Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)[CH2:5][CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[O:1][CH2:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)CCCCN(CCc1ccccc1O)Cc1ccc(C(=O)OC)cc1
Reactant: ClCc1ccc(C=Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(/C=C/c2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
1.0 g (2.50 mmol) of methyl 4-{[(2-hydroxyphenethyl)-(5-methoxy-5-oxopentyl)-amino]methyl}benzoate from Ex. I, 0.687 g (3.00 mmol) of 4-(chloromethyl)stilbene and 0.520 g (3.75 mmol) of potassium carbonate in 10.0 ml of acetonitrile are heated at reflux for 18 hours. The solution is filtered and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography over silica gel using the mobile phase cyclohexane/ethyl acetate 4/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[CH2:17]1[O:19][CH:18]1[CH2:20][OH:21]>C(O)C>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([CH3:16])[O:12][CH2:13][CH2:14][O:15]2)=[CH:4][CH:3]=1
Reactant: CC1(CCCc2ccc(N)cc2)OCCO1
Reactant: OCC1CO1
Solvent: CCO
Product: CC1(CCCc2ccc(NCC(O)CO)cc2)OCCO1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 10 g (0.045 mol) of 230113 (Example 9--Step 3) in 60 ml of ethanol, are added 3.34 g (0.045 mol) of glycidol and left under stirring overnight. After concentration, the product is obtained by chromatography (silica, eluent: CH2Cl2 :97, CH3OH:3); Yield=44%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7]C(=O)OC(C)(C)C)=[C:4]([C:17](=[O:20])[NH:18][CH3:19])[CH:3]=1.[C:21]([C:25]([OH:27])=[O:26])([F:24])([F:23])[F:22]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:25]([OH:27])=[O:26].[NH2:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=1[C:17]([NH:18][CH3:19])=[O:20]
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(F)ccc1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-(methylcarbamoyl)benzylcarbamate (7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid using literature methods) in CH2Cl2 (100 mL) was added CF3CO2H (25 mL) and the mixture stirred at room temperature for 15 min. This was concentrated in vacuo and the residue triturated with diethyl ether to provide 8.0 g (Yield 99%) of the title compound as a white powder. 1H NMR (300 MHz, D2O) δ ppm: 2.93 (3H, s) 4.20 (2H, s) 7.35 (1H, dt, J=8.5, 3 Hz) 7.42 (1H, dd, J=9.0, 2.7 Hz) 7.57 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 183 (M+H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N+:11]([O-:25])=[C:10]([CH3:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Solvent: ClCCl
Product: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc[n+]1[O-]
Yield: 92.3 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine (11.47 g, 0.248.4 mmol) was stirred with 57-80% m-CPBA (25.8 g) in dichloromethane (100 ml) in a water bath for 24 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (3:1)) to afford 11.3 g (93%) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine 1-oxide as a white solid. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.94 (9H, s), (3H, s), 2.52 (3H, s), 4.67 (2H, s), 6.97 (1H, d, J=6.7 Hz), 7.08 (1H, s), 8.10 (1H, d, J=6.7 Hz).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].Cl.CN(C)[CH2:25][CH2:26][CH2:27]N=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH2:25][CH2:26][CH3:27])=[O:12])(=[O:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCOC(=O)CC(CSCCNC(C)=O)C(=O)c1cccnc1
Yield: 74.9 %

Procedure:
A solution of 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid (0.1 g), 1[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (68.1 mg) and 4-dimethylaminopyridine (0.1 eq) in dimethyl formamide (2 mL) was stirred for 24 h. The solution was purified on preparative HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 0.085 g (75%) of the title compound; ESMS (M+1)+353.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][C@H:11]([OH:10])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(Cc2ccc(Cl)nc2)C1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.2 mmole) in 10 mL of dry acetonitrile is added 1.03 mL (12.4 mmol) of (S)-3-hydroxy-pyrrolidine followed by 858 mg (6.2 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 20 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 900 mg (68% yield) of (S)-1-(6-Chloro-pyridin-3-ylmethyl)-pyrrolidin-3-ol. Diagnostic C13 NMR (100 MHz, CDCl3) 35.1, 52.5, 56.7, 63.0, 71.4, 124.2, 133.4, 139.6, 149.9, 150.4; MS 213.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.O1CCCC1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[S:23][C:24]([CH2:27][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Nc2ncc(CN3CCOCC3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 57 from 17 mg (0.19 mmol) morpholine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (1 ml), and methylene chloride (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 43 mg (59%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-morpholin-4-ylmethyl-thiazol-2-yl)-amine as a yellow oil. MS ISP (m/e): 386.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.65 (s, 1H), 7.27 (s, 1H), 7.19 (d, 1H), 7.11 (s, 1H), 6.97 (d, 1H), 6.87 (s, 1H), 3.86 (s, 3H), 3.71 (t, 4H), 3.61 (s, 2H), 2.49 (t, 4H), 2.30 (s, 3H).
Reaction SMILES: [S: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:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].[NH2:20]C1NN=C(CCCO)C=1C1SC2C=CC=CC=2N=1.N>C(O)C>[NH2:20][CH2:17][CH2:16][CH2:15][C:14]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:11]([NH2:19])[NH:12][N:13]=1
Reactant: Nc1[nH]nc(CCCO)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Agent: N
Solvent: CCO
Product: NCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (12 mg) was prepared using 130 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine, which was derived from 3-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol, and a saturated solution of ammonia gas in ethanol. MS (m/z, ES+): 274.2 (M+1, 100%), 257.2 (M-NH2, 70%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH2:21][CH2:20]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(O)[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(O)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of give 6-chloro-3-(3-fluorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.404 mmol) in NMP (2 mL) was added 2-(trans-4-aminocyclohexyl)propan-2-ol (95 mg, 0.6 mmol) and NaHCO3 (101.8 mg, 1.21 mmol). The mixture was purged with nitrogen and kept at 180° C. for 30 min with M.W. reaction. LCMS showed the reaction was complete. The mixture was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-75 (10.6 mg, 7.2%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:22]4[C:23](=[O:27])[CH:24]=[CH:25][CH:26]=[N:21]4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: O=c1cccn[nH]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-n4ncccc4=O)cc3s2)C1

Procedure:
The product of Example 1E (30 mg, 0.085 mmole), 3(2H)-pyridazinone (CAS # 504-30-3) (16 mg, 0.17 mmole), copper (11 mg, 0.17 mmole), and potassium carbonate (71 mg, 0.51 mmole) were mixed in degassed pyridine (1 ml) and the mixture was heated at reflux overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 23 mg (74% yield) of title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (m, 1H) 8.05 (m, 1H) 7.92 (dd, J=3.74, 1.87 Hz, 1H) 7.69 (dd, J=8.73, 2.18 Hz, 1H) 7.20-7.32 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.86-3.99 (m, 1H) 3.58-3.70 (m, 1H) 3.15-3.27 (m, 1H) 3.01-3.13 (m, 1H) 2.74-2.87 (m, 1H) 2.28-2.71 (m, 4H) 1.90-2.03 (m, 1H) 1.79-1.90 (m, 1H) 1.66-1.78 (m, 1H) 1.44-1.65 (m, 1H) 1.16 (s, 3H) MS: (M+H)+=367.
Reaction SMILES: [CH:1]1([C:5]2[C:6](=[O:21])[NH:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42]1[CH:46]=[N:45][C:44]([CH2:47]O)=[N:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:5]2[C:6]([O:21][CH2:47][C:44]3[N:45]=[CH:46][N:42]([CH3:41])[N:43]=3)=[N:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Reactant: Cn1cnc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2nc3c(-c4ccccc4F)nnn3cc2C2CCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.6 %

Procedure:
6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (50 g, 0.18 mmol), triphenylphosphine (120 mg, 0.44 mmol) and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (50 g, 0.44 mmol) were suspended in dry tetrahydrofuran (1.5 ml). Diethyl azodicarboxylate (70 μl, 0.44 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 48 hours during which time a precipitate formed in the reaction mixture. The crude reaction mixture was evaporated and recrystallised from EtOAc. The pale pink crystalline solid thus produced was collected by filtration and washed with diethyl ether to afford 6-cyclobutyl-3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]pyrimidine (40 mg, 60%) as pale needles, m.p. 202-205° C.; δH (400 MHz, CDCl3) 1.84-1.92 (1H, m, CH(CH2)3), 2.06-2.16 (3H, m, CH(CH2)3), 3.67 (1H, quintet, J=9 Hz, CH(CH2)3), 3.94 (3H, s, NCH3), 7.19-7.29 (2H, m, ArH), 7.32-7.36 (1H, m, ArH), 8.04 (1H, s, triazole CH), 8.12 (1H, td, J=7.5 and 1.8 Hz, ArH), 8.55 (1H, d, J=1.5 Hz, pyrimidine CH); m/z (ES+) 380 (M+H+).
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>O1CCOCC1.[NH4+].[Cl-]>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16]([O:23][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])([C:19]([F:20])([F:21])[F:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)(C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
tBuOK (136 mg; 1.2 mmol; 1.5 eq.) was added at 10° C. to a solution of 3-hydroxy-3-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (247 mg; 0.97 mmol; 1.2 eq.) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added. The reaction mixture was stirred at 100° C. for 3 hours then diluted with sat. aq. NH4Cl and extracted with EA (2×). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM) afforded the title compound (95 mg, 33%) as a colourless oil. HPLC (max plot) 98.2%, Rt 4.87 min.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.ClN1C(=O)CCC1=O.[CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[CH2:22].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:22][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=NO)cc1
Reactant: C=CP(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2ccc(N(C)C)cc2)=NO1
Yield: 46.7 %

Procedure:
In analogy to Example 1, 40 g (0.24 mol) of 4-dimethylaminobenzaldoxime, 36.17 g (0.27 mol) of N-chlorosuccinimide, 32.7 g (0.24 mol) of dimethyl vinylphosphonate and 52.3 ml (0.376 mol) of triethylamine are reacted. The resulting oily crude product is purified by chromatography on silica gel and recrystallization from tert.butyl methyl ether. 33.4 g of the isoxazoline of melting point 123° C. (decomposition) are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ncccc1CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1cccnc1OC)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a 100-mL round-bottomed flask were added 3-(bromomethyl)-2-methoxypyridine (1.10 g, 5.44 mmol), ethyl N-(diphenylmethylene)glycinate (1.46 g, 5.44 mmol, Acros, N.J.) and 5N sodium hydroxide (5.44 mL, 27.2 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(2-methoxy-3-pyridinyl)alaninate (1.52 g) as viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=1)#[N:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C#N)cc2)o1
Yield: 30 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (1.09 mg, 5.00 mmol) was converted using 4-cyanobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=100:0 to 50:50, 490 mg, 30%) which was obtained as a white solid. MS: m/e=329.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+]>[CH2:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:11][C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 39 %

Procedure:
α-(1,2-Dihydro-2-oxoquinol-4-yl)propionic acid (217 mg.) was dissolved in a mixture of hexamethylphosphoramide (2 ml.) and 2N-sodium hydroxide (2 ml.). A solution of benzyl bromide (0.528 ml.) in hexamethylphosphoramide (2 ml.) was added dropwise to the stirred solution during 2 hours. The mixture was then poured into water (10 ml.), and the resulting mixture washed with chloroform (3 × 5 ml.). The aqueous solution was acidifed to pH 1 with concentrated hydrochloric acid, and the resulting mixture was filtered and the white solid residue washed with water and dried in vacuo over phosphorus pentoxide. The solid was crystallised from ethanol to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid, m.p. 178°-180° C. (decomposition), in 39% yield.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Rh]>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
A mixture of 100 mg of the resultant compound of Example 21 and 100 mg of 5% rhodium on carbon in 3 ml of methanol was shaken under 4 atmospheres of H2 for 1 day. The resulting mixture was filtered and concentrated in vacuo. Silica gel chromatography of the residue using 20% ethyl acetate in hexane provided 92 mg (90%) of the desired compound. 1H NMR (CDCl3) δ 0.75-1.90 (br envelope, 28 H), 1.44 (s, 18H), 3.30 (br, 1H), 3.63 (m, 2H), 3.72 (m, 1H), 4.41 (br, 1H), 4.66 (br d, 1H). Mass spectrum: (M+H)+ =497.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29]O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:57]>CN(C=O)C.O>[Br:57][CH2:29][C:19]1[CH:20]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([S:9]([N:8]([C:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[O:5][N:4]=2)[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])(=[O:11])=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CBr
Reaction time: 5 h
Yield: 68.6 %

Procedure:
To a solution of the title compound of step E (0.37 g, 072 mmol) in 5 mL of DMF at 5° C., triphenylphosphine (0.283 g, 1.08 mmol) and carbon tetrabromide (0.358 g, 1.08 mmol) were added and the mixture stirred for 5 hours. The solution was then diluted with 100 mL of water and the aqueous solution was extracted with 3×100 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated. The residue thus obtained was chromatographed on 20 g of silica gel using 2:1 hexane:EtOAc to afford 0.285 g (69%) of the title compound of this step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[C:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:31][C:28]1[CH:29]=[N:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][CH:27]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: Nc1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (1.096 g, 4.38 mmol, 1.50 equiv) in dichloromethane (20 mL), 2-phenylpyrimidin-5-amine (500 mg, 2.92 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (838 mg, 4.39 mmol, 1.50 equiv), and 4-dimethylaminopyridine (713 mg, 5.84 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction was diluted with 100 mL of water and the resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, washed with 1×100 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE:EA:CH2Cl2 (20:1:0-3:1:1). The product was obtained as 150 mg (11%) of a yellow solid.