Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[NH4+].[Cl-]>CCO.O.C(OCC)(=O)C.[Zn]>[NH2:19][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:22])[O:3][C:2]([CH3:1])([CH3:23])[C:7]=3[CH:8]=2)[NH:16][C:15]=1[C:17]#[N:18]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc([N+](=O)[O-])c(C#N)[nH]3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(N)c(C#N)[nH]3)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
To 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-3-nitro-1H-pyrrole-2-carbonitrile (0.14 g, 0.45 mmol) in EtOH/H2O (5:1, 20 mL:4 mL) was added Zn powder (0.35 g, 5.3 mmol) and NH4Cl (0.70 g, 13 mmol) and the mixture was heated to 60° C. for 25 min. After cooling to room temperature and stirring 24 h, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of celite. The filtrate was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (60% ethyl acetate/hexane) on silica gel gave the product as an orange foam (30 mg, 24%). 1H NMR (500 MHz, d6-DMSO) δ 1.63 (s, 6H), 5.01 (s, 2H), 5.95 (d, 1H, J=2.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=2.0, 8.3 Hz), 7.54 (d, 1H, J=2.0 Hz), 10.30 (s, 1H), 11.17 (d, 1H, J=2.5 Hz). MS (ESI) [M−H]− m/z 281.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[C:14]([O:20][CH3:21])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].N1CCCCC1.C(O)(=O)C>C(Cl)Cl.O>[C:16]([C:15](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=1)[C:14]([O:20][CH3:21])=[O:19])(=[O:17])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc(C(F)(F)F)c(Cl)c1)C(C)=O

Procedure:
32.3 g (155 mol) of 3-chloro-4-trifluoromethylbenzaldehyde and 18.0 g (155 mmol) of methyl acetoacetate are dissolved in 200 ml of methylene chloride, and 1.2 ml of piperidine and 1 ml of glacial acetic acid are added. The mixture is heated for 5 hours, using a water separator. It is then washed with water, dried over MgSO4 and concentrated. The product is recrystallized twice from methanol. 25.6 g (54% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:29])[F:30])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: C1CNCCN1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCNCC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazine following General Procedure C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[NH:19][C:18](=O)[O:17][C:13]4([CH2:16][CH2:15][CH2:14]4)[C:11]=3[CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:21]#[N:22].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[NH:19][C:18](=[S:32])[O:17][C:13]4([CH2:16][CH2:15][CH2:14]4)[C:11]=3[CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:21]#[N:22]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCC1)OC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCC1)OC(=S)N2
Yield: 99.9 %

Procedure:
A solution of 1-methyl-5-(2-oxo-1,2-dihydrospiro [3,1-benzoxazine-4,1′-cyclobutan]-6-yl)-1H-pyrrole-2-carbonitrile (0.33 g, 1.1 mmol) and Lawesson's Reagent (0.23 g, 0.55 mmol) in toluene (10 mL) was heated at 100° C. Upon completion by TLC, the reaction mixture was poured into saturated sodium carbonate (100 mL) and extracted with ethyl acetate (50 mL), dried over magnesium sulfate, and concentrated. Trituration of the residue with ether (20 mL) gave 1-methyl-5-(2-thioxo-1,2-dihydrospiro[3,1-benzoxazine-4,1′-cyclobutan]-6-yl)-1H-pyrrole-2-carbonitrile (0.17 g, 49%) as a tan solid. 1H NMR (DMSO-d6): δ 12.35 (s, 1H), 7.64 (d, 1H, J=2.0 Hz), 7.51 (dd, 1H, J=8.2, 2.0 Hz), 7.15 (d, 1H, J=8.3 Hz), 7.05 (d, 1H, J=4.03 Hz), 6.43 (d, 1H, J=4.03 Hz), 3.73 (s, 3H), 2.59-2.53 (m, 2H), 2.09-2.02 (m, 2H), 1.93-1.85 (m, 2H). MS (ESI) m/z 310 ([M+H]+); MS (ESI) m/z 308 ([M−H]−); HRMS: calcd for C17H15N3OS, 309.0936; found (ESI_FT), 310.10057.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>C1(C)C=CC=CC=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: Clc1ncc(Br)cn1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cnc(Oc2ccccc2)nc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5.00 g, 0.0259 mol), phenol (3.16 g, 0.0336 mol), dibenzo-18-Crown-6 (0.47 g, 0.0013 mol) and ground potassium hydroxide (3.51 g, 0.0626 mol) in toluene (75 ml) was heated at reflux for 5 hours with azeotropic removal of water. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The layers were separated and the aqueous phase was extracted with chloroform three times. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica using n-heptane/ethyl acetate (98:2) as an eluent to give 5-bromo-2-phenoxy-pyrimidine as a white solid (3.55 g, 0.0141 mol): 1H NMR (DMSO-d6, 400 MHz) 8.80 (s, 2H), 7.45 (t, 2H), 7.27 (t, 1H), 7.22 (d 2H); TLC (n-heptane/ethyl acetate=95:5) Rf 0.20.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]>CN(C)C=O.O>[CH3:13][CH:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1NC(=O)C2CC12
Reactant: CCCCCCC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(C)N1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) and 2-bromooctane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[OH:1][C:2]1[C:7]([I:11])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(I)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 236.3 %

Procedure:
2-Hydroxy-5-nitropyridine (7.0g, 50 mmol) was suspended in 100 mL of 20% sulfuric acid and then treated with potassium iodate (4.2g, 19.6 mmol) dissolved in 10 mL of water. The mixture was heated to 100° C. and potassium iodide (8.0g, 48.2 mmol) dissolved in 20 mL of water was added dropwise over one h. The reaction mixture turns a purplish-red and a precipitate forms. After 0.5 h, the reaction mixture is cooled and filtered. The solid is stirred for 15 minwith 10% sodium meta-bisulfite solution, filtered, washed with water and dried at 80° C. overnight on a vacuum pump to give the desired compound 765A (12.32 g, 92%) as a yellow solid. The product was characterized by 1H NMR.
Reaction SMILES: CO[C:3](=[O:16])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[CH:17]([Mg]Cl)([CH3:19])[CH3:18].[Cl-].[NH4+].Cl>O1CCCC1>[C:6]([NH:5][CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3](=[O:16])[CH:17]([CH3:19])[CH3:18])(=[O:8])[CH3:7]
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1ccccc1)C(=O)C(C)C
Reaction time: 0.25 h

Procedure:
A solution of 2.30 g of N-acetylphenylalanine methyl ester (10.40 mmol) in 15 ml of tetrahydrofuran is chilled at -60° C. with a dry ice/acetone bath. To the mixture is added dropwise 10.40 ml of 2M solution of isopropylmagnesium chloride in tetrahydrofuran (20.8 mmol) with stirring and the mixture allowed to stand for 15 minutes and returned to room temperature. The mixture was stirred for 3 hours. To the mixture is added saturated aqueous ammonium chloride under ice cooling, followed by the addition of 5% hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude product is chromatographed on a column of silica gel, eluting with methylene chloride and ethyl acetate (4:1) to give 1.40 g of the objective 4-acetylamino-2-methyl-5-phenyl-3-pentanone 5. Yield, 57.7%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3C=CC=C[CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C(N1CCN(C2SC(C([O-])=O)=C(C)N=2)C1=O)C>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:23])[CH3:18]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCN1CCN(c2nc(C)c(C(=O)[O-])s2)C1=O
Product: CCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Yield: 80 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with 2-(3-ethyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 80% yield: 1H NMR (300 MHz, DMSO-d6) δ 3.97-3.91 (m, 2H), 3.54-3.48 (m, 2H), 3.23 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 0.98 (t, J=7.2 Hz, 3H); MS (ES+) m/z 256.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.00 g) in N,N-dimethylformamide (20 mL) was added N-bromosuccinimide (1.56 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give the title compound as a white solid (yield 2.28 g, 86%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][C:7]1=[O:14].[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][C:7]1=[O:14]
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-2-oxopiperidine-4-carbaldehyde (1.00 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.66 g) in 2-propanol (10 mL) was added piperidinium acetate (0.41 g). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Ethyl acetate was added to the residue, and the precipitate was removed. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethanol/heptane to give the title compound (0.48 g).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[CH:46]=[N:47][N:48]([CH2:52][CH2:53][CH2:54][OH:55])[C:49]=1[C:50]#[N:51]>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[CH:46]=[N:47][N:48]([CH2:52][CH2:53][CH2:54][OH:55])[C:49]=2[C:50]#[N:51])=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: N#Cc1c(Br)cnn1CCCO
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2C#N)ccc1N
Yield: 29.3 %

Procedure:
Prepared analogously to 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 475.3 mg, 1.715 mmol) and 4-bromo-1-(3-hydroxypropyl)-1H-pyrazole-5-carbonitrile (Compound 52D, 434 mg, 1.89 mmol) to afford 151 mg of the title compound (29%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 4.47 (t, J=7.1 Hz, 2H), 3.60 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.15 (quin, J=6.6 Hz, 2H). MS (ESI): m/z=301.24 [M+H]+. UPLC: tR=0.79 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])C(OC)=O.Cl.[C:21](O)(=O)C>>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[CH3:21]
Reactant: CC(=O)O
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Product: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a suspension of 2-(4-bromo-2-nitro-phenyl)-malonic acid dimethyl ester (crude, 8.1 mmol) in acetic acid (10 mL) is added 6N HCl (10 mL). The mixture is heated at 110° C. overnight (about 15 hr). The reaction mixture is evaporated to dryness. The crude is used in the next step without further purification. To a solution of the crude in ethanol (40 mL) is added concentrated H2SO4 (3 drops) and the resulting reaction mixture is heated at reflux over night. Solvent is removed under reduced pressure. It is purified by flash column chromatography. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 7.72-7.7 (m, 1 H), 7.26-7.22 (m, 1 H), 4.23-4.13 (q, 2 H), 3.97 (s, 2 H), 1.29-1.23 (t, 3 H).
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.S1(CCCC1)(=O)=O.C[C:22]([O:24][CH2:25][C:26]1[CH2:35][S:34][C@@H:29]2[C@H:30]([NH2:33])[C:31](=[O:32])[N:28]2[C:27]=1[C:36]([OH:38])=[O:37])=O>>[NH2:33][CH:30]1[C:31](=[O:32])[N:28]2[C:27]([C:36]([OH:38])=[O:37])=[C:26]([CH2:25][O:24][CH3:22])[CH2:35][S:34][C@H:29]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 15 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
11.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2) and 2.10 g of trimethyl borate were added to 15 ml of sulfolane. The mixture was cooled to 15° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 15° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.16 g (yield 88%) of the desired compound at a high purity.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[N:17][OH:18])[C:13]([F:16])([F:15])[F:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O>C1COCC1>[CH2:8]([C:7]1[C:2]2[O:18][N:17]=[C:12]([C:13]([F:14])([F:15])[F:16])[C:3]=2[CH:4]=[CH:5][C:6]=1[OH:11])[CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(=NO)C(F)(F)F)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,4-Dihydroxy-3-propylphenyl)-2,2,2-trifluoroethanone oxime (prepared by the method described in WO 97/28137, 4.2 g, 15.96 mmol) and triphenylphosphine (8.82 g, 33.6 mmol) were dissolved in THF (250 mL) and the mixture was cooled to 0° C. A solution of diethyl azodicarboxylate (5.02 mL, 32.0 mmol) in THF (150 mL) was then slowly added over a period of 30 minutes. The reaction mixture was stirred for 1 h at 0° C. After addition of water (500 mL), the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the product purified via silica gel flash chromatography (ethyl acetate/hexane (v/v)=1:6). The product was obtained as a white-yellow powder in a yield of 1.96 g (8.0 mmol, 50%). 1H NMR (300 MHz, CDCl3) δ 1.00 (t, 3H), 1.73 (m, 2H), 2.88 (t, 2H), 5.34 (s, 1H), 6.93 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH:17]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[CH:17]1([CH2:22][CH2:23][C:24]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)CCC1CCCC1
Solvent: ClCCl
Product: O=C(CCC1CCCC1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 63.8 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.13 g, 0.60 mmol), 3-cyclopentylpropionyl chloride (0.10 g, 0.63 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (15 mL) provided 3-cyclopentyl-N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)propanamide (0.13 g). MS (ESI) m/z 340 ([M+H]+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[N+]([O-])=O)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:20]([NH:23][CH2:24][CH:25]=[CH2:26])[CH:21]=[CH2:22]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=[C:7]([N:23]([CH2:24][CH:25]=[CH2:26])[CH2:20][CH:21]=[CH2:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc(Cl)c([N+](=O)[O-])c12
Reactant: C=CCNCC=C
Solvent: O
Product: C=CCNc1nc(N(CC=C)CC=C)nc2ccc(Cl)cc12
Yield: 85.1 %

Procedure:
In a sealed tube were stirred 268 mg (1.06 mmol) of 4-allylamino-2,6-dichloronitroquinazoline and 787 mg (8.10 mmol) of diallylamine at 120° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column to give 284 mg (yield: 85.1%) of the title compound.
Reaction SMILES: O.[OH-].[Li+:3].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1>CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[CH:20][CH:19]=1.[Li+:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Lithium hydroxide monohydrate (44.6mg) was added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (500 mg) in methanol (10 ml), which was stirred at room temperature for 30 minutes and concentrated. The remaining crystals were recrystallized from methanol-diethyl ether to obtain lithium E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (485 mg, yield 96%) as colorless crystals. m.p. 201-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(cyclobutylcarbonyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.018 g, 0.048 mmol) and ammonium acetate (0.0373 g, 0.484 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.12 mL, 0.12 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C20H26ClN4O (M+H)+: m/z=373.2; Found: 373.2.