Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].C1(C)C(C)=CC=CC=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][OH:3])[CH:21]1[O:23][CH2:22]1
Reactant: CC(C)(CO)C(=O)O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(CO)C(=O)OCC1CO1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
96 parts by wt. 50% sodium hydroxide solution (in water) were added dropwise in 1 hour to 118 parts by wt. (1 1 mole) hydroxypivalic acid and 200 ml xylene, the temperature of the reaction mixture being kept at 110° C. The whole was kept at 110° C. for half an hour. After cooling to 50° C., 276 parts by wt. (3 mole) epichlorohydrin and 50 g Dowex were added to the reaction mixture. The temperature of the reaction mixture rose to 105° C. At this temperature the mixture was afterreacted for 1 hour. After cooling to 50° C. the water was removed azeotropically at reduced pressure (200 mbar). The salt formed and the Dowex were filtered off. The residue was washed twice with 20 ml ECH. The entire organic phase (ECH+xylene) was removed by means of rotary film evaporation. Thus 160 parts by wt. hydroxypivalic glycidyl ester were obtained in the form of a light yellow liquid with an epoxide content of 5.6 meq/g and a hydroxy content of 310 mg KOH/g.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])(=[O:5])=[O:4].[NH2:19][CH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=1>C(#N)C>[CH3:28][O:27][C:25]1[N:24]=[C:23]([O:29][CH3:30])[N:22]=[C:21]([CH2:20][NH:19][C:16]([NH:15][S:12]([C:7]2[C:6]([S:3]([N:2]([CH3:18])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:13])=[O:14])=[O:17])[N:26]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(CN)nc(OC)n1
Solvent: CC#N
Product: COc1nc(CNC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)nc(OC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
A solution of 1.3 g of 2-(N,N-dimethylsulfamoyl)-benzenesulfonyl isocyanate in 25 ml of dry acetonitrile was treated at room temperature with 0.58 g of the product from Example 4. The resulting suspension was heated to 50°-55° C. for 11/2 hours and was then stirred at room temperature for an additional 15 hours. The solution was filtered and the collected solid washed well with 1-chlorobutane and then dried to yield 0.96 g of N'-[(4,6-dimethoxy-1,3,5-triazin-2-yl)methylaminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide as a light yellow powder, m.p. 183°-189° C., contaminated with some of the unreacted heterocyclic amine. Stirring the crude product with 5% hydrochloric acid at room temperature for 15 minutes followed by filtration gave the pure product as a white powder, m.p. 199°-201° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([CH3:43])[C:35](=[O:44])[CH:34]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][CH2:52][N:53]([CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)[CH2:54][CH2:55][CH2:56]O)[CH:46]=1.C(OC(=O)C)C.[ClH:71]>C(OCC)(=O)C.O1CCCC1>[ClH:71].[ClH:71].[ClH:71].[CH3:43][N:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([O:32][CH2:56][CH2:55][CH2:54][N:53]([CH2:52][CH2:51][C:47]2[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=2)[CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)=[CH:34][C:35]1=[O:44]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(OCCCN(CCc2cccnc2)Cc2ccncc2)c2ccccc21
Reaction time: 8 h

Procedure:
Triphenyl phosphine (102 mg) and diethyl azodicarboxylate (68 mg) were added to a tetrahydrofuran (THF) solution (5 ml) of 4-hydroxy-1-methyl-1H-quinolin-2-one (63 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propane-1-ol (81.4 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.29 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and dried to give the title compound (126.8 mg) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH3:20])=[CH:10][C:9]3=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:31]2)[CH2:26][O:25]1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.228 g, 0.75 mmol) in N,N-dimethylformamide (4 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.192 g, 0.97 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and triethylamine (0.153 g, 1.51 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 70% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.175 g, 48%) as a pink solid: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603, 1H NMR (200 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.66 (m, 2H), 1.68-1.81 (m, 1H), 2.19 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.28-4.42 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.63 (s, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.16-7.33 (m, 3H), 7.36 (d, J=7.5 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[C:29]([NH:34][NH:35][C:36](=[O:47])[CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=O)[CH:30]([CH3:32])[CH3:31]>ClCCl>[CH:30]([C:29]1[O:47][C:36]([CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[N:35][N:34]=1)([CH3:31])[CH3:32]
Reactant: CC(C)C(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
20.00 g (43.00 mmol) PS-triphenylphosphine are placed in 240 ml dichloromethane, 10.88 g (42.87 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 12.10 ml (87.29 mmol) triethylamine are added dropwise. 5.83 g (21.33 mmol) tert-butyl [3-(N′-isobutyryl-hydrazino)-3-oxo-propyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 24 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down and purified by chromatography.
Reaction SMILES: C([O-])(=O)C.[CH:5]1([CH2:8][NH3+:9])[CH2:7][CH2:6]1.C([O:12][C:13](=O)[CH2:14][S:15][C:16]#[N:17])C>>[CH:5]1([CH2:8][NH:9][C:16]2[S:15][CH2:14][C:13](=[O:12])[N:17]=2)[CH2:7][CH2:6]1
Reactant: [NH3+]CC1CC1
Reactant: CCOC(=O)CSC#N
Agent: CC(=O)[O-]
Product: O=C1CSC(NCC2CC2)=N1
Temperature: 90 °C
Yield: 47 %

Procedure:
A mixture of cyclopropylmethylammonium acetate (0.45 g, 3.44 mmol) and thiocyanato-acetic acid ethyl ester (0.5 g, 3.44 mmol) was heated to 90° C. for 2 h. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The aqueous layer was also concentrated to dryness and the residue was triturated with DMF. The DMF solution was filtered and concentrated to dryness. The residues were combined and purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylmethylamino-thiazol-4-one (275 mg, 47%).
Reaction SMILES: [NH2:1][C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[N:11]1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=2)=[N:11]1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)c1ccon1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2ccon2)n1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 3-isoxazolecarboxylic acid (3.78 mmol, 0.428 g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were dissolved in DCM (70 ml) under nitrogen atmosphere. The mixture was stirred at RT for a day. The solvent was evaporated to dryness and the residue was dissolved in pyridine and refluxed for 6 h and overnight at RT. Pyridine was evaporated and the residue was diluted with DCM and water. The aqueous phase was extracted four times with DCM. The combined organics were washed with aqueous HCl solution, saturated NaHCO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.396 g of the title compound was obtained. Rotamers were obtained in 1H-NMR and analysis was repeated at elevated temperature. 1H-NMR (400 MHz, DMSO-d6, +60° C.): δ 1.38 (t, 3H), 4.49 (q, 2H), 7.21 (d, 1H), 9.05 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([F:22])[F:21])=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([F:21])[F:22])=[N:6][CH:7]=1
Reactant: CNc1nc(Nc2ccc(C(=O)OC)cc2OC(F)F)ncc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(C(=O)O)cc2OC(F)F)ncc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
Methyl 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate (500 mg) was dissolved in 5 mL of THF and 5 mL of water. After dissolution, 234 mg of lithium hydroxide was added and the reaction was stirred at room temperature over night. The mixture was checked by LCMS and then carefully acidified with 1N HCl and partitioned with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography to give 250 mg of 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoic acid.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)=[O:36])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)NC(=O)c2ccc(F)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.38 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (263 mg, 1.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (397 mg, 2.08 mmol) and 1-hydroxy-1H-benzotriazole (212 mg, 1.38 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (558 mg, 81%).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][CH:24]([F:27])[CH2:25]I>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:25][CH:24]([F:27])[F:23])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)CI
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
18 g (81.72 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 500 ml of abs. THF, and 39.22 ml (98.06 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 15 min. Subsequently, the reaction solution was warmed up to 0° C. 17.25 g (89.89 mmol) of 1,1-difluoro-2-iodoethane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed three times with semisaturated aqueous sodium chloride solution. The combined aqueous phases were reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:dichloromethane/cyclohexane 1/1). 13.57 g of the target compound were obtained (49% of theory, 84% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:26])(=[O:25])[N:20]=CN(C)C)=[CH:15][CH:14]=3)[C:11]([CH3:27])=[C:10]([C:28](N(OC)C)=[O:29])[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:20])(=[O:26])=[O:25])=[CH:17][CH:18]=3)[C:11]([CH3:27])=[C:10]([C:28](=[O:29])[CH2:35][CH3:36])[C:9]=2[CH3:34])=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c1C
Solvent: C1CCOC1
Product: CCC(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C

Procedure:
To a stirred solution of 5-(4-Chlorophenyl)-1-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N,2,4-trimethyl-1H-pyrrole-3-carboxamide (step 3, 0.750 g, 1.49 mmol) in anhydrous THF (50 ml) at 0° C., ethyl magnesium bromide (Grignard reagent, 0.994 g, 7.4 ml, 7.46 mmol) was added dropwise and reaction mixture was heated to reflux for 1 h. The completion of reaction was monitored by TLC. After cooling, reaction mixture was quenched by addition of solution of saturated ammonium chloride (10 ml) and extracted with ethyl acetate (1×50 ml). Combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 0.4% methanol in dichloromethane as an eluent to yield the title compound which was finally purified by preparative HPLC (0.062 g, 10%)
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:36])[C:32]([F:34])([F:35])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: FC(F)(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 17.8 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.188 g) was added to a solution of 4-{4-(2,2,3,3,3-pentafluoropropoxy)phenoxy]-piperidine hydrochloride (0.30 g) in dichloromethane (10 ml) and triethylamine (0.70 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by prep HPLC (using λ230 nm as the detecting wavelength) eluting with 0-95% acetonitrile, H2O, +0.2% trifluoroacetic acid. Yielded a solid product, which was dried under vacuum at 50° C. to give the title compound (0.076 g). NMR: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 7.0 (m, 4H), 4.75 (t, 2H), 4.45 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum: M−H− 513.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]2[C:16](OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-:21].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:21])[C:10]2=[CH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1CN(C)CCC1c1cccc(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1C(=O)N(C)CCC1c1cccc(OC)c1
Yield: 93.1 %

Procedure:
The ester ethyl 4-(3'-methoxyphenyl)-1-methylpiperidine-3-carboxylate (23 (5.0 g, 17.5 mmol), NaOH (1.49 g, 35 mmol), CH3OH (50 mL), and H2O (25 mL) were refluxed for 5 h. After the thorough removal of solvents, the residue was mixed with acetic anhydride (50 mL) and refluxed for 1 h, then cooled and evaporated and the crude reaction product partitioned between CHCl3 (50 mL) and saturated NaHCO3 (50 mL, pH 8). The aqueous layer was extracted with CHCl3 (2×50 mL) and the combined organic phases dried and evaporated. Distillation gave 3.77 g (92%) of 4-(3'-methoxyphenyl)-1-methyl-3-methylene-2-piperidone (24). Recrystallization (CH3Cl2 /hexane) gave the analytical sample: mp 67°-70° C.: NMR δ 7.29 (m, 1 H), 6.82 (m, 3H), 6.40 (t,J=2 Hz, 1H), 5.07 (t,J=2 Hz, 1H), 3.75 (s, 3H), 3.34 (m, 2H), 3.04 (s, 3H), 2.17 (m, 2H); IR (KBr) 1645, 1600 cm-1 ; mass spectrum m/e (rel intensity) 231 (100), 216 (13). Anal. Calcd for C14H17NO2 : C, 72.7; H, 7.4; N, 6.1. Found: C, 72.6; H, 7.3; N, 6.0.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])O.[Na+].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: NCCn1ccnn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(NCCn1ccnn1)c1ccc(O)cc1
Reaction time: 4 h
Yield: 72 %

Procedure:
To a mixture of 9.31 g (83.1 mmol) 2-[1,2,3]triazol-1-yl-ethylamine and 13.96 g (166 mmol) sodium hydrogencarbonate in 320 ml THF was added dropwise a solution of 16.0 g (83.1 mmol) 4-hydroxy-benzenesulfonylchloride in 160 ml THF at room temperature. Stirring was continued at 80° C. for 4 hours, then the solvent was evaporated and the residue triturated with 100 ml water to leave 16.05 g (72%) title compound as white solid melting at 220–223° C. (dec).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=4)[C:22]([O:24]CC)=O)=[N:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.CCO.[CH3:35][NH2:36]>O>[CH3:35][NH:36][C:22](=[O:24])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([C:16]2[N:14]3[CH:15]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:31])[F:30])=[CH:5][CH:6]=4)[CH:11]=[CH:12][C:13]3=[N:18][N:17]=2)[CH:20]=1
Reactant: CN
Reactant: CCOC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1
Solvent: CCO
Solvent: O
Product: CNC(=O)c1cccc(-c2nnc3ccc(-c4ccc(OC(F)(F)F)cc4)cn23)c1

Procedure:
Ethyl 3-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate, prepared as described above was stirred in 40% CH3NH2 in H2O 2O (2.5 mL) and EtOH (1.5 mL) at 60° C. in a sealed tube overnight. The reaction mixture was concentrated and purified by HPLC followed by further purification with prep-TLC (5% MeOH/CH2Cl2) to afford N-methyl-3-(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzamide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=1>CN(C=O)C.CCOC(C)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:19]([Cl:24])[CH:18]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
415 mg (3.00 mmol) K2CO3 and 170 mg (1.00 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride is added to a solution of 207 mg (1.00 mmol) 4-bromo-2-chloro-phenol in 5 mL DMF and the mixture is stirred for 24 h at RT. The reaction mixture is diluted with 50 mL EtOAc, extracted once with 30 mL water and twice with 30 mL semisaturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([C:12](=[O:26])[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([O:21][C:22](=O)C)[C:14]=1F)=[CH:6][NH:7][CH:8]([CH3:11])CO)[CH3:2].[F-].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[C:12](=[O:26])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]3[O:21][CH2:22][CH:8]([CH3:11])[N:7]([CH:6]=1)[C:14]=23)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1cc(F)c(F)c(OC(C)=O)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2C
Reaction time: 2 h
Yield: 41 %

Procedure:
In 30 ml of dimethylformamide was dissolved 4.30 g of the ethyl-2-(3-acetoxy-2,4,5-trifluorobenzoyl)-3-(2-hydroxy-1-methylethyl)aminoacrylate (X) thus obtained and 1.92 g (0.033 mole) of potassium fluoride was added to the mixture and the mixture was stirred at 140° to 150° C. for 2 hours. After completion of the reaction, the solvent was distilled under reduced pressure. To the residue was added water and the mixture was extracted with dichloromethane, and the organic layer was washed with water, dried and then condensed under reduced pressure. Then, the residue was washed with ethanol, and the residue was recrystallized from acetone to give 1.40 g of ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (IV) as pale brown fine needle crystals.