Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C:3]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][N:4]=1.[O-][CH2:17][CH3:18].[Na+]>CCO.O>[CH2:17]([O:15][C:13]([C:12]1[NH:11][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:8]=2[C:9]=1[NH2:10])=[O:14])[CH3:18]
Reactant: CCc1nccc(NCC(=O)O)c1C#N
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccncc2c1N
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of ethyl-4-(3-cyanopyridine)glycinate (2.47 g, 12.1 mmol) under nitrogen in EtOH (60 mL) was added sodium ethoxide (0.90 g, 13.3 mmol) and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool to ambient temperature then quenched by the addition of water (3 mL) and saturated ammonium chloride solution (5 mL). The solvent was concentrated in vacuo, to provide a residue that was diluted with water (30 mL), and extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound as a brown solid (1.35 g, 55%). LCMS (method B): RT=0.61 min, M+H+=206.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Brc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2ccccc2)c(F)c1
Temperature: 90 °C

Procedure:
2,4-Difluorophenylboronic acid (15 g, 129 mmol) was added to a solution of bromobenzene (19.8 g, 126 mmol) in DME (500 mL). To this was added a solution of sodium carbonate (55.8 g, 520 mmol) in water (260 mL). The solution was degassed by bubbling argon through the mixture and then stirred under argon. Pd(dppf)Cl2 (1.5 g, 2.1 mmol) was added and the flask was flushed with argon and heated at 90° C. overnight. The mixture was then cooled to room temperature and water (150 mL) and ethyl acetate (500 mL) were added. The layers were separated and the organic layer washed with 2 M NaOH (100 mL), water (100 mL) and brine (100 mL). The black ethyl acetate layer was dried over MgSO4, charcoal was added, and the mixture was filtered through a short pad of silica. Evaporation of the solvents gave 2,4-difluorobiphenyl as a brown oil, which crystallised on standing (21.2 g).
Reaction SMILES: CN(C=O)C.C([O-])(O)=O.[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21](=O)[C:20](=[CH:23]N(C)C)[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1.[NH:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1)[C:36]([NH2:38])=[NH:37]>CCO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[C:21]3[N:37]=[C:36]([NH:35][C:39]4[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=4)[N:38]=[CH:23][C:20]=3[CH2:19][C:18](=[O:27])[N:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]=2[CH:34]=1
Reactant: CN(C)C=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and KCO3), 8-chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-i) and 4-guanidinobenzoic acid were converted to I-10 (61%): HRMS Calcd. for C25H17ClN4O3: 457.1067, Found 457.1076.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[C:11]([O:30][Si](C(C)(C)C)(C)C)[C@H:12]([CH3:29])[C@@H:13]([CH3:28])[C@@H:14]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:15](OC)OC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C:11](=[O:30])[C@H:12]([CH3:29])[C@@H:13]([CH3:28])[C@@H:14]([O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22])[CH:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(OC)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](C)C(=CS(=O)(=O)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C=C(S(=O)(=O)c2ccccc2)C(=O)[C@@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The compound prepared in Example C4 (1.39 g, 2.43 mmol) was dissolved in anhydrous methylene chloride (30 ml) under an argon atmosphere. The solution was cooled to −78° C., and tin(IV) chloride (0.3 ml, 2.56 mmol) was dropwise added to the cooled solution. The reaction solution was stirred for one hr, tin(IV) chloride (0.6 ml, 5.12 mmol) was again dropwise added to the reaction solution, and the mixture was stirred for additional 2 hr. After the completion of the reaction, an aqueous sodium hydrogencarbonate solution was added thereto, and the temperature of the mixture was raised to room temperature, followed by separation. The organic layer was concentrated under reduced pressure, and the concentrate was then purified by column chromatographic separation on silica gel (toluene:ether=15:1) to give the title compound (0.87 g,91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17]C4(CCCCC4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1>CO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]([OH:15])[CH2:18][OH:17])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CO
Product: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of (S)—N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.072 g, 0.20 mmol) in methanol (10 mL) was added concentrated HCl (3 drops) and the reaction heated to 80° C. for 3 hr. The reaction was concentrated in vacuo. The material was triturated with ethyl acetate/methanol 1/1 (10 mL) to give (S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridine-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.070 g, 0.16 mmol, 83%) as a white solid (APCI POS 424,426 M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:11][C:12]1[C:13](Br)=[N:14][CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.[Ni](Cl)Cl.C(Cl)Cl>[CH2:1]([C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Brc1cccnc1Br
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
30 mmol of n-octylmagnesiumbromide in 50 ml of absolute THF are added dropwise at from -15° to -10° C. to a solution of 5 g (21.1 mmol) of dibromopyridine and 0.12 g of 1,3-bis(diphenylphosphino)propane!nickel (II) chloride in 150 ml of absolute THF. The mixture is stirred at -10° C. for a further 3 hours. Saturated NH4Cl solution is subsequently added until a pH of 7 has become established, and CH2Cl2 is added for phase separation. The organic phase is separated off, the aqueous phase is extracted three times with CH2Cl2, the combined organic phases are dried over MgSO4, and the solvent is stripped off in a rotary evaporator. The crude product is chromatographed on SiO2 using CH2Cl2.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI>O>[CH3:3][N:24]([C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(C(=O)c1ccncc1)c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Sodium hydride (60% (w/w) oil mixture) (200 mg, 0.500 mmol) was added at 0° C. to an N,N-dimethylformamide (DMF; 0.5 ml) solution of N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (121 mg, 0.496 mmol), obtained as described in Referential example 1-3. The resulting mixture was stirred for one hour, and an N,N-dimethylformamide (DMF) solution of methyl iodide (0.8 M, 0.62 ml, 0.496 mmol) was added thereto at 0° C. The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12 g, hexane/ethyl acetate=1/1). Thus, N-methyl-N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0614) (65.9 mg, 51.5%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH2:16].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][CH3:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 15.1 g (78 mmol) of (3,4-dimethoxyphenyl)acetone (1) in 102 mL of methanol was cooled to 4° C. and was treated with 35 mL of 40% aqueous methylamine. To the reaction mixture, 3.5 g (92.5 mmol) of sodium borohydride was then added, and the temperature of the reaction was maintained at 4° C. The reaction mixture was allowed to stir for an additional 30 minutes, then concentrated under reduced pressure. To the residue, 60 mL of water was added, and the resulting reaction mixture was acidified to pH 1 using 6N HCl. The aqueous layer was extracted with 5×50 mL of dichloromethane, and the pH was adjusted to pH 13 using 6N NaOH. The aqueous layer was extracted with 4×75 mL of dichloromethane. The organic layers were combined, dried and concentrated to give 15 g (72 mmol, 92%) of 1A as a colorless oil (M+H, 210).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)[CH2:5][OH:6].[BrH:16]>>[BrH:16].[NH2:3][CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[CH2:5][OH:6]
Reactant: COc1cccc(CC(N)CO)c1
Agent: Br
Agent: Cl
Product: NC(CO)Cc1cccc(O)c1

Procedure:
8 gm of the hydrochloride obtained in (a) were admixed with 80 ml of 48% hydrobromic acid, and the mixture was refluxed for one hour. Thereafter, the reaction mixture was evaporated to dryness, the residue was stripped of water by entrainment with xylene, the solvent was distilled off, and the residue was recrystallized from ethyl acetate, yielding 6 gm (66% of theory) of the compound of the formula ##STR9## which had a melting point of 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH:13][O:14][CH3:15])[CH2:11][F:12].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31])[CH2:11][F:12]
Reactant: CONC(CF)Cc1ccc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(CF)Cc1ccc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
To a stirred solution of N-[2-(2,4-dichlorophenyl)-1-fluoromethyl-ethyl]-O-methyl-hydroxylamine (0.21 g; 0.82 mmol), prepared as described in example P7c and triethylamine (0.13 ml; 0.90 mmol) in dichloromethane (1.9 ml) under nitrogen at 15° C. was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.16 g; 0.82 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen. The mixture was poured in water and extracted three times with dichloromethane. Combined organics were dried over sodium sulfate and the solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 10:90) to afford 0.22 g (64% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)-1-fluoromethyl-ethyl]-methoxy-amide as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].Cl.[CH3:13]O>>[CH3:13][O:4][C:3](=[O:5])[C@@H:2]([NH2:1])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N[C@@H](CC1CCCC1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CC1CCCC1
Temperature: 65 °C
Yield: 73 %

Procedure:
(S)-2-Amino-3-cyclopentyl-propionic acid (Chemimpex, 1.0 g, 6.36 mmol), methanol (15 mL) and concentrated hydrochloric acid (2 mL) was placed in a reaction flask and heated at 65° C. for 16 h. After such time, the reaction mixture was concentrated in vacuo and then dissolved in water. The resulting solution was then treated with a saturated aqueous sodium bicarbonate solution until pH ˜7-9. It was then extracted with ethyl acetate and the organic layers combined, dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo to afford (S)-2-amino-3-cyclopentyl-propionic acid methyl ester (796 mg, 73%) as a clear colorless oil: HR-ES(+) m/e calcd for C9H17NO2 [M+H]+ 172.1332, observed 172.1332; 1H NMR (300 MHz, DMSO-d6) δ ppm 3.60 (s, 3H), 3.25 (dd, J=6.04, 7.85 Hz, 1H), 1.34-1.96 (m, 9H), 0.92-1.14 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O:23]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:31][CH:32]=2)=[O:38])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Oc2ccccc2)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-phenoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CO.C(N(CC)C(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:5]1[CH:4]=[CH:3][C:2]([C:7]([O:9][CH3:10])=[O:8])=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Reaction time: 12 h
Yield: 76 %

Procedure:
tert-Butyl 5-bromo-2-chlorobenzoate (1.9 g) (WO2003095430) was dissolved in methanol (18 ml) with N,N-diisopropylethylamine (2 mL) and dichlorobis(triphenylphosphine)-palladium(II) (0.134 g). The mixture was carbonylated at 85° C. for 12 h. The cooled solution was evaporated and purified by flash chromatography, eluting with 5:95 ethyl acetate/isohexane, to yield the subtitle compound as a colourless oil (0.67 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9]2=[O:16]>OS(O)(=O)=O.O=S(=O)=O>[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[C:11](=[O:15])[NH:10][C:9]2=[O:16]
Reactant: O=C1NC(=O)c2cc(F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C1NC(=O)c2cc([N+](=O)[O-])c(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To 753 mmol fuming nitric acid at 0° C. was added dropwise 150 ml 20% oleum. 150.6 mmol 5-fluoro-isoindole-1,3-dione was then added portionwise and the resulting suspension was allowed to warm to room temperature over 4 hours and then stirred for a further 16 h at room temperature and finally was heated at 50° C. for 3 h. The reaction mixture was poured onto ice and the resulting mixture was filtered and the filter cake dried in vacuo to afford the title compound as a yellow solid (68% yield). MS (m/e): 209.1 ([M−H]−, 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:18][C:15]1([CH3:19])[N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13](=[O:20])[N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)[C:16]1=[O:17]
Reactant: CCCCCCCCCBr
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C

Procedure:
Using the procedure of Example 1, 1 g of 1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl-imidazolidine-2,5-dione prepared from a 50% suspension of 170 mg of sodium hydride in oil and 0.7 ml of 1-bromo-nonane were reacted to obtain after chromatography on silica 1.08 g of the desired product melting at 63° C.
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH3:19][C:16]1([CH3:20])[CH2:17][CH2:18][C:13]([CH2:12][N:9]([OH:8])[CH:10]=[O:11])([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14][CH2:15]1
Reactant: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCC(CN(O)C=O)(C(=O)NNc2nccc(C(F)(F)F)n2)CC1
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of N-benzyloxy-N-{4,4-dimethyl-1-[N′-(4-trifluoromethyl-pyrimidin2-yl)-hydrazinocarbonyl]-cyclohexylmethyl}-formamide (0.11 g, 0.23 mmol) in methanol (10 mL) was added 10% Pd/C (0.032 g). The reaction mixture was subjected to hydrogenation for 1 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with methanol (20 mL). Removal of the solvent provided the title compound as a white solid (0.066 g, 74%). MH+390.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[N:20]1([CH2:26][CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCN1CCOCC1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCN2CCOCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-morpholin-4-yl-ethylamine and DIEA to give 2-(2-morpholin-4-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 368 (MH+).
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[CH:2].C=O.[CH:20](NC(C)C)(C)C.Cl>O1CCOCC1>[CH:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[C:2]=[CH2:20]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)NC(C)C
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: C=C=CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 20 °C

Procedure:
10 g of α-ethynyl-3-phenoxybenzyl alcohol, 2.1 g of paraformaldehyde, 5.3 g of diisopropylamine, 0.215 g of CuBr and 50 ml of dioxane are refluxed for 2 hours. The reaction mixture is cooled to 20° C., poured into a solution of 2 N HCl and extracted with ether. The organic phase is washed with 10% potassium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed over silica gel with a 7:3 mixture of hexane/ether as eluant, affording the compound of the formula ##STR5## with a refractive index of nD20° =1.5942.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:12])=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH3:12])[C:4]=2[CH:3]=1
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
In a 100 ml round-bottomed flask, 1 eq. of the compound obtained in Step A, 10 eq. of polyphosphoric acid and 1 eq. of phosphoric anhydride are mixed together. The mixture is stirred for 3 hours at 180° C. and is then hydrolysed. Extraction with ether is carried out, and the organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](F)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Tl].[C:25]1(=[O:30])[CH2:28][C:27](=[O:29])[CH2:26]1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([CH:26]3[C:27](=[O:29])[CH2:28][C:25]3=[O:30])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)F
Reactant: O=C1CC(=O)C1
Agent: [Tl]
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)C1C(=O)CC1=O

Procedure:
In the same manner, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid fluoride is reacted with the thallium salt of cyclobutane-1,3-dione to yield 2-[[2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]]cyclobutane-1,3-dione (V; Y is H, Z is CF3, R1 is CH3 and n is zero).
Reaction SMILES: C(O)=O.C([O:11][CH2:12][C:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([C:23]3[C:24]([O:40][CH2:41][CH3:42])=[N:25][CH:26]=[C:27]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:28]=3)=[N:17][C:16]=2[N:15]([CH2:43][CH3:44])[N:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH2:41]([O:40][C:24]1[C:23]([C:18]2[NH:19][C:20](=[O:22])[C:21]3[C:13]([CH2:12][OH:11])=[N:14][N:15]([CH2:43][CH3:44])[C:16]=3[N:17]=2)=[CH:28][C:27]([S:29]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH2:37]2)(=[O:31])=[O:30])=[CH:26][N:25]=1)[CH3:42]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(c(COCc3ccccc3)nn2CC)c(=O)[nH]1
Agent: [Pd]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(c(CO)nn2CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
Formic acid (1.5 ml) was added to a mixture of the title compound of example 23 (750 mg, 1.3 mmol) and 10% palladium on charcoal (750 mg) in ethyl acetate (15 ml), and the reaction stirred under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through Arbocel, the filter pad washed with water (30 ml) and ethyl acetate (30 ml), and the filtrate basified using 2N sodium hydroxide solution. The layers were separated, the aqueous extracted with dichloromethane (3×100 ml), and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with ether, to afford the title compound as a white solid, (375 mg).