Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[N:16]=[CH:17][O:18][C:19]=2[C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[O:14])[CH:9]=[N:8]1.Cl[C:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:37][O:36][C:30]1[CH:31]=[C:32]([O:34][CH3:35])[N:33]=[C:28]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][O:18][C:19]=3[C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:14])[CH:9]=[N:8]2)[N:29]=1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3)c2)c1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(OC)nc(N2CCCC2Cn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Yield: 55.2 %

Procedure:
To a microwave tube was added rac-N-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (40 mg, 0.11 mmol), 2-chloro-4,6-dimethoxypyrimidine (18 mg, 0.10 mmol) and Cs2CO3 (175 mg, 0.228 mmol) in MeCN (0.8 mL). The reaction mixture was irradiated at 180° C. for 30 min in the microwave, then the reaction mixture was diluted with DCM (30 mL). The organic layer was separated and washed with H2O (5 mL) and brine (5 mL). The combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (hex/EtOAc 3:7) Rf=0.4) yielded the title compound (27 mg) as a yellowish solid. LC-MS conditions D: tR=1.16 min, [M+H]+=490.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](O)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:38][O:39][C:40](=[O:52])[NH:41][CH:42]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH2:43]1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][CH:42]([NH:41][C:40]([O:39][CH3:38])=[O:52])[CH2:43]2)=[O:17])[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC(=O)O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)NC1CNc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)C1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
8.88 ml of triethylamine are added to a solution of 6.67 g of 4(S)-(3-carboxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester in 200 ml of methylene chloride under argon. The mixture is cooled to 15° C. and 5.54 g of bis(2-oxo-3-oxazolidinyl)phosphinic chloride are added. The mixture is stirred at room temperature for 2 hours. A solution of 4.36 g of (1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester [177202-73-2] in 100 ml of methylene chloride is added, followed by addition of 2.11 g of 4-N,N-dimethylaminopyridine. The reaction mixture is stirred at room temperature for 17 hours. The mixture is poured into 1M NaOH and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a slightly yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.39 (1:3 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.NC(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:14]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
2-chloro-5-methoxycarbonylpyridine (7.0 g) and urea-hydrogen peroxide adduct (6.93 g) were suspended in acetonitrile (100 mL), and trifluoroacetic anhydride (9.92 mL) was dropwise added thereto at 0° C. The reaction mixture was stirred at room temperature for 5 hours, and evaporated in vacuo to remove the solvent. After addition of saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate to the residue, the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The organic solvent was evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:8) to give the title compound as a pale brown solid (8.0 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCN
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)NCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 83 g. of N,N-dimethylethylenediamine in 730 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate of 4-acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide collected by filtration, washed with water and dried; m.p. 87-89° C. after crystallization from 2-propanol/hexane.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[F:19][C:20]([F:24])([F:23])[CH2:21][O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCC(F)(F)F
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCC(F)(F)F

Procedure:
The title compound, white solid, m.p.=125-127° C. and MS: m/e=337.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2,2,2 trifluoro-ethanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH:24](OCC)=[O:25]>C1COCC1>[CH:24]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]2=[O:23])=[O:25]
Reactant: CCOC=O
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CNC=O)cc2c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A suspension of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (400 mg, 1.14 mmol) in ethyl formate (27.4 mL, 340.7 mmol) and THF (25 mL) was stirred at 60° C. for 16 h. Subsequently the solvent was evaporated and the residue dried in vacuo for 2 h. The crude product was purified by flash-master chromatography (DCM 100-90/MeOH 0-10, %-gradients) to yield N-(6-formylaminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (316 mg, 0.831 mmol, 73%) as a light-yellow solid. 1H-NMR (DMSO-d6, 400 MHz) 3.17 ppm (s, 3H, SO2—CH3); LC-MS rt=2.32 min; MS: m/z 380.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 18.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (47.9 mg, 0.075 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (104 mg, 0226 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk37) (14.6 mg, 19%).
Reaction SMILES: C(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][N:35](C)[CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)CC.ClC(OC(Cl)C)=[O:41].[Na+].[I-].Cl>C(Cl)(Cl)Cl.ClCCCl>[N:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:41][CH2:10][CH2:9]1
Reactant: CCC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc(=O)c2cc(F)cc(N3CCNCC3)c2o1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Dry 6-flouro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (Example 72)(1 g 1.9 mmol) was added to 100 mL of rigorously dried 1,2-dichloroethane in a flask under N2 atmosphere and magnetic stirring. The mixture was cooled to 0° C. and freshly distilled 1-chloroethyl chloroformate (650 ul, 858 mg, 6 mmol, 3 eq) was added drop wise. The reaction was then heated under reflux for 5 hours at which time LC/MS revealed complete consumption of starting material. NaI (1 g, 1 eq) was added and heating continued for 2 days more. The reaction was then allowed to cool and filtered and evaporated to dryness under reduced pressure. MeOH (100 mL) was added and heated to reflux for 4 h, filtered hot and evaporated to dryness. The product was isolated by chromatography using silica gel and CHCl3/5% MeOH as an eluent. This gave 700 mg of the product HCl salt as a yellow solid. LCMS−m/z=508.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41].FC(F)(F)C([O-])=O>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41]
Reactant: Cc1ccc2[nH]c(=O)n(CCC(C)(C)N)c2c1
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc2[nH]c(=O)n(CCC(C)(C)NCC(O)c3cc(O)cc4c3OCC(=O)N4)c2c1

Procedure:
The compound is prepared according to general method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-6-methyl-1,3-dihydro-benzimidazol-2-one. Yield: 170 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]+=441.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCN2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(N3CCc4ccccc43)c2c1
Yield: 85 %

Procedure:
0.60 g of 4-chloro-6-iodoquinazoline, 0.31 ml of 2,3-dihydro-1H-indole and 0.50 ml of triethylamine in 5.00 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient EA: methanol 0-20% in 16 min.), giving 0.60 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline as yellowish solid (yield 85%, content 97%); MS-FAB (M+H+)=373.8; Rf (polar method): 2.21 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(O)(=O)C.[H][H]>C1COCC1.[Pd].C([O-])([O-])=O.[Ca+2]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]2)=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccc(N2C=CC(=O)CC2)c(F)c1

Procedure:
In a 500 ml Parr bottle, 1-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 3, 35 g, 148.3 mmol), Pd/CaCO3 (3.5 g, 10 wt %) and acetic acid (17 ml, 297 mmol) are combined in THF (350 ml). The mixture is hydrogenated at 40° C. under 15 psi hydrogen for 6 h at which time the reaction is complete by HPLC. The reaction mixture is filtered through a GF/F filter and the catalyst cake washed with THF (350 ml). The filtrate is partitioned between 500 ml of NaHCO3 and 500 ml of ethyl acetate. The organic layer is washed again with 500 ml of NaHCO3. The organic layer is separated and dried over MgSO4. The mixture is filtered, and the filtrate is concentrated under reduced pressure to afford 29.0 g (95% recovery) of the title compound, MS (ESI−) for C11H11FN2O m/z 205.0 (M−H)−; 1H NMR (MeOD) δ 7.37 (d, 1 H), 7.02 (t, 1 H), 6.47 (m, 3 H), 5.07 (d, 1 H), 3.84 (t, 2 H), 2.58 (t, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[NH2:19]>C(Cl)Cl>[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[N:19]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(F)cc1F

Procedure:
A solution of 5.3 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated with 5 parts of 2,4,6-trifluoroaniline at once. After refluxing for 24 hours, the acetic acid was stripped from the reaction mixture under 300 mm hg pressure. The residue was dissolved in 100 parts of methylene chloride and washed with 100 parts of 10% aqueous sodium carbonate. After drying over anhydrous sodium sulfate, the solution was stripped under 300 mm hg pressure. The resulting pink oil was crystallized from 70 parts of methanol at -40°C to yield 4.7 parts white crystals of 2-(2,4,6-trifluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 91°-92°C.
Reaction SMILES: [N+:1]([C:4]1C=C([N+]([O-])=O)C=C[C:5]=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.[OH-].[Na+]>C(#N)C>[CH3:5][C:4]1[N:1]=[C:16]2[C:17]([CH2:21][OH:22])=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Reactant: N[n+]1cccc(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc2c(CO)cccn2n1
Reaction time: 12 h
Yield: 26.6 %

Procedure:
To a solution of 1-amino-3-(hydroxymethyl)pyridinium 2,4-dinitrobenzenolate (100 g, 323 mmol) in acetonitrile (1.08 L), was added 2 N sodium hydroxide (485 mL) at room temperature, and the mixture was stirred for 12 hr. Acetonitrile was evaporated under reduced pressure, and the residual aqueous solution was extracted with 3 times with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (14.0 g, yield 29%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([C:10]3([CH3:15])[CH2:12][C:11]3([F:14])[F:13])[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]([C:10]2([CH3:15])[CH2:12][C:11]2([F:14])[F:13])([OH:8])[CH2:9][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:4][CH:3]=1
Reactant: CC1(C2(Cc3ccc(F)cc3)CO2)CC1(F)F
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C(O)(Cc2ccc(F)cc2)Cn2cncn2)CC1(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 6.3 g (0.026 mol) of 2-(4-fluorobenzyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-oxirane in 5 ml of dimethylformamide is added dropwise with stirring at 80° C. to a mixture of 4.6 g (0.066 mol) of 1,2,4-triazole and 0.5 g (0.0045 mol) of potassium tert.-butylate in 10 ml of dimethylformamide. When the addition is complete, the reaction mixture is stirred for 8 hours at 80° C. The solvent is subsequently stripped off under reduced pressure and the residue which remains is dissolved in ethyl acetate. The organic solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using dichloromethane as the eluent. After the eluate has been evaporated, 1.7 g (21% of theory) of 1-(4-fluorophenyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance of melting point 114° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl.C([NH:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>C(O)(C)C>[O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:23][CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1cc(OCC2CO2)c2ccoc2c1
Reactant: O=C(CCNCc1ccccc1)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(CCNCC(O)COc1cccc2occc12)NCc1ccccc1

Procedure:
In a similar manner to that described above but using a mixture of 1-(benzo[b]furan-4-yloxy)-2,3-epoxypropane (1.9 g.), β-benzylamino-N-benzylpropionamide hydrochloride (3.05 g.), sodium hydrogen carbonate (0.84 g.), water (5 ml.) and isopropanol (40 ml.) there is obtained 1-(benzo[b]furan-4-yloxy)-3-β-(N-benzylcarbamoyl)ethylamino-2-propanol, m.p. 109°-110° C. The β-benzylamino-N-benzylpropionamide hydrochloride used as starting material may also be prepared in the manner described above, m.p. 237°-239° C.
Reaction SMILES: OS(O)(=O)=O.O.[CH2:7]([OH:9])[CH3:8].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[CH2:22])[C:19](N)=[O:20]>C(Cl)Cl.[Cu]>[CH2:7]([O:9][C:19](=[O:20])[C:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])=[CH2:22])[CH3:8]
Reactant: CCO
Reactant: C=C(C(N)=O)c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: C=C(C(=O)OCC)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
Add the cyanohydrin prepared in Example 5(a), 2,4-dichloroacetophenone cyanohydrin-O-trimethylsilylether, (75 g) dropwise to a solution of concentrated H2SO4 containing 4% SO3 (60 mL) and 250 mg of copper powder at 40° C. During the addition, maintain the reaction temperature between 80°-85° C. (water bath). After all cyanohydrin is added, raise the temperature to 100° C. and heat the reaction mixture at this temperature for 30 min. Cool the reaction mixture to 90° C. and carefully treat with water (26 mL) and ethanol (60 mL). Heat the mixture at 100° C. for 15 hrs, cool and dilute with ice cold water (200 mL). Separate the organic layer, dilute with CH2Cl2 (100 mL) and wash with brine (100 mL). Extract the combined aqueous phase containing solids twice with EtOAc (400 mL), wash with saturated NaHCO3, water (100 mL each) and dry over Na2SO4. Eyaporate EtOAc in vacuo to give an oil containing a crystalline solid. Dilute this residue with a small yolume of CH2Cl2 -separated crystals of α-(2,4-dichlorophenyl)-α-methyleneacetamide which were collected by filtration (26 g). Combine the filtrate with the organic layer obtained earlier and chromatograph the concentrate on silica gel (300 g) to provide ethyl-α-(2,4-dichlorophenyl)-α-methyleneacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15])[CH3:8]>C(#N)C.C(Cl)Cl>[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:15])[CH3:8]
Reactant: CCc1oncc1C(=O)Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCc1oncc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.2 mol (17.0 g) of piperidine is added dropwise to 0.1 mol (16.0 g) of 5-ethyl-4-isoxazolecarboxylic acid chloride dissolved in 200 ml of acetonitrile, at room temperature with stirring. Stirring is continued for 20 minutes and the mixture is then cooled to room temperature and the piperidine hydrochloride precipitated is filtered off with suction. The filtrate is concentrated under reduced pressure. An oily residue is obtained, and is taken up in 200 ml of methylene chloride, and the mixture is washed first with 100 ml of 2N hydrochloric acid and then with water. After drying over sodium sulfate, the mixture is concentrated under reduced pressure and the oily residue is distilled under reduced pressure (bulb tube distillation). N-(5-Ethyl-4-isoxazolylcarbonyl)-piperidine of boiling point (7 mbar) 90°-110° C. is thus obtained.