Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)([C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)c1c[nH]cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1cc(F)cc(C(c2cc(F)cc(F)c2)c2c[nH]cn2)c1
Yield: 42.1 %

Procedure:
Bis-(3,5-difluoro-phenyl)-(1H-imidazol-4-yl)-methanol (0.5 g, 1.55 mmol) was dissolved in 10 ml ethanol and 0.66 ml of 12M hydrochloric acid was added. The mixture was hydrogenated (5% Pd/C, 0.07 g; 100 bar H2, 100° C.) for 20 h. Then the mixture was filtered through Celite®, and the solvent was evaporated. The residue was partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to yield 0.2 g (42%) of 4-[bis-(3,5-difluoro-phenyl)-methyl]-1H-imidazole as a white solid; MS (ISP): 307.1 ((M+H)+.).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 600.1 [(M−H−]; mp 227° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C>[Cl:18][C:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1csc(-c2cc[nH]n2)c1
Solvent: CN(C)C=O
Product: Clc1c[nH]nc1-c1cccs1

Procedure:
Following protocol L, 3-thiophen-2-yl-1H-pyrazole was treated with NCS in DMF, to yield title compound.
Reaction SMILES: [Na+].[Br-:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])[CH:7]=[CH:8][CH:9]=1>CC(C)=O.CCCCCC>[Br:2][CH:12]([CH3:13])[C:11](=[O:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: [Br-]
Reactant: CC(Cl)C(=O)Cc1cccc(Br)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(Br)C(=O)Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of NaBr (197 mg, 1.9 mmol) and 1-(3-bromophenyl)-3-chlorobutan-2-one (100 mg, 0.38 mmol) in acetone (2 ml) was stirred at 70° C. for 3 h. The mixture was diluted with hexane and filtered to remove the solid. The solvent was removed under reduced pressure and the residue was used for the next step without further purification. MS (ES+) C10H10Br2O requires: 303, 305 found: 304, 306 [M+H]+(1:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:26][C:21]5(OCC[O:22]5)[CH2:20][CH:19]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1.Cl>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:26][C:21](=[O:22])[CH2:20][CH:19]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(s2)CC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-5,7-dihydro-4H-spiro[benzo[d]thiazole-6,2′-[1,3]dioxolan]-2-amine (54 mg, 0.105 mmol, example 74), aqueous 1.0 M HCl (0.16 mL), and acetone (0.13 mL) was heated at reflux for 24 h. Partial conversion of the starting material to the desired product was evident by LCMS analysis of a crude aliquot. An additional portion of aqueous 1.0 M HCl (0.20 mL) was added and the acetone was removed in vacuo. The resulting mixture was heated at 75° C. for an additional 24 h. The crude reaction was quenced with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (50% acetone/hexanes) to give 22 mg (43% yield) of the titled compound as an oil. LC-MS (M+H)+ 469.2. 1H NMR (400 MHz, chloroform-d) δ ppm 7.54 (d, J=1.51 Hz, 1 H) 7.46 (d, J=2.52 Hz, 1 H) 7.09-7.20 (m, 3 H) 6.94-7.07 (m, 3 H) 6.77 (dd, J=8.44, 2.39 Hz, 1 H) 4.46 (t, J=6.42 Hz, 1 H) 3.63-3.67 (m, 2 H) 3.62 (s, 3 H) 3.08 (dd, J=14.35, 6.55 Hz, 1 H) 2.86 (dd, J=14.23, 6.42 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:17](CC)([O-])=O.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:17]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccsc2)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(OCc2ccsc2)cc1O

Procedure:
A mixture of 2-hydroxy-4-(3-thienylmethoxy)benzaldehyde (7.7 g), nitroethane (4.74 mL), sodium acetate (5.4 g) and glacial acetic acid (6.6 mL) is heated at reflux for 14 hours. The mixture is then cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate solution (3×50 mL), dried over magnesium sulphate, and concentrated in vacuo. The resulting residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (3:7 v/v), to give 2-hydroxy-4-(3-thienylmethoxy)benzonitrile (7.6 g), in the form of a pale yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[C:17]1(C)C(C)=CC=CC=1>>[CH3:17][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: Cc1ccccc1C
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: [Na]
Product: Cc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 37.5 °C

Procedure:
2-{[2-diethylamino)ethoxy]methyl}-9H-thioxanthen-9-one (intermediate 4): 2′-diethylaminoethanol (1.17 g) was dissolved in 50 ml of absolute xylol; then during constant vigorous mixing and warming to 35-40° C. 0.24 g of solid sodium was added in small portions followed by mixing and warming of the mixture for one hour. Intermediate 3 (1.5 g) was added to the mixture in small portions, and the whole mixture was mildly refluxed for 56 hours. The solid material was removed by filtering the mixture. The organic phase was washed four times with 150 ml water. Then, the water was removed by filtration through solid water-free Na2SO4. After distillation (to remove xylol), the resulting oily, yellow-brown material was not yet pure as determined by thin layer chromatography (Kiesel gel) using benzol:ethanol:water (50:15:1.5, v/v) as solvent. The mixture was fully purified through the following steps. The mixture was first dissolved in an (CH3)2CO (acetone)/absolute ethanol (1:1, by volume) mixture followed by the addition of concentrated HCl until the solid material (HCl salt) was formed. The solid precipitate was washed with cold acetone. The HCl salt of intermediate 4 was dissolved in ethanol:water (10:90, v/v), and the solution was made basic (pH 14) by the addition of solid Na2CO3. The oily material was extracted with ethylacetate and then dried over solid Na2SO4. Intermediate 4 is 99-100% pure as determined by 1H-NMR and thin layer chromatography. The yield of intermediate 4 is ˜55%.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: COc1ccccc1CN
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccccc3OC)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-methoxybenzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 450.5. HPLC (Condition A), Rt: 4.72 min (HPLC purity: 92.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11](N2[C@@H]3C[C@@H]4C(C)(C)[C@]3(CC4)CS2(=O)=O)=[O:12])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(=O)=O.[Cl-].[NH4+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[O:12])=[CH:6][CH:7]=1
Reactant: CC1(C)[C@@H]2CC[C@]13CS(=O)(=O)N(C(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1)[C@@H]3C2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of the early-eluting, S,S-diastereomer ([(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01.5]dec-4-yl)}methanone) described in Example 29D in dichloromethane was stirred under a dry nitrogen atmosphere at −78° C. A 1 M solution of diisobutylaluminum hydride in dichloromethane was added dropwise to the mixture. When the addition was complete, the mixture was stirred at −78° C. for 3 hours. Methanol was then added dropwise at −78° C. The dry ice bath was then replaced with an ice water bath and saturated aqueous ammonium chloride was added to quench the mixture. After 10 minutes, the insoluble material was removed by filtration and the organic layer was separated, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (9:1 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:22]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][O:25][CH2:26][CH3:27]>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][O:25][CH2:26][CH3:27])[N:10]([CH2:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:28])[CH3:29])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Under a nitrogen atmosphere, isopropyl isocyanate (206 μL, 2.10 mmol) was added to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The resulting precipitate was isolated by filtration and then dried under vacuum at 70° C. to provide 669 mg of 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-3-(1-methylethyl)urea as white powder, mp 172.5-173.5° C. Anal. calcd for C20H29N7O2: % C, 60.13; % H, 7.32; % N, 24.54. Found: % C, 59.88; % H, 7.55; % N, 24.51.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][N:2]1[CH2:3][C@H:4]([CH3:5])[NH:6][C@@H:7]([CH3:12])[C:8]1=[O:9]
Reactant: CNC[C@H](C)N[C@@H](C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C[C@@H]1N[C@@H](C)CN(C)C1=O
Yield: 43 %

Procedure:
The crude (S)-methyl 2-((S)-1-(methylamino)propan-2-ylamino)propanoate was dissolved in ethanol (30 mL) and p-toluenesulfonic acid (175 mg) was added. The reaction mixture was heated to reflux for 18 h and then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (40 mL) and saturated NaHCO3 (20 mL). The aqueous layer was separated and extracted again with CH2Cl2 (20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give (3S,5S)-1,3,5-trimethylpiperazin-2-one (230 mg, 43% which contains 2,6-lutidine, ca 2:1 product:2,6-lutidine) as an amber oil. 1H NMR consistent.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:8][CH:9]=1)=[O:3]
Reactant: Cc1ccc(C=C2C(=O)Nc3ccccc32)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc(C)ccc2C=C2C(=O)Nc3ccccc32)cc1

Procedure:
The resultant compound 29 (22.0 g) was added to 1000 ml methanol, and the mixture was refluxed with heat for 8 hours through use of 50 ml of conc. sulfuric acid. After completion of reaction, the reaction mixture was cooled, methanol evaporated, followed by extraction with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate water, and saturated brine, and subsequently dried over sodium sulfate, and then evaporated. The resultant crude product was purified by silica gel column chromatography (chloroform), to thereby obtain 5.0 g (yield 21.9%) of the E-isomer of the title compound in the form of orange-colored crystals and 16.7 g (yield 73.2%) of the Z-isomer of the title compound in the form of yellow-colored crystals. The melting point and elementary analysis data are shown in Table 11, and NMR and MS spectrum data are shown in Table 12.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:13][C:14]1[C:15]([C:19]([F:25])([F:24])[C:20]([F:21])([F:22])[F:23])=[N:16][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(I)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 21.6 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (8.57 g), 4-iodo-3-pentafluoroethyl-1H-pyrazole (16.00 g) and potassium carbonate (7.66 g) were stirred in DMF (70 ml) at 70° C. for 1 hour. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with sodium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (4.60 g).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(c2ccncc2)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccncc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of crude rac-5-methyl-5-(4-pyridyl)-imidazolidinedione (29 mg), 7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole (27 mg) from Example 7, and Cs2CO3 (71 mg) in DMF (3.0 mL) was allowed to react overnight. Water (0.4 mL) was added and the resulting mixture separated by HPLC to yield the title compound as a clear oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([F:33])=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Br:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][C:10]=1[F:33])[N:22]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([Br:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)c(F)cc1Nc1cc(Cl)c(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)c(F)cc21
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.80 g, 3.27 mmol) and MeOH (16.3 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.291 ml, 1.307 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 70° C. heating bath. After 16 h, the mixture was cooled and concentrated under vacuum. The residue was triturated with 2-PrOH and filtered to give 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one (1.23 g, 2.44 mmol, 74.6% yield) as a tan solid. m/z (ESI) 504.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:30])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)CC(C)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:30])[C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:19][CH2:18]1)=[N:3][N:4]=[CH:5]2
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Reactant: CN(C(=O)C(F)(F)F)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: COc1cc2cnnc(N3CCC(N(C)C(=O)C(F)(F)F)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
1-Chloro-6,7-dimethoxyphthalazine (4.5 g), N-(piperid-4-yl)-N-methyltrifluoracetamide hydrochloride (9.9 g) and triethylamine (5.5 ml) were heated together for 5 hours at 100° in iso-amylalcohol (100 ml). The solution was cooled to room temperature and the excess iso-amylalcohol was removed by distillation in vacuo. The residue was dissolved in dilute hydrochloric acid to pH 2, extracted with chloroform (2×100 ml), the chloroform extract shaken with dilute sodium hydroxide, and then quickly separated. The organic phase was washed with water (150 ml), dried over magnesium sulphate, and taken to dryness in vacuo. The resultant brown oil was triturated with ether, filtered, and the filtrate was left standing at room temperature for two hours, during which time a yellow solid precipitated from solution. This solid was collected and crystallized from iso-propylalcohol, yielding 6,7-dimethoxy-1-[4-(N-methyltrifluoracetamido)piperidino]phthalazine (2.9 g), m.p. 150°-152°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][NH:13][S:14]([CH2:17][Cl:18])(=[O:16])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH3:12][N:13]([S:14]([CH2:17][Cl:18])(=[O:16])=[O:15])[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNS(=O)(=O)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(=O)(=O)CCl
Temperature: 20 °C
Yield: 64.1 %

Procedure:
A solution of 19 g of 3,4-dichlorophenyl isocyanate in 150 ml of ethyl ether was added to a solution of 14.4 g of N-methyl-N-chloromethylsulfonyl-amine in 150 ml of ethyl ether and after the addition of 0.1 ml of triethylamine, the mixture was stirred for a hour at 20° C. The crystals formed were recovered by vacuum filtration, were washed, dried and dissolved in chloroform. The insolubles were removed by filtration and the filtrate was concentrated to dryness. The product was crystallized from methyl ethyl ketone to obtain 21.3 g of N-methyl-N-chloromethylsulfonyl-N'-(3,4-dichlorophenyl)-urea melting at 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=O.N1CCCCC1.Cl>C(O)C>[C:9]([C:8](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c(O)c1)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
To a mixture of 758 mg (5.00 mmole) of 4-chlorophenylacetonitriie (purchased from Tokyo Kasei), 691 mg (5.00 mmole) of 3,4-dihydroxybenzaldehyde (purchased from Tokyo Kasei) and 10 ml of ethanol (purchased from Kokusan Kagaku) were added 0.54 ml of piperidine (purchased from Wako Junyaku Kogyo), the mixture was refluxed with heating for 6 hours and air-cooled, the reaction product was added to 100 ml of 1N hydrochloric acid, and deposits were filtered, washed with water, dissolved in ethyl acetate, washed with a 20% sodium hydrogensulfite solution twice and subsequently with saturated saline once and dried over sodium anhydrous sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified according to silica gel column chromatography (effluent with a ratio of hexane to ethyl acetate of 5:1 to 5:2 used) to obtain 919 mg (yield: 67.6%) of α-cyano-4-chloro-3',4'-dihydroxystilbene (yellow crystal) represented by the following formula: ##STR147##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.ClCCCOC1C=CC(C2(C#N)CCCCC2)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>CN1C(=O)CCC1>[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][N:52]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:51]1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Reactant: CO[C@H]1CCNC1
Agent: N#CC1(c2ccc(OCCCCl)cc2)CCCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CCN(CCCOc2ccc(C3(C#N)CCCCC3)cc2)C1
Temperature: 160 °C
Yield: 41 %

Procedure:
A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+.