12 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.45 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=5.6 min.
Reaction SMILES: [NH2:1][C:2](=[C:7]1C(=O)O[C:10](C)([CH3:14])[O:9][C:8]1=[O:16])[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Na].[Cl-].[Na+].O>C(O)C.ClCCl>[CH2:10]([O:9][C:8](=[O:16])[CH:7]=[C:2]([NH2:1])[CH2:3][CH:4]1[CH2:5][CH2:6]1)[CH3:14]
Reactant: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C=C(N)CC1CC1
Yield: 70 %

Procedure:
5-(1-Amino-2-cyclopropyl-ethylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (397 mg, 2 mmol) was added to a solution of sodium (45 mg, 2 mmol) in ethanol (3 ml). The reaction mixture was heated under reflux for 14 h, diluted with dichloromethane and poured onto ice water/brine 1/1. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 231 mg (1.4 mmol, 77%) of the title compound as orange oil.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1>C(OCC)(OCC)(OCC)CC>[Cl:14][C:7]1([CH2:6][CH3:5])[N:10]2[C:9]3[C:4]([N:3]=[CH:2][C:11]2=[N:12][NH:13]1)=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=3
Reactant: NNc1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: CCOC(CC)(OCC)OCC
Product: CCC1(Cl)NN=C2C=Nc3cc(Cl)c(Cl)cc3N21
Yield: 54 %

Procedure:
2,6,7-Trichloro-3-hydrazinoquinoxaline (4.9 g., 0.018 mole) in triethyl orthopropionate (50 ml.) was heated at 100° C. for 2 hours. The precipitate which formed was collected by means of filtration at room temperature and washed with cyclohexane. Recrystallization from chloroform/cyclohexane two times then afforded 2.9 g. (54% yield) of pure 1,7,8-trichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline as a pink solid (m.p. 198°-201° C.).
Reaction SMILES: CO[N:3]=[CH:4][CH:5]1[CH:11]([CH:12]=NOC)[CH:10]2[CH2:16][CH:6]1[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9]2.F[C:25](F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:18]1([CH2:17][N:8]2[CH2:7][CH:6]3[CH2:16][CH:10]([C:11]4[C:5]3=[CH:4][N:3]=[CH:25][CH:12]=4)[CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CON=CC1C2CC(CN(Cc3ccccc3)C2)C1C=NOC
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC3CC(C2)c2cnccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(phenylmethyl)-3-azabicyclo[3.2.1]octane-6,7-dicarbaldehye bis (O-methyloxime) (Preparation 33, 5.0 g, 15.2 mmol) in dichloroethane (150 ml) was added trifluoroacetic acid (17 ml) and the reaction mixture was stirred under nitrogen at room temperature for 20 min. The reaction mixture was heated under reflux for 2 h and then concentrated to give a brown oil. Ethyl acetate (100 ml) was added and the solution was treated with saturated sodium carbonate solution (70 ml) the layers were separated and the organic layer washed with brine and dried (Na2SO4) and concentrated to give an oil (4.0 g). The crude oil was purified by flash chromatography using silica gel eluting with ethyl acetate to give the title compound as an orange oil (1.93 g, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccccc2)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 30.00 g. of 3,5-dinitro-2-biphenylol, 15 ml. of dimethylformamide, and 113 ml. of phosphorous oxychloride is heated on a steam bath for 2.25 hours. The mixture is then cooled to room temperature and poured slowly into approximately 600 g. of crushed ice. The precipitate that forms is isolated by filtration and washed with water. The solid is dissolved in chloroform and the chloroform solution is washed several times with 10% Na2CO3 and once with water. The chloroform solution is dried over MgSO4 and concentrated. The product is recrystallized from benzenehexane to give 19.07 g. of material (melting at 119°-20° ).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[N:20]=[C:19]([CH:22]=[O:23])[C:18]([CH2:24][N:25]4[CH2:30][CH2:29][N+:28]([O-])([CH3:31])[CH2:27][C:26]4=[O:33])=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CS(C)=[O:41]>>[C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH:27]([OH:41])[C:26]4=[O:33])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CS(C)=O
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[N+](C)([O-])CC4=O)c(C=O)nc32)ncc1C#N
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)C(O)C4=O)c(C=O)nc32)ncc1C#N
Reaction time: 30 h

Procedure:
A solution of 4-((8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-formyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1-methyl-3-oxopiperazine 1-oxide (Example 222, 5 mg, 0.01 mmol) in DMSO (1 ml) was stirred at room temperature. After 30 h, the reaction mixture was concentrated and the residue purified by reverse phase chromatography: Atlantis C18 T3 column (3.5 um, 4.6×150 mm, 45° C.), eluting with 1:1 acetonitrile/water (containing 10 mM NH4OAc, 0.02% TFA). The product containing fraction was evaporated to give the title compound as a gray solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]([C@@H:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:27][C@@H:29]1[CH2:30][O:31]1)[CH3:2]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H]1CO1
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To a solution of the compound of Example 32 (315 mg, 896 μmol) in isopropanol (10 mL) and 3 N aq. NaOH (2 mL), (R)-epichlorohydrine (249 mg, 2.69 mmol) is added. The mixture is stirred at rt for 18 h before another portion of (R)-epichlorohydrine (249 mg, 2.69 mmol) is added. Stirring is continued at rt for 24 h. The mixture is diluted with EA and washed with water. The org. extract is concentrated and the crude product is purified on prep. TLC plates using heptane:EA 7:3 to give 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-5-isobutyl-4-methyl-pyridine (233 mg) as a colourless oil; LC-MS: tR=1.18 min, [M+H]+=408.09.