Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:39]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:24])([F:25])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)(=[O:41])[CH3:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt (65 mg, 0.13 mmol) in methylene chloride (5 mL) was added triethylamine (0.15 mL). The mixture was cooled in an ice bath and acetyl chloride (12 □L) was added. The mixture was stirred at room temperature for 30 minutes and partitioned between methylene chloride and brine. The organic layer was dried over sodium sulfate and the solvents were evaporated. The residue was first dried in vacuum and then triturated with methanol (3 mL) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide (21 mg) as a solid. LC-MS calcd for C22H20F3N5O3 (m/e) 459.2, obsd 460.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:81]1[CH:85]=[CH:84][CH:83]=[C:82]1[C:86](O)=[O:87]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:12][NH:13][C:86]([C:82]1[S:81][CH:85]=[CH:84][CH:83]=1)=[O:87]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
To a solution of (S)-3-Amino-2-({5-[(1H-indazol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester trifluoro-acetic acid salt (0.31 g, 0.46 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.20 mL, 1.38 mmol), HBTU (0.26 g, 0.69 mmol), HOBT (0.074 g, 0.55 mmol), and 2-Thiophenecarboxylic acid (0.071 g, 0.55 mmol). The mixture was stirred at room temperature 2 d, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-100% EtOAc in hexane) to give 0.13 g (49%) colorless oil product. MS m/e 579.9 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([OH:16])=[C:14]([CH:25]=[O:26])[C:13]([CH3:17])=[N:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(O)n(-c2ccc(C(C)(C)C)cc2)n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccc(C(C)(C)C)cc2)c(O)c1C=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
1.89 g (9.33 mmol) of 1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazole was dissolved in 3.6 ml of dry dimethylformamide, and 1.05 ml (11.26 mmol) phosphorus oxychloride was added gradually at 20° C. or below under cooling with ice. After the addition, the mixture was heated at 100° C. for 3 hours, then cooled to room temperature and poured into 30 ml of ice-cold water. The mixed solution was stirred at room temperature for 18 hours, and the precipitated solid was collected by filtration, washed with 20 ml of water and dried to obtain 1.61 g of the above-identified desired product as a yellow solid (yield 70%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[Li].C[Si]([NH-])(C)C.Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[K+].[Br-]>O>[OH:39][C:38]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=2)[O:12][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[NH-]
Agent: [Br-]
Solvent: O
Product: O=c1oc(-c2cccc(OC(F)(F)F)c2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'trifluoromethoxyacetophenone (3 g, 14.7 mmol), lithium bis(trimethylsilylamide (2.45 g, 14.7 mmol), chlorotrimethylsilane (2.47 g, 14.7 mmol) and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 128-132° C.; 1H NMR (400 MHz, DMSO-d6) δ4.03 (s, 2 H), 6.81 (s, 1 H), 7.2 (m, 2 H), 7.28 (m, 3 H), 7.56 (dd, 1 H), 7.69 (t, 1 H), 7.75 (s, 1 H), 7.86 (d, 1 H); IR (KBr) 2963, 1651, 1550, 1394, 1369, 1395, 1263, 1098, 1024, 800 cm-1 ; MS (CI): m/e 395 (M+H, 37), 309 (8), 273 (7), 205 (3), 119 (10); Analysis calc'd for C19H13O4S1F3.H2O: C, 55.34; H, 3.67; found: C, 54.94; H, 4.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20](O)[CH:19]=[C:18]([CH3:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:20]1[CH:19]=[C:18]([CH3:23])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: COc1cc(Nc2nc(C)cc(O)n2)ccc1-n1cnc(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Yield: 100 %

Procedure:
A solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-ol (1.45 g (46.6 mmol) in phosphorous oxychloride (4.7 mL) was heated to reflux for 2 h. The excess of phosphorous oxychloride was evaporated under reduce pressure and the residue was treated carefully with ice and then, under ice cooling, with 25% aqueous ammonia. The precipitate formed was filtered off, washed with water and then with diethyl ether and dried to give the title compound (1.53 g, 100%) as a pale-brown solid.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[CH:17]=[N:18][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:21]=2[C:22]#[N:23])=[CH:11][C:10]=1[S:28](=[O:38])(=[O:37])[N:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:13]1[C:12]([C:16]2[CH:17]=[N:18][C:19]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:21]=2[C:22]#[N:23])=[CH:11][C:10]([S:28](=[O:38])(=[O:37])[N:29]([CH3:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:9]([CH:14]=1)[O:8][CH2:7][C:6]([OH:39])=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccccc1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCC(=O)O
Yield: 17.4 %

Procedure:
[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid tert-butyl ester (27 mg, 0.046 mmol) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) and was stirred at r.t. for 1 h. The solvent was removed and purification by prep TLC eluting with 70% acetone/hexane gave [5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid 19-1 (4 mg, 0.008 mmol). MS [M+H]+: 526.0; tR=7.98 min. (method 2)
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:26])[C:13]([CH2:23][CH2:24][CH3:25])=[C:14]([C:20](=[O:22])[CH:21]=2)[C:15]([O:17]CC)=[O:16])=[CH:7][CH:6]=1>O.C(O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:26])[C:13]([CH2:23][CH2:24][CH3:25])=[C:14]([C:20](=[O:22])[CH:21]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1
Reactant: CCCc1c(C(=O)OCC)c(=O)cc(-c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)c(=O)cc(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
4.0 g (0.05 mol) of 50% aqueous sodium hydroxide is added to a suspension of 2.7 g (0.01 mol) ethyl 6-(4-chlorophenyl)-1-methyl-2-n-propyl-4-oxonicotinate hydrochloride in 50 ml of water and 10 ml of ethanol. The mixture is refluxed and stirred for 3 hrs, allowed to stand at room temperature for 18 hrs., refluxed for an additional 1 hr. and cooled to room temperature. The solution formed is extracted with three 50 ml portions of methylene dichloride and the aqueous solution is acidified to pH 1 with 12N hydrochloric acid. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is dried to afford 1.65 g (54% yield) of 6-(4-chlorophenyl)-1-methyl-2-n-propyl-4-oxonicotinic acid, mp 184°-187° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:9]([CH2:23][CH2:24][C:25]([O-:27])=[O:26])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[O:7]([C:9]1([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[CH2:23][CH2:24][C:25](=[O:26])[O:27]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CCC(Oc2ccccc2)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
Phenol (941 mg), 1-(4-nitrobenzyl) 2-oxoglutarate (3.09 g) and DCC (2.27 g) were dissolved in 100 ml of dichloromethane and stirred for 3 hours at room temperature. The precipitated crystals were filtered off and the filtrate was subjected to silica gel column chromatography eluting with dichloromethane-ethyl acetate (3:1) to obtain 1.55 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
In a 100 mL flask, methyl 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetate (3.45 g, 9.14 mmol) and lithium hydroxide.hydrate (1.15 g, 27.4 mmol) were diluted with tetrahydrofuran (24.4 mL), methanol (24.4 mL), water (12.2 mL). The reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting solid was diluted with water and adjusted to pH 3 with hydrogen chloride (1 N). The resulting precipitate was extracted with ethyl acetate (5×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (3.27 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.40 (s, 1H), 8.15-8.03 (m, 4H), 7.63 (dq, J=7.9, 1.0 Hz, 2H), 7.49-7.36 (m, 2H), 3.66 (s, 2H), 3.35 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43](=[O:50])[NH:44][CH:45]4[CH2:49][CH2:48][O:47][CH2:46]4)=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:30]=1.O([Si](C)(C)C)[K]>C1COCC1>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43](=[O:50])[NH:44][CH:45]4[CH2:49][CH2:48][O:47][CH2:46]4)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:12][CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]3)[NH:7][C:6]=2[CH:30]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccc(C(=O)NC6CCOC6)cc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CC1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(NC1CCOC1)c1ccc(-c2ccc(-c3cc4nc(OC5CCC(C(=O)O)CC5)[nH]c4cc3Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-[(6-chloro-5-[4′-(tetrahydrofuran-3-ylcarbamoyl)biphenyl-4-yl]-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-benzimidazol-2-yl)oxy]cyclohexanecarboxylate (0.115 g, 0.160 mmol) in THF (3 mL) was added KOTMS (0.062 g, 0.483 mmol). The reaction was maintained overnight at ambient temperature. Then the volatiles were removed in vacuo, and the resulting residue was acidified with 1 N aqueous HCl, and extracted with EtOAc. The organic phase was concentrated to afford the desired carboxylic acid intermediate, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C([O-])(=O)C.[K+].CO>O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[N:29][O:28][CH2:26][CH3:27])[CH3:2])[C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:20]=1
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1C(C)=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCON=C(C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reaction time: 5 h
Yield: 67.3 %

Procedure:
1.0 g of methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, 1.18 g of ethoxyamine hydrochloride and 1.18 g of potassium acetate were added to 30 ml of methanol, and the resultant mixture was refluxed with stirring for 5 hours. The reaction mixture was then poured into a cold water, and was extracted with ethyl acetate. The organic layer thus formed was washed with firstly dilute hydrochloric acid, then aqueous solution of sodium hydrogencarbonate and water in sequence. The organic layer was then dried and concentrated to obtain a solid. The solid product thus obtained was washed with n-hexane to obtain 0.76 g of the aimed compound (melting point=93° to 95° C.) at a yield of 67% as a colorless transparent crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1cccnc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.7 mg, 36%) having the following characteristics.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C)C=O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 3 h
Yield: 52.9 %

Procedure:
Methyl isocyanate (0.18 g) was added to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.51 g) in dry N,N-dimethylformamide (5 ml). The resulting mixture was stirred for 3 hours, diluted with a few ml. of ethanol and filtered. The solid was crystallised from methanol to give the title compound (0.33 g), m.p. 258°-260° C. Found: C,65.46; H,6.83; N,22.25. C17H21N5O requires: C,65.57; H,6.80; N,22.49%.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>[Zn].C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:14]2[CH:25]=[CH:26][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)([OH:16])[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 50.5 %

Procedure:
A mixture of 8.25 g of ethyl 2-bromopropionate, 11.81 g of 4,4'-dimethoxybenzophenone, 7.16 g of zinc and 70 ml of benzene was heated on an oil bath for 4 hours under reflux. The mixture was then allowed to stand to cool, after which the reaction solution was filtered. The filtrate was washed with 10% w/v aqueous sulfuric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. After the mixture had been dried, the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography through silica gel (about 400 mesh, 300 g). 7.92 g of the title compound were obtained as white crystals, melting at 67°-69° C. (after recrystallisation from a mixture of methylene chloride and hexane), from those fractions eluted with a 100:2 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:44][NH:45][C:46]([C:48]1[CH:52]=[C:51]([CH2:53][OH:54])[O:50][N:49]=1)=[O:47]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:54][CH2:53][C:51]4[O:50][N:49]=[C:48]([C:46](=[O:47])[NH:45][CH3:44])[CH:52]=4)[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(CO)on1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)on1
Yield: 82.1 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.20 g (0.43 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 1 (step 1.5.), 0.122 g (0.95 mmol) of N,N-diisopropylethylamine, 0.026 g (0.22 mmol) of N,N-dimethylaminopyridine and 0.074 g (0.47 mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol, and after chromatography on silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.170 g of pure product is obtained in the form of a white powder.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[C:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([C:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)([OH:20])[CH3:19])=[CH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2ncco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80336.6 %

Procedure:
To a stirred solution of DIPA (0.13 mL, 0.00092 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.76 mL, 0.001226 mmol). The mixture was allowed to stir at 0° C. for 30 min, was again cooled to −78° C., and then a solution of 2-(4-fluorophenyl)oxazole (0.1 g, 0.000613 mmol) in THF (2 mL) was added dropwise during 30 min 4-Acetyl pyridine (0.07 mL, 0.000674 mmol) in THF (2 mL) was then added, the reaction mixture was stirred for an additional 1 hour at −78° C., quenched with saturated ammonium chloride (2 mL), diluted with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (200-400 mesh, 2% of methanol in dichloromethane) to give 1-(2-(4-fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol (0.14 g, 82%) as white solid in 98.5% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 2H), 7.95-7.91 (m, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.14 (d, 1H), 6.38 (s, 1H), 1.81 (s, 3H); LC-MS m/z calculated for [M+H]+285.10. found 285.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:10][C:8]=2[CH:9]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[NH4+].[Cl-]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:3][OH:2])=[CH:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: OCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a cooled (0° C.) solution of 5-(benzothiazol-2-yloxy)-benzofuran-2-carboxylic acid methyl ester (170 mg, 0.52 mmol) in DCM (2 mL) was added DIBALH (0.63 mL, 89 mg 0.63 mmol) and the reaction mixture was warmed (rt, 2.5 h). The reaction mixture was treated with saturated aqueous Rochelle's Salt (2 mL) and stirred (rt, 2 h). The biphasic mixture was poured into saturated aqueous NH4Cl and extracted with DCM (2×50 mL). The organic layer was dried, filtered and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography using MeOH:DCM (3-40%) to afford the title compound (55 mg, 36%). MS (ESI): mass calcd for C16H11NO3S, 297.04; m/z found, 298.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C)C=O>[CH2:38]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[CH3:39]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (452 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).