Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:19]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-leucine ethyl ester hydrochloride according to the procedure of Example 154 as a white flake; 1H NMR (300 MHz, CDCl3) δ 0.99 (t, J=6.2 Hz, 6H), 1.30 (t, J=7.1 Hz, 3H), 1.60-1.80 (m, 3H), 2.56 (t, J=6.0 Hz, 4H), 3.72 (t, J=6.0 Hz, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.80-4.90 (m, 1H), 6.42 (d, J=8.2 Hz, 1H), 6.94 (d, J=7.0 Hz, 2H), 7.77 (d, J=7.0 Hz, 1H); MS (ES) m/z: 361.3 (MH+); HRMS Calcd. for C20H28N20O4 (M+): 360.2049. Found: 360.2081.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CCBr
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 45 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 1-bromo-3-methylbutane (40 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (27 mg, 0.063 mmol) as a yellow oil. MS: [M+H]+=426.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2)[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[NH:7][C:6](=[O:22])[O:12][C:5](=[O:13])[C:4]=12)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.114 mol) of 4-ethylisatin are suspended in 75 ml of 100 percent acetic acid, treated portionwise with 26 g (0.137 mol) of m-chloroperbenzoic acid, the temperature not rising above 50°, and then the mixture is stirred at this temperature for a further 15 minutes. The mixture is poured into ice-water and filtered. The crude product obtained is taken up in ethyl acetate and extracted cautiously with a mixture of 2 N sodium hydroxide and ice. The ethyl acetate phase is dried over magnesium sulphate and concentrated to give crude 6-ethylisatoic acid anhydride which melts at 202°-204° after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC(F)(F)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above (4,4-difluorocyclohexyl)methanol was dissolved in 5 ml of pyridine. Thereto 2.2 g of p-toluenesulfonyl chloride was added at 0° C. and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.1 g of 4,4-difluorocyclohexylmethyl p-toluenesulfonate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:8]([Br:21])[CH:7]=1>O.CO>[Br:21][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]([OH:22])=[O:4]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
NaOH (48.8 g, 1.22 mol, 2.0 eq) in H2O (1.26 L) was added to a solution of 3-bromo-4-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester (210 g, 0.61 mol, 1.0 eq) in MeOH (1.26 L). The reaction mixture was stirred at 50° C. for 2 hrs. The reaction was cooled to room temperature and concentrated to half volume. The residue was acidified to pH 5 by adding 1M HCl solution. The resulting solid was collected and dried to give the title intermediate (200 g, 99.4% yield) as white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].[NH2:20]OS(O)(=O)=O>C(O)=O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][NH:20][C:2]2=[O:1])[CH2:9][C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1ccc(C(CC(=O)O)C2CCCCC2=O)cc1
Solvent: O=CO
Product: Cc1ccc(C(CC(=O)O)C2CCCCNC2=O)cc1
Temperature: 25 °C

Procedure:
The title material of Example 201 in formic acid is added to a solution of hydroxylamine-O-sulfonic acid in formic acid over a 5 min. period with stirring under N2. The mixture is heated under reflux for 3 hours and then cooled to room temperature. The reaction is quenched with cold water and the solution is neutralized with 6N NaOH. It is then extracted three times with CH2Cl2. The combined organic layers are dried over MgSO4 and the solvent is removed on a rotary evaporator. The desired products are purified and isolated by HPLC to give both the 3- and 7-substituted title products.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>CCCCCCC.C(O)(C)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:24][C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Reactant: CC(C)(Br)c1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc(-c2ccn(C[C@H](C)c3ccccc3)n2)sc1C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide and 2-(bromo-1-methyl-ethyl)-benzene as described in Example 90 and isolated by chiral separation (90/10, heptane/isopropyl alcohol). 1H NMR (400 MHz, CDCl3) δ 7.35-7.41 (m, 5H), 7.20-7.35 (m, 3H), 7.14 (d, J=4 Hz, 2H), 7.08 (d, J=2 Hz, 1H), 6.75-6.82 (bs, 1H), 6.66 (d, J=2 Hz, 1H), 4.60 (d, J=8 Hz, 2H), 4.20-4.32 (m, 2H), 3.38-3.46 (m, 1H), 2.73 (s, 3H), 1.30 (d, J=4 Hz, 3H); MS (M+H)+=417.2; Rt=1.32 min; HRMS (M+H)+=417.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH3:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:37]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])[CH:33]([CH3:32])[CH2:38]3)=[O:29])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Preparation 1(i), but using 3.06 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 1.34 g of N,N'-carbonyldiimidazole and 2.30 g of 2-methyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 4.07 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([OH:8])[CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(O)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(O)cc2c1O
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 4-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 250° C. for 45 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. The solid is suspended in 250 mL MeOH and brought to a boil. The insoluble material is filtered and the filtrate is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2 then with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.644 g of ethyl 4,6-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.372 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:16][CH:15]=1.[NH2:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:32])[NH:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)C1
Reactant: CCOP(=O)(CN)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-nitrophenyl 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate (200 mg, 0.42 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), a solution of diethyl aminomethylphosphonate (144 mg, 0.63 mmol, 1.50 equiv) in N,N-dimethylformamide (1 mL) and triethylamine (64 mg). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 mg (17%) of diethyl (3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)methylphosphonate as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH:8](Cl)[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:15][C:16](=[CH:18][CH3:19])[CH3:17].C(O)(C)(C)C>CCOCC>[Cl:7][C:8]1([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:18]([CH3:19])[C:16]1([CH3:17])[CH3:15]
Reactant: CC=C(C)C
Reactant: ClC(Cl)c1ccsc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC1C(C)(C)C1(Cl)c1ccsc1
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium-t-butoxide (2.0 g, 18 mmol) was added over 5 min to a rapidly stirred solution of 3-dichloromethylthiophene produced as in a) (1.00 g 6.0 mmol) in dry ether (10-20 ml) at 0° C., containing 2-methylbut-2-ene (>8 equiv.). After 1 h at 20° C., the products were worked up as in Example 3a) to give oils which contained no starting material, although traces of t-butanol were present. The product was a mixture of geometrical isomers (anti/syn=1.31) (0.7 g, 59%). Kugelrohr distillation (oven temperature 80° C. at 0.1mmHg) afforded the product as a colourless oil (0.47 g, 40%) with no change in the isomer ratio (Found M+ 200.0431. C10H13SCl requires M, 200.0426). Chromatography on silica with petroleum as eluent resulted in decomposition of the minor (syn) isomer affording pure major anti-isomer (27%) (Found M+ 200.0437. C10H13SCl requires M, 200.0426) which showed νmax (film) 752s, 773s, 838s, 1453m, 2927s, 2950s and 2996 m cm-1 ; δH (200 MHz; CDCl3) 0.85 (3H, s), 1.22 (3H, s), 1.24 (4H, m), 7.11 (2H, m), 7.24 (1H, q, J 3, 5 Hz); m/z 200 (M+), 185 (M -CH3), 165 (M+ -Cl). From the 1H n.m.r. of the mixture, the minor (syn) isomer showed δH (200 Mz; CDCl3) 0.94 (3H, s), 1.05 (3H, d, J 6.5 Hz), 1.35 (1H, q, J 6.5 Hz), 1.48 (3H, s), 7.05 (1H, dd, J 1.5, 5.0 Hz) and 7.25 (2H,m); m/z 200 (M+), 185 (M+ -CH3), 165 (M+ -Cl).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:16]1([NH:23][C:24]([NH2:26])=[S:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:23][C:24]2[S:25][CH:2]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[C:3](=[O:5])[N:26]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1c[nH]c2ccccc12

Procedure:
Synthesis was performed from (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[CH2:13]([Zn]CC)[CH3:14].O.Cl>O1CCOCC1>[CH2:7]([N:5]1[CH:6]=[C:2]([CH2:13][CH3:14])[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4]1)[CH3:8]
Reactant: CCn1cc(Br)c(C(=O)OC)n1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCc1cn(CC)nc1C(=O)OC
Temperature: 75 °C
Yield: 43.9 %

Procedure:
Methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate (2.5 g, 11.4 mmol) was dissolved in anhydrous dioxane (90 mL). A solution of diethyl zinc (10.4 mL, 11.4 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (125 mg, 171 μmol). The mixture was heated at 75° C. overnight, and water plus 1 N HCl were added. The mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-30% hexane/ethyl acetate to afford methyl 1,4-diethyl-1H-pyrazole-3-carboxylate (912 mg, 48% yield).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([CH2:26]Br)=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]>C(COC)OC.CS(C)=O>[F:19][C:20]1[C:25]([CH2:26][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-hydroxyphthalimide (8.15 g, 0.05 mol) was dissolved in a mixture of dry dimethoxyethane (40 ml) and dry dimethyl sulphoxide (10 ml). To this solution was added, in one portion, potassium carbonate (3.46 g, 0.05 mol). An orange suspension resulted. The pentafluorobenzyl bromide (10.8 g, 0.05 mol) in dry dimethoxyethane (10 ml) was added dropwise over 1 h at room temperature. The reaction mixture was stirred at room temperature for 64 h and then quenched by pouring into water (1 l). The resulting slurry was filtered, the crystals washed with water and dried in vacuo to give N-(pentafluorobenzyloxy)phthalimide as white crystals (15.9)g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[N:24][CH:25]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(C(F)(F)F)cn1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and C-(5-trifluoromethyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 361 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14](Br)[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CC(C)C)c1
Yield: 62.3 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml), NaH (55-65%, 1.44 g, 36 mmoles) and isobutylbromide (4.97 g, 36 mmoles), 3.8 g of the title compound were obtained (yield: 62.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:6]([CH:11]=[O:12])=[N:7][NH:8][C:9]=2[CH:10]=1.C([O-])([O-])=O.[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:6]([CH:11]=[O:12])=[N:7][N:8]([CH:24]([CH3:26])[CH3:25])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1c(C=O)nn2C(C)C
Reaction time: 0.17 h

Procedure:
To a stirred solution of methyl 6-bromo-3-formyl-1H-indazole-4-carboxylate 1 (11.5 g, 40.63 mmol) in DMF (230 mL)) was added K2CO3 (14.08 g, 102.02 mmol) at RT under argon, and stirred for 10 min. Then 2-iodopropane (7.24 g, 42.58 mmol) was added at RT and the mixture stirred at 40° C. for 2 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue (12.4 g) was purified by silica gel chromatography (eluent: 0-10% ethyl acetate: pet ether) to afford the title compound as an off white solid (5.55 g, 42%). 1H NMR (CDCl3, 400 MHz): δ 1.659 (d, J=6.4 Hz, 6H), 4.017 (s, 3H), 4.862-4.960 (m, 1H), 7.807 (s, 1H), 7.854 (s, 1H), 10.375 (s, 1H). HPLC: 98.66%.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]2=[O:32])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][N:14]1[C:15]2[CH:16]=[C:17]3[O:24][CH2:23][CH2:22][O:21][C:18]3=[CH:19][C:20]=2[C:12]2([C:3]3[C:2](=[CH:11][C:6]4[O:7][CH2:8][CH2:9][O:10][C:5]=4[CH:4]=3)[O:1][CH2:33]2)[C:13]1=[O:32]
Reactant: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-one was obtained (74%): mp 146-148° C.; 1H NMR (300 MHz, CDCl3) δ6.64 (s, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 6.22 (s, 1H), 4.67 (ABq, 2H), 4.27-4.03 (m, 8H), 3.98-3.65 (m, 4H), 3.65-3.55 (m, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 155.0, 144.4, 143.8, 139.6, 138.2, 136.4, 124.7, 121.4, 113.3, 111.5, 99.3, 99.2, 80.1, 71.9, 70.4, 68.1, 64.6, 64.5, 64.1, 63.9, 59.0, 57.8, 40.3; MS (ES+) m/z 455.9 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1.N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([O:1][CH:2]1[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1)(=[O:16])[CH3:15]
Reactant: OC1C=CC(O)C1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC1C=CC(O)C1
Yield: 100.5 %

Procedure:
0.70 gram (7.0 mmols) of 3,5-dihydroxycyclopent-1-ene and 0.83 gram (10.5 mmols) of pyridine were dissolved in 20 milliliters of anhydrous tetrahydrofuran, after which a solution of 0.70 g (9.0 mmols) of acetic acid chloride in 6 milliliters of anhydrous tetrahydrofuran was added dropwise over a period of 15 hours at room temperature in a stream of dried nitrogen, using a syringe drive. After concentrating the solvent with a rotary evaporator, 20 milliliters of ethyl acetate was added, following which the reaction mixture was washed with dilute hydrochloric acid (5 ml × 2), saturated sodium bicarbonate solution (5 ml × 2) and saturated sodium chloride solution (5 ml × 2). The organic layer was then separated and dried with anhydrous sodium sulfate. On distilling off the solvent, 1.00 gram of a colorless oil substance was obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[F:11][C:12]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:13]=1[NH:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: Fc1ccc(C(F)(F)F)cc1Nc1nc2ccccc2o1
Reaction time: 16 h

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g., 0.1 mole) in 150 ml. of tetrahydrofuran was added dropwise to a solution of 2-fluoro-5-(trifluoromethyl)aniline in 200 ml. of refluxing tetrahydrofuran. Reflux of the reaction mixture was continued on a steam bath for 16 hours. The tetrahydrofuran solvent was then removed by distillation under vacuum. The oily residue was solidified by addition of approximately 100 ml. of water. The solid material was separated by filtration and was recrystallized from an acetone-water solvent mixture to give 2-[2-fluoro-5-(trifluoromethyl)anilino]benzoxazole having a melting point of 164°-165° C.