Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH:33]([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:7][CH:6]=1)#[N:4].O>ClCCl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH:33]([CH3:38])[C:34]([OH:36])=[O:35])=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Aqueous lithium hydroxide (2 M, 1.06 mL, 2.12 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)propanoate (intermediate 58, 350 mg, 0.70 mmol), and the mixture is stirred at room temperature over night. Water and dichloromethane are added, and the phases are separated. The organic layer is discarded, and the aqueous layer is acidified with aqueous hydrogen chloride (1 M) and extracted with dichloromethane. The organic phase is dried over MgSO4 and concentrated under reduced pressure. Yield: 274 mg; ESI mass spectrum [M+H]+=484; Retention time HPLC: 0.90 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]=[C:11](B3CC(C)(C)C(C)(C)O3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](OS(C(F)(F)F)(=O)=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Li+].[Cl-]>C(COC)OC.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:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:11]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[O:9][CH:10]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cccc2c(B3CC(C)(C)C(C)(C)O3)coc12
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12
Temperature: 150 °C
Yield: 104.7 %

Procedure:
To a solution of 2-(7-methoxybenzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (1.10 g, 4.0 mmol) in dimethoxyethane (1 mL) was added CsCO3 (0.650 g, 2.0 mmol), H2O (1 mL), 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.480 g, 1.45 mmol), LiCl (0.10 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.05 mmol). The reaction was heated in the microwave for 5 min at 150° C. The solvent was removed in vacuum, the residue taken up in 300 mL of methylene chloride, washed with 200 mL portions of saturated aqueous sodium carbonate and 1 N NH4OH (aq), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was filtered through 150 mL of silica gel with 15% ethyl acetate/hexane as eluant to give 0.50 g of the title compound. 1 H NMR (300 MHz, CDCl3); δ 1.5 (s, 9H), 2.51 (t, 2H), 3.66 (t, 2H), 4.04 (s, 3H), 4.12 (dd,2H), 6.24 (brs, 1H), 6.91 (d, 1H), 7.17 (t, 1H), 7.39 (d, 1H), 7.59 (s, 1H), MS (ES) m/z (relative intensity): 330 (M+H,100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH3:19])[CH2:9][CH2:8][C:7]2[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:17][O:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH2:3][CH2:2][O:1][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])([CH3:19])[CH2:9][CH2:8][C:7]=2[C:10]=1[CH3:18]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Pyridine (150 ml) was added to 40 g (160 mmol) of 3,4-dihydro-2-(2-hydroxyethyl)-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran for dissolution of the latter. Then the solution was cooled to 0° C. and thereto was added with vigorous stirring 34.5 g of p-toluenesulfonyl chloride gradually. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 1 liter of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate and filtered. After removal of low-boiling substances from the filtrate by distillation, the residue was purified by silica gel column chromatography to give 49.8 g (78.6% yield) of 3,4-dihydro-6-methoxy-2-[2-(p-toluenesulfonyloxy)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran, which has the following FD mass spectrum.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([CH2:16][C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH3:29])[C:20]=2[CH3:30])=O)[C:13]([OH:15])=[O:14])=[C:4]1[CH3:31])[CH3:2]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][CH3:29])[C:20]=3[CH3:30])[O:15][C:13]2=[O:14])=[C:4]1[CH3:31])[CH3:2]
Reactant: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of 40.0 g (0.096 mole) of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid (prepared as in Example 3, part A) and 450 ml of acetic anhydride was stirred approximately seventeen hours at ambient temperature under an atmosphere of air. The solid that formed was collected by filtration and washed first with acetic anhydride and then with diethyl ether. After drying at 60° C. in vacuo there was obtained 34.0 g of 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone (Formula II: R=CH3CH2 ; R1 =CH3 ; Y=H) as a white solid which melted over the range 186°-188° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:34])[CH:32]([CH3:36])[CH3:31]
Reactant: CC(C)C(=O)O
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 42.2 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), 2-methylpropanoic acid (50 μL, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 ml) as starting materials and in the same manner as in Example 380, the title compound (74 mg, 42%) was obtained as a pale-green powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:26]=[CH:27][CH:28]=4)=[O:31])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnn1-c1ccccc1
Yield: 17 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-phenyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (15 mg, 17%). 1H-NMR (δ, ppm, DMSO-d6): 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.89 (d, 1H, Harom, J=8.0 Hz), 7.06 (d, 1H, Hpyrrazole, J=2.1 Hz), 7.37-7.49 (m, 7H, Harom), 7.53 (d, 1H, Harom, J=8.0 Hz), 7.78-7.81 (m, 2H, Hpyrrazole+Py,6), 10.64 (s, 1H, NHamide), 11.16 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C22H17N6O3: 413.1362; found: 413.1366.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:41])[C:23]([NH:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[C:28]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:27]=1[F:40])=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:37]2[CH2:38][CH2:39][CH:34]([C:28]3[C:27]([F:40])=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:41])[C:31]([F:32])=[CH:30][C:29]=3[F:33])[CH2:35][CH2:36]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCNCC2)c1F
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1F

Procedure:
Example 171 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9](C(OCC2C=CC=CC=2)C([O-])=O)=[C:8]([O:22][CH3:23])[C:7]([O:24][CH3:25])=[C:6]([O:26][CH3:27])[CH:5]=1)([O-])=O>CO.[Pd]>[OH:24][CH2:7][C:8]1[O:22][C:9]2[C:8]([O:22][CH3:23])=[C:7]([O:24][CH3:25])[C:6]([O:26][CH3:27])=[CH:5][C:4]=2[N:1]=1
Reactant: COc1cc([N+](=O)[O-])c(C(OCc2ccccc2)C(=O)[O-])c(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(CO)oc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(6′-Nitro-2′,3′,4′-trimethoxyphenyl)benzyloxyacetate (1.38 g) was dissolved in methanol (40 mL), 10% palladium on carbon was added to the solution, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in xylene (50 mL), p-toluenesulfonic acid monohydrate (350 mg) was added to the solution, and the mixture was stirred for 1 hour under reflux. After the reaction mixture was concentrated under reduced pressure, water was added to the residue to conduct extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=10:1) to obtain the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[NH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13](=O)[N:8]2[N:7]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13]([Cl:22])[N:8]2[N:7]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(=O)n2nc(COC(C)=O)nc2[nH]1
Product: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1

Procedure:
Methyl 2-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-5-carboxylate (500 mg) (1.87 mmol) are suspended in 20 l of phosphorus oxychloride. The suspension is held under reflux for 5 hours. The mixture is concentrated in a water-jet vacuum, the residue is treated with dichloromethane and ice/water and extracted several times with dichloromethane. After drying and evaporation of the extract the product is crystallized from methanol. There are obtained 400 mg of methyl 2-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-5-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:31]2[C:26](=[CH:27][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:30]=2)[NH:25][CH2:24]1.[H-].[Na+]>CN(C=O)C>[CH3:22][C:23]1([CH3:38])[C:31]2[C:26](=[CH:27][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:30]=2)[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:3]=2[CH3:21])[CH2:24]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3-(4-chloro-7-fluoro-3-methylquinolin-2-yl)benzonitrile (220 mg, 0.74 mmol), 3,3-dimethyl-6-morpholinoindoline (189 mg, 0.816 mmol), sodium hydride (36 mg, 1.48 mmol) in DMF (2.0 mL) and heating at 130° C. overnight. After purification 3-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-quinolinyl)benzonitrile was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 7.94-7.98 (1H, m), 7.85-7.91 (2H, m), 7.75-7.82 (2H, m), 7.64 (1H, t, J=7.8 Hz), 7.23-7.31 (1H, m), 7.10 (1H, d, J=8.2 Hz), 6.35 (1H, dd, J=8.2, 2.3 Hz), 5.55-5.63 (1H, m), 3.68-3.79 (6H, m), 2.91-3.04 (4H, m), 2.28 (3H, s), 1.50-1.54 (3H, m), 1.47 (3H, s). Mass Spectrum (ESI) m/e=493 (M+1).
Reaction SMILES: C(=O)([O-])O.[Na+].CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[SH:24][C:25]1[S:29][CH:28]=[N:27][C:26]=1[C:30]([O:32][CH3:33])=[O:31]>O>[NH2:18][CH:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:24][C:25]3[S:29][CH:28]=[N:27][C:26]=3[C:30]([O:32][CH3:33])=[O:31])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COC(=O)c1ncsc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ncsc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 5 h
Yield: 67.1 %

Procedure:
1.7 g (2 eq.) of sodium hydrogencarbonate were added to a suspension of 2.7 g (10 mmol) of 7-ACS in 20 ml of water and 1.7 g (10 mmol) of methyl 5mercapthothiazole-4carboxylate (Preparation Example 5) were added after dissolution. The solution was then kept at 65° C. for 5 h and extracted twice with ethyl acetate after cooling. The aqueous phase was then acidified to pH 3 and the precipitated product was filtered off with suction and dried. 2.6 g (68%) of the desired title compound were obtained.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>ClC(Cl)C.C(Cl)(Cl)Cl>[C:1]([NH:6][C:7]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[F:9])=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)N=C=O
Reactant: Nc1ccccc1F
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)Nc1ccccc1F

Procedure:
To methacryloyl isocyanate (5.55 g; 50 mmol) in dichloroethane (15 ml), a solution of o-fluoroaniline (5.55 g; 50 mmol) in chloroform (30 ml) was dropwise added. After completion of the addition, the precipitated crystals were collected by filtration. From the filtrate, the solvent was removed by evaporation under reduced pressure. The residue and the crystals were cobmined together and recrystallized from benzene to give N-methacryloyl-N'-o-fluorophenylurea as colorless needles. M.P., 155°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Li][CH2:18]CCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([CH3:18])=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1
Reactant: [Li]CCCC
Reactant: COCOc1cc(OC)cc(OCOC)c1
Solvent: C1CCOC1
Solvent: CI
Product: COCOc1cc(OC)cc(OCOC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of 8 (441 mg, 1.93 mmol) in anhydrous THF (1.55 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.16 mL, 2.90 mmol) in anhydrous THF (1.26 mL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (480 μL, 7.73 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1→4:1; Hexane:EtOAc) to afford 9 as a yellow oil (314 mg, 67%): 1H NMR (CDCl3, 500 MHz) 6.38 (d, J=2.2 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 5.08 (d, J=3.6 Hz, 2H), 5.06 (d, J=2.6 Hz, 2H), 3.72 (s, 3H), 3.40 (s, 6H), 1.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) 160.3, 157.8, 155.4, 108.2, 93.9, 93.8, 93.7, 92.9, 55.0, 55.0, 54.6, 7.0; IR (film) νmax 2953, 2934, 2905, 1597, 1497, 1396, 1215, 1144, 1126, 1074, 1059, 1028, 922, 822 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C12H18O5, 243.1233. found, 243.1223.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[C:16]3[N:15]=[C:14]([CH2:17][OH:18])[N:13]([CH3:19])[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].O[C:23]1[CH:55]=[CH:54][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[N:30]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]2=[O:53])=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH2:17][O:18][C:23]4[CH:55]=[CH:54][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[N:30]([C:34]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)([C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=6)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:29]5=[O:53])=[CH:25][CH:24]=4)[N:13]([CH3:19])[C:12]=3[CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CO)nc2c(Oc3ccc(C#N)cc3)cccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Oc3ccc(C#N)cc3)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A mixture of 4-cyanophenoxy-2-hydroxymethyl-1-methyl-1H-benzimidazole (279 mg), 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (558 mg), azodicarbonylpiperidine (378 mg), tri-n-butylphosphine (303 mg) and toluene (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=1/1 as the eluant to give the title compound (706 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:30][NH:29][N:28]=1>>[N:35]1[CH:34]=[CH:33][C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)=[CH:37][CH:36]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 50.2 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (127 mg, 50%). MS (ISP) 507.4 [(M+H)+]; mp 251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(c1c(Cl)cccc1Cl)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(Cl)cccc2Cl)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (403 mg), EDCI (121 mg) and HOBt (135 mg) in DMF (8 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue crystallized from EtOAc to give 2-(2,6-dichlorophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=238-240° C.; MS (m/z) 439 (M−1); 1H NMR DMSO-d6, 400 MHz) δ 10.49 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=7.83 Hz, 1H), 8.24 (d, J=7.58 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.67 (t, 1H), 7.59 (s, 1H), 7.53 (d, J=8.08 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(O)(=O)C.O>[C:16]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 60 h
Yield: 97.9 %

Procedure:
2 g (8.348 mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene are added, at a temperature in the region of 20° C., under an argon atmosphere, to 20 g (244 mmol) of sodium acetate in solution in 100 cm3 of acetic acid. After stirring for 60 hours at a temperature in the region of 100° C., the reaction mixture is diluted with 200 cm3 of water and then extracted with 2 times 300 cm3 of dichloromethane. The organic phases are combined, washed with 100 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 2.15 g of 2-nitro-4-trifluoromethylbenzyl acetate in the form of an orange oil;
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.[Br:16][CH2:17][CH2:18][NH2:19]>[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:19][CH2:18][CH2:17][Br:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NCCBr)OCc1ccccc1

Procedure:
A solution of 0.46 mol (78.5 g) of benzyloxycarbonyl chloride in 1 volume of acetone is added slowly to a solution of 0.45 mol (92.2 g) of 2-bromoethylamine in 1 liter of nomal sodium hydroxide solution. When the reaction has ended (about 48 hours), the acetone is evaporated off under reduced pressure and the residue is then acidified to between pH 1 and 2 and extracted with ether. Benzyloxycarbonylamino-2-bromoethane is obtained after evaporation. This product is reacted with N-hydroxyphthalimide following the procedure of Example 1-a to give N-2-benzyloxycarbonylaminoethoxyphthalimide in the form of white crystals melting at 95° C. with a yield of 73%. After treatment with hydrazine under the conditions of Example 1-a, 2-benzyloxycarbonylaminoethoxyamine hydrochloride melting at 178° C. is obtained (yield=95% relative to the phthalimide).