Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[CH3:11][CH:12]([C:18]([CH3:20])=O)[C:13](OCC)=[O:14]>>[CH3:11][C:12]1[C:13](=[O:14])[N:6]2[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:3][C:2]2=[N:1][C:18]=1[CH3:20]
Reactant: COC(=O)c1cnc(N)s1
Reactant: CCOC(=O)C(C)C(C)=O
Product: COC(=O)c1cn2c(=O)c(C)c(C)nc2s1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-amino-thiazole-5-carboxylic acid, methyl ester (5 g) was reacted with ethyl 2-methyl-acetoacetate (9.11 g) in polyphosphoric acid (25 g: 13.3 g of H3PO4 and 11.7 g of P2O5) under stirring at 100° C. for three hours. After cooling, dilution with ice water and neutralization with 20% NaOH, the precipitate was filtered, washed with water and crystallized from CH2Cl2 -hexane to give 6,7-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 158°-159° C. (5.46 g), which was reacted with benzaldehyde (3.52 g) in methanol (120 ml) in the presence of sodium methylate (2.7 g) under stirring at reflux temperature for 120 hours. After cooling and concentration in vacuo, the precipitate was filtered and dissolved in a mixture of dimethylformamide and formic acid. The solution was diluted with ice water and the precipitate was filtered, washed with water until neutral and crystallized from isopropyl alcohol to give 2.8 g of 6-methyl-7-trans-(2-phenylethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 257°-259° C., N.M.R. (CF3COOD) δp.p.m.: 2.50 (s) (3H, --CH3), 7.36 (d) (1H, β-ethenyl proton), 7.40-7.90 (m) (5H, phenyl protons), 7.73 (d) (1H, α-ethenyl proton), 9.07 (s) (1H, C-3 proton), JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=O)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[F:20][C:21]1[C:22]([NH2:36])=[N:23][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:25][CH:26]=1>C(Cl)(Cl)Cl>[F:20][C:21]1[C:22]([N:36]=[C:3]([N:2]([CH3:7])[CH3:1])[CH2:4][CH3:5])=[N:23][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[N:25][CH:26]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CCC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=Nc1nc(OCc2ccc(F)cc2)ncc1F)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of N,N-Dimethylpropionamide (0.202 g, 2.0 mmol) in CHCl3 (2 mL) was added phosphorous oxychloride (POCl3, 0.066 g, 0.43 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1 h. Triethylamine (0.22 g, 2.2 mmol) and 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.40 mmol) were added, and the mixture was agitated at 50° C. for 3 h, cooled to room temperature, partitioned between chloroform and water, the phases separated, and the organics evaporated under reduced pressure. Purification by reverse phase chromatography afforded the title compound (0.042 g, 31% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.99 (m, 2H), 5.30 (s, 2H), 3.13 (s, 6H), 2.55 (q, J=7.7 Hz, 2H), 1.15 (t, J=7.7 Hz, 3H); HPLC-MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[I-].[K+].C(#N)C>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:4][CH:5]=1)(=[O:8])[NH2:9]
Reactant: CCOP(OCC)OCC
Reactant: NC(=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(N)=O)cc1)OCC
Yield: 93.3 %

Procedure:
The compound (44.83 g, 0.264 mol) obtained in Example 1, triethyl phosphite (53.21 g, 0.320 mol), potassium iodide (39.4 g, 0.237 mol) and acetonitrile (224 mL) were charged and stirred under reflux for 4 hrs. The reaction mixture was allowed to return to room temperature, and water (336 mL) was added. The mixture was concentrated under reduced pressure, and the residue (315 g) was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with cold water (20 mL) and dried in vacuo at 40° C. for 7 hrs. to give the title compound (66.79 g, yield 93.2%) as slightly yellow crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([O:10]C([O-])=O)=O)([CH3:6])([CH3:5])[CH3:4].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][CH:27]1[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:37][C:38]#[N:39])[C:28]1=[O:40])=[O:25])=[CH:18]2>CO.C1COCC1.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][CH:27]1[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:37][CH2:38][NH:39][C:8](=[O:10])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[C:28]1=[O:40])=[O:25])=[CH:18]2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
Prepared using an identical procedure as for Example 44 with sodium borohydride (1298 mg, 34.3 mmol), cobalt chloride hexahydrate (1632 mg, 6.86 mmol), tert-butyldicarbonate (1497 mg, 6.86 mmol) and 5-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 11, 1299 mg, 3.43 mmol) in MeOH (15 mL) and THF (10 mL). The reaction was stirred at ambient temperature for 1.5 h to give the title compound (1560 mg, 94%) as a pale tan solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:47]([C:49]1[C:50]([C:65]([F:68])([F:67])[F:66])=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([CH2:58]/[C:59](=[N:62]/[H])/[NH:60]O)[C:53]([CH3:64])=[CH:52]2)#[N:48]>CC#N>[CH3:64][C:53]1[N:54]([CH2:58][C:59]2[N:62]=[C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:12])[N:8]=3)[O:11][N:60]=2)[C:55]2[C:51]([CH:52]=1)=[C:50]([C:65]([F:67])([F:66])[F:68])[C:49]([C:47]#[N:48])=[CH:57][CH:56]=2
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Reactant: [H]/N=C(/Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 45.9 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-pyridinecarboxylic acid (ref: European Journal of Organic Chemistry (2003), (8), 1569-1575) (0.032 g, 0.169 mmol) in 2 mL of MeCN was added DIEA (0.022 g, 0.169 mmol) and HATU (0.064 g, 0.169 mmol). After stirring at rt for 2 min, (1Z)-2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.050 g, 0.169 mmol) was added. After stirring at rt for 30 min, the mixture was heated in a sealed tube at 150° C. for 1.5 h. Upon cooling, the mixture was concentrated to dryness and the residue was purified by silica gel chromatography using a 5-50% EtOAc-hexanes gradient. The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.035 g, 46% yield): MS (ES) m/z 452 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH2:32][CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)CCc1ccccc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)CCc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 22 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-phenylethanesulfonyl chloride, the title compound (yield 22%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18]>C(Br)C.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: Cc1ccsc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
To a mixture of 1.2 g (0.05 mole) of magnesium turnings and 50 ml of anhydrous tetrahydrofuran was added under a nitrogen stream one drop of ethyl bromide, followed by adding 10 g (0.0395 mole) of 4-(3-methyl-2-thienyl)-1-bromobenzene (boiling point 171°-175° C./16-17 mmHg). After refluxing for 30 minutes, the mixture was cooled. To the mixture was added a solution of 2.8 g (0.0205 mole) of anhydrous zinc chloride in 50 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. To the mixture was added 7.2 g (0.0398 mole) of ethyl 2-bromopropionate. After having been stirred at 50° to 60° C. for one hour, the mixture was freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of 2 N hydrochloric acid and 50 ml of benzene. The organic layer was separated, washed with water, and freed from the solvent by distillation under reduced pressure. The residue was mixed with 50 ml of an ethanol solution containing 2.3 g of sodium hydroxide, heated under reflux for 3 hours, and then freed from the ethanol by distillation. The residue was mixed with 100 ml of water and 50 ml of benzene. The aqueous layer was separated, neutralized with hydrochloric acid, and the liberated oily substance was extracted with cyclohexane. The extract solution was dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: cyclohexane) to obtain 3.2 g (32.9% yield) of intended 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH:15]2[CH3:30])=[CH:10][CH:9]=1.[OH-].[Na+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH3:30])=[CH:10][CH:9]=1
Reactant: COc1ccc(N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2C)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N2CCNCC2C)cc1

Procedure:
To 11.9 parts of water was added dropwise 11.5 parts of sulfuric acid with stirring and while cooling. Then there was added portionwise 4.6 parts of dl-1-(4-methoxyphenyl)-2-methyl-4-(4-methylphenylsulfonyl)piperazine and after addition was complete, the whole was stirred and refluxed for 20 hours. After cooling the reaction mixture was poured onto crushed ice. The whole was alkalized with sodium hydroxide solution 15N and extracted three times with 4-methyl-2-pentanone. The combined extracts were dried over potassium carbonate and evaporated. The oily residue was distilled in vacuo, yielding 1.7 parts of oily 1-(4-methoxyphenyl)-2-methylpiperazine; bp. 144°-147° C. at 0.3 mm pressure; nD20 =1.5633; d2020 =1.0782 (76).
Reaction SMILES: [CH:1]1([C:5]2([CH2:9][OH:10])[CH2:8][O:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>ClCCl.N1C=CC=CC=1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][CH2:9][C:5]2([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:8][O:7][CH2:6]2)=[O:17])=[CH:14][CH:13]=1
Reactant: OCC1(C2CCC2)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCC1(C2CCC2)COC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyclobutyl-3-hydroxymethyloxetane (2.84 g, 20 mmol) in dry dichloromethane (40 ml) and pyridine (3 ml) at 0° C. under nitrogen was added a solution of 4-iodobenzoyl chloride (5.33 g, 20 mmol) in dry dichloromethane (10 ml). The solution was stirred overnight at room temperature, washed with water, dried over anhydrous sodium sulphate and evaporated. (3-Cyclobutyloxetan-3-yl)methyl 4-iodobenzoate was obtained as a white solid (7.42 g, 99%) which was not purified further.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2cccc(OCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)N1CCC(Oc2cccc(O)c2)CC1
Yield: 70.8 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[O:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[O:22])=[C:19]([OH:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(O)c2C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A solution of tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl}piperazine-1-carboxylate (0.054 g, 0.11 mmol) in methylene chloride (3.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and the solid was collected by filtration and dried to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-(piperazine-1-carbonyl)benzofuran-3(2H)-one (0.018 g, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C(C)=NNc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=NNc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A mixture of ethyl 2-[(4-hydroxy-2-nitrophenyl)hydrazono]propanoate (30 g), methyl iodide (21.3 g), potassium carbonate (21 g) and N,N-dimethylformamide (300 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and saturated brine, dried (MgSO4), and concentrated. The obtained residue was crystallized from diethyl ether to give the title compound (28 g, yield 89%) as orange crystals. MS: 282 (MH+).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][O:51][CH:52]1[CH2:57][CH2:56][N:55]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:54][CH2:53]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:61]3[CH2:60][CH2:59][CH:58]([N:55]4[CH2:56][CH2:57][CH:52]([O:51][CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:53][CH2:54]4)[CH2:63][CH2:62]3)=[O:40])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: CCOC(=O)COC1CCN(C2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.30 mL (2.16 mmol) triethylamine were added to a mixture of 300 mg (0.54 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 220 mg (0.64 mmol) ethyl([1,4′]bipiperidinyl-4-yloxy)-acetate (Example A13c) and 200 mg (0.62 mmol) TBTU in 3 mL DMF and the reaction mixture was stirred for 4 h at RT. Ice and saturated NaHCO3 solution were added and the precipitate was filtered off. This was taken up in DCM and a little EtOH and dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)[C:6]([NH2:20])=[N:7][O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]>O1CCOCC1>[C:1]([O:4][CH:5]([C:6]1[N:20]=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[O:8][N:7]=1)[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)C(N)=NOC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)c1noc(-c2ccc([N+](=O)[O-])cc2)n1
Yield: 43.6 %

Procedure:
The mixture of 2-acetoxy-5-(1-benzylpiperidin-4-yl)-1-(4-nitrobenzoyloxyimino)pentylamine (1.5 g) and molecular sieves 4A (7.5 g) in dioxane (50 ml) was refluxed for 2 hours. After molecular sieves were removed by filtration, the filtrate was evaporated in vacuo. The residue was chromatographed on silica eluting with 3% methanol in chloroform to give 3-[1-acetoxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole (0.63 g, 43.6%). The compound (74 mg) was dissolved in a solution of fumaric acid (18 mg) in ethanol to give 3-[1-acetoxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole fumarate (80 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:4]=1[N:5]([C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=O)[CH3:2].Cl.C([NH2:25])=O>>[CH2:1]([C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:4]=1[N:5]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:25]=[CH:6]1)[CH3:2]
Reactant: NC=O
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)cccc1CC
Agent: Cl
Product: CCOC(=O)c1cncn1-c1c(CC)cccc1CC

Procedure:
17.8 g (0.06 mole) of ethyl 2-(2,6-diethyl-N-formylanilino)-3-hydroxyacrylate were heated with stirring together with 10 ml of concentrated hydrochloric acid and 50 ml of formamide for 8 hours at an oil bath temperature of 160° C. (internal temperature 140° C.). After cooling, the product was extracted by shaking with a mixture of 100 ml of water and 100 ml of diisopropyl ether, the organic layer was separated off and the aqueous phase was extracted once more with diisopropyl ether. The combined organic phases were dried over sodium sulphate and evaporated. 14.8 g (90% of theory) of the title compound were obtained in the form of a colorless oil of boiling point 145° C./0.01 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(C(C)C)CC)(C)C.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=1)=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 83.8 %

Procedure:
Part A: 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). After one hour the mixture is concentrated in vacuo to give an oil. This oil is crystallised from ethanol to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield). 1H-NMR (200 MHz, DMSO-d6): δ 10.90 (br s, 1H), 7.91 (br d, J=8 Hz, 2H), 7.63–7.77 (m, 4H), 7.57 (dt, J=8 Hz, J=2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:17])[CH2:15][OH:16])[C@H:9]([CH3:18])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][C:27]([Cl:33])=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[Cl:33][C:27]1[CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:24]([O:16][CH2:15][C:14]([N:10]2[CH2:11][C@H:12]([CH3:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH2:8][C@H:9]2[CH3:18])=[O:17])=[N:25][CH:26]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.90 g, 3.2 mmol) in toluene (20 mL) at 0° C. was added sodium hydride (0.18 g, 4.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 15 minutes, then 2,5-dichloro-3-nitro-pyridine (0.65 g, 3.38 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The reaction was quenched by the slow addition of water (5 mL) then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (1.25 g).