Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.[O:10]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([CH2:20][N:21]3[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]3=[O:28])[CH:18]=[CH:19][C:11]1=2.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[O:10]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[CH:24]=[CH:23][C:22]3=[O:28])[CH:18]=[CH:19][C:11]1=2
Reactant: O=c1ccc(I)cn1Cc1ccc2c(c1)OCCO2
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1csc(-c2ccc(=O)n(Cc3ccc4c(c3)OCCO4)c2)c1
Reaction time: 0.07 h
Yield: 61.2 %

Procedure:
A 10-mL CEM vial was swept with Ar, and charged with Fibrecat 1029 (0.034 g, 0.0092 mmol), 4-methylthiophen-2-ylboronic acid (0.052 g, 0.37 mmol), a stirbar, 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-iodopyridin-2(1H)-one (0.0340 g, 0.092 mmol) dissolved in 1 mL dry dioxane, and sodium carbonate (0.092 ml, 0.18 mmol). The Argon line was removed and the vial quickly sealed. The slurry was irradiated to 120° C. (100 W, powermax=on, ramp time=2 min, to 65° C., then from 2-7 minutes, 200 W, temp=120° C., held for 5 minutes). The solution was diluted with 5 mL DCM and loaded onto an unbuffered, 10 mL Varian Chem elute CE 1005 (PN 12198007) and extracted with DCM (3×30 mL). The combined extracts were concentrated in vacuo. The sample was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end). A=10.7 mM NH4 HCO3 in water, B=ACN. A band that eluted from 25.2-26.4 minutes was isolated. The solvent was removed in vacuo to afford 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-(4-methylthiophen-2-yl)pyridin-2(1H)-one (0.0191 g, 61% yield). MS (ESI pos. ion) m/z (MH+): 340; calcd for C19H17NO3S+H+=340.1). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (d, J=1.08 Hz, 3 H) 4.23 (s, 4 H) 5.05 (s, 2 H) 6.63 (d, J=9.49 Hz, 1 H) 6.77 (t, J=1.08 Hz, 1H) 6.81-6.86 (m, 3 H) 6.84 (dd, J=2.45, 0.98 Hz, 1 H) 7.46 (d, J=2.54 Hz, 1 H) 7.53 (dd, J=9.49, 2.64 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ ppm 15.75 (s, 1 C) 51.64 (s, 1 C) 64.29 (s, 2 C) 114.82 (s, 1 C) 117.12 (s, 1 C) 117.67 (s, 1 C) 119.28 (s, 1 C) 121.20 (s, 1 C) 121.32 (s, 1 C) 124.90 (s, 1 C) 129.29 (s, 1 C) 133.15 (s, 1 C) 138.48 (s, 1 C) 138.66 (s, 1 C) 139.09 (s, 1 C) 143.48 (s, 1 C) 143.71 (s, 1 C) 161.65 (s, 1 C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[CH:20]=[C:21]([Cl:27])[C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[Cl:27]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reaction time: 20 h

Procedure:
4.4 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine were added to a suspension of 0.8 g of sodium hydroxide in 100 ml of ethanol and stirring was carried out for 20 hours at room temperature. The reaction mixture was evaporated down, the residue was taken up in water and the solution was brought to pH 3 with 10% strength HCl. The precipitate which had separated out was isolated, washed with water and petroleum ether and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1.[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([O:16][C:54]([NH:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:55])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3O)c2)c(C(C)(C)CC)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3OC(=O)Nc3ccccc3)c2)c(C(C)(C)CC)c1

Procedure:
0.01 mole of 1-(2,4,6-trichlorophenyl)-3-[3-{α-(2,4-di-t-amylphenoxy)acetamido}benzamido]-4-hydroxy-5-pyrazolone and 0.01 mole of phenyl isocyanate are dissolved in 100 ml of dehydrated toluene, added with 0.02 moles of pyridine and heated for 5 to 6 hours under reflux. The solvent is eliminated under reduced pressure after the reaction, and n-hexane is added. The solid is collected by filtration, then washed with n-hexane and dried to obtain the coupler (1) in a state of colorless powder with a melting point 72°-77° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>C1COCC1>[C:19]([C:18]1[N:14]([CH3:13])[C:15]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: COc1cc(Br)ccc1NC#N
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C#N)n2C)ccc1NC#N
Yield: 15.9 %

Procedure:
(4-bromo-2-methoxyphenyl) cyanamide (0.113 g, 0.5 mmol) tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate, filtered through a plug of silica gel, solvent evaporated and the residue was flash chromatographed using 4/1 Hexane/THF to give [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methoxyphenyl]cyanamide (0.020 g, 16%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]([CH3:29])([CH2:18][N:19]1[CH:28]=[C:22]2[N:23]=[CH:24][C:25]([Br:27])=[CH:26][C:21]2=[N:20]1)[C:16]#[N:17]>C1COCC1>[Br:27][C:25]1[CH:24]=[N:23][C:22]2=[CH:28][N:19]([CH2:18][C:15]([NH:14][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)([C:16]#[N:17])[CH3:29])[N:20]=[C:21]2[CH:26]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=452, RT=0.59 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][CH:22]=2)=[N:11][CH:10]=1
Reactant: O=Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ncc(O)cn2)cc1
Yield: 88.5 %

Procedure:
A mixture of 10.0 g of 4-(5-benzyloxypyrimidin-2-yl)benzaldehyde, 0.2 g of sodium carbonate and 250 ml of ethyl acetate was treated with 1.0 g of palladium on active charcoal (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. The inorganic material was filtered off over Sillit and the filtrate was concentrated. Recrystallization of the crude product from hexane gave 6.1 g of pure 4-(5-hydroxypyrimidin-2-yl)benzaldehyde.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[CH3:19][O-].[Na+].CI.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([CH3:19])[C:4]#[N:5]
Reactant: CSC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSC(C)(C#N)c1cccc(Oc2ccccc2)c1
Yield: 82 %

Procedure:
956 ml of alpha-(methylthio)(m-phenoxyphenyl)-acetonitrile was dissolved in 5 ml of anhydrous methanol, and 1.7 ml of a 2.5 M methanol solution of sodium methoxide was added at room temperature in an atmosphere of argon. The mixture was stirred, and 0.34 ml of methyl iodide was added dropwise. The mixture was further stirred for 1 hour at room temperature. An aqueous solution of ammonium chloride (3 g/20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 25 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 817 mg (yield 82%) of alpha-(methylthio)-alpha-(m-phenoxyphenyl)-propionitrile as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][C:14]3[C:22]4[N:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[C:18]=4[CH:17]=[CH:16][CH:15]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:3]1.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[NH:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:13][C:11]([N:9]3[CH2:8][CH2:7][N:6]4[C:2](=[O:1])[O:3][C:4]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:5]4[CH2:10]3)=[O:12])[C:22]=2[N:21]=[CH:20]1
Reactant: CC(C)(C)OC(=O)n1cnc2c(NC(=O)N3CCN4C(=O)OC(c5ccccc5)(c5ccccc5)C4C3)cccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2[nH]cnc12)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
1,1-Dimethylethyl 4-[[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]-1H-benzimidazole-1-carboxylate (74 mg, 0.13 mmol) was suspended in ethyl acetate (5 mL). A 4 M hydrogen chloride/ethyl acetate solution (6 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and then ethyl acetate was added to the residue. The obtained crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (51 mg, yield 79%).
Reaction SMILES: O=[C:2]([CH3:12])[CH:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5].Br.[NH2:14][NH2:15]>CCO.O>[CH3:12][C:2]1[NH:15][N:14]=[C:4]([NH2:5])[C:3]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: CC(=O)C(C#N)c1cccnc1
Agent: Br
Solvent: CCO
Solvent: O
Product: Cc1[nH]nc(N)c1-c1cccnc1

Procedure:
3-Oxo-2-pyridin-3-yl-butyronitrile (step 1) (1.00 g, 6.49 mmol) was dissolved in EtOH (10 ml) and water (2 ml). Hydrazine hydrobromide (2.82 g, 24.97 mmol) was added and the reaction mixture was heated at reflux for 1 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc and sat. NaHCO3. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was removed in vacuo to afford the title compound which was used without further purification; 1H NMR (d6-DMSO, 400 MHz) δ 11.51 (1H, br), 8.60 m), 8.40 (1H, m), 7.72 (1 h, m), 7.39 (1H, m), 4.60 (2H, br), 2.19 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1C(=O)N(Br)C(=O)C1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[S:22][CH2:18][CH2:19][CH2:20][S:21]1
Reactant: SCCCS
Reactant: O=Cc1ccccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Fc1ccccc1C1SCCCS1
Reaction time: 0.75 h
Yield: 78.2 %

Procedure:
To a solution of 2-fluorobenzaldehyde (10.03 g, 80.8 mmol, 1.0 eq.) and NBS (2.16 g, 12.1 mmol, 0.2 eq.) in CH2Cl2 (400 mL) was added 1,3-propanedithiol (9.8 mL, 97.6 mmol, 1.2 eq.). After 0.75 h, the reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2 and water, and the layers were separated. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and triturated with hexanes to give 2-(2-fluorophenyl)-1,3-dithiane as a white solid (13.55 g, 78% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:10]C=C)=[N:7][C:6]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([Cl:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)=[N:5]1)[CH:2]=[CH2:3]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Cl:33][C:31]1[N:30]=[CH:29][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:6]3[N:7]=[C:8]4[CH:9]([C:13]5[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=5[Cl:20])[CH2:10][CH:3]=[CH:2][CH2:1][N:4]4[N:5]=3)=[CH:23][C:24]=2[O:34][CH3:35])[CH:32]=1
Reactant: C=CCC(c1ccc(Cl)cc1Cl)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nn1CC=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: COc1cc(Nc2nc3n(n2)CC=CCC3c2ccc(Cl)cc2Cl)ccc1-n1cnc(Cl)c1
Yield: 136.7 %

Procedure:
1-Allyl-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-5-(1-(2,4-dichlorophenyl)but-3-enyl)-1H-1,2,4-triazol-3-amine (450 mg, 0.094 mmol) was subjected to a ring closing metathesis procedure analogous to Step C of Example 1 (160° C., 15 min, 25 mol % Hoveyda-Grubbs Catalyst 2nd Generation) to afford (Z)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(2,4-dichlorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (64.5 mg, 15% yield) as a dark brown solid. LC-MS (M+H)+=501.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.51 (d, J=1.53 Hz, 1 H) 7.45 (d, J=2.14 Hz, 1 H) 7.39 (d, J=2.14 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.21-7.25 (m, 1 H) 7.09 (d, J=−8.55 Hz, 1 H) 7.02 (d, J=1.53 Hz, 1 H) 6.80 (dd, J=8.39, 2.29 Hz, 1 H) 6.63 (s, 1 H) 5.99-6.10 (m, 2 H) 4.81-5.01 (m, 3 H) 3.79 (s, 3 H) 2.78-2.97 (m, 1 H) 2.58-2.78 (m, 1 H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[NH3:33].[OH-].[Na+]>CO.O1CCCC1>[C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:16][CH:17]=1)[C:6]([NH2:33])=[O:7])(=[O:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
Ethyl 2-acetylamino-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.63 g, 3.73 mmol) obtained in Example 33 was dissolved in methanol-tetrahydrofuran (1:1, 50 ml). 28% Aqueous ammonia (20 ml) was added and the mixture was stirred at room temperature for 2 days. Thereto was added 1N aqueous sodium hydroxide solution (30 ml) and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and the obtained residue was partitioned between tetrahydrofuran-ethyl acetate (1:1, 100 ml) and water (50 ml). The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue (1.00 g) was washed with hot methanol to give the title compound (560 mg, yield 36%) as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([N:15]1[CH2:16][CH2:17][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22]2)[CH2:19][CH2:20]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g (44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH and the reaction mixture was refluxed for 1 h and then stirred overnight at RT. The solvent was eliminated i. vac. and the residue was dried for 1 h under an oil pump vacuum. The crude product was reacted further without purification.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26]/[C:27](=[N:58]\[OH:59])/[C@H:28]([NH:35][C:36]([CH:38]1[N:42]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:41][CH2:40][S:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:49]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=[CH:51][C:46]([S:43]([N:42]2[CH2:41][CH2:40][S:39][CH:38]2[C:36]([NH:35][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:27](/[NH:26][C:8](=[O:10])[CH2:7][CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:58]\[OH:59])=[O:37])(=[O:45])=[O:44])=[CH:47][CH:48]=1
Reactant: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: CC(C)(C)OCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OCCC(=O)N/C(=N/O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Carboxylic acid, e.g., 3-tert-butoxypropionic acid (35 mg, 0.24 mmol), was dissolved in THF (2 mL). The resulting solution was cooled down to −15° C. NMM (84 μL, 0.76 mmol), followed by isobutyl chloroformate (33 μL, 0.25 mmol), were added. The mixture was stirred at −15° C. for 30 min. Intermediate Id, e.g. N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (108 mg, 0.22 mmol) in THF (2 mL) was added dropwise. The mixture was stirred overnight, letting the temperature increasing up to RT. Solvents were evaporated. The resulting oil was dissolved in AcOEt, and washed with sat NH4Cl and sat NaHCO3. Aqueous phases were extracted with two portions of AcOEt. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id′, e.g. 3-(biphenyl-4-ylsulfonyl)-N-[(2E)-2-[(3-tert-butoxypropanoyl)amino]-2-(hydroxyimino)-1-phenylethyl]-1,3-thiazolidine-2-carboxamide (118 mg, 86% yield), which was directly used in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[O:18]([CH2:17][CH2:16][O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1OCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2ccccc2c1OCCOc1ccccc1
Yield: 83 %

Procedure:
To 9.60 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester in 105 ml of THF were added 30 ml of 2 M aqueous sodium hydroxide and 40 ml of methanol. After 3 h at reflux the organic solvents were removed in vacuo. The residue was treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, and concentrated and dried in vacuo to yield 7.62 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 101.7 %

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in ethanolamine(5.0 ml). The reaction mixture was reacted at the same condition of Step 3 in the Example 42 to obtain 310 mg of desired compound as solid in 52% of yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:8](=[O:10])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[C:6]=12
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccccc1

Procedure:
In a preferred embodiment tetrachlorophthalic anhydride is refluxed with aniline in the presence of glacial acetic acid for 5 to 10 hours to form tetrachloro-N-phenylphthalimide which is reacted with KF in sulfolane in the presence of tributylhexadecylophosphonium bromide under nitrogen at 140° C. to 160° C. for 10 to 15 hours to form tetrafluoro-N-phenylphthalimide which in turn is hydrolyzed by refluxing with 50% H2SO4 for 15 to 25 hours. The tetrafluoro-N-phenylphthalimide is a novel compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1)[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH:22]=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH2:22][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:24]=[CH:25][C:26]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1
Reactant: O=Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCCC3)cc2F)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 50 mg of 5-[3-fluoro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 2 mL of methanol was added 0.03 mL of pyrrolidine. The resulting solution was stirred at room temperature for 1.5 h then 13.5 mg of sodium cyanoborohydride was added. After stirring at room temperature for 4 h, the reaction mixture was concentrated under reduced pressure. Ethyl acetate/water was added to the residue. The organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 80/methanol 20) to give 9 mg of 3-{2-fluoro-4-[4-pyrrolidin-1-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as a beige solid.