Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[O:19]1[CH2:21][CH:20]1[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(OCC)C>C1COCC1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:21][CH:20]([OH:19])[CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc2c(ccn2CC2CO2)c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc2c(ccn2CC(O)COc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.34 g (2.02 mmol) 4-phenyl phenol are dissolved in 5 ml absolute THF under nitrogen and mixed drop-wise with 0.1 ml (1.0 mmol) tert-butyllithium with constant stirring. The mixture is stirred at room temperature for 5 min. Thereafter, the solution of 0.20 g (1.0 mmol) 1-oxiranylmethylindole-5-carbonitrile (Example 26A) in 5 ml absolute THF is added drop-wise. The batch is heated at 100° C. for 4 hours. Having cooled down, the batch is mixed with 100 ml diethyl ether and extracted three times using water. The aqueous phase is extracted twice using ethyl acetate and the combined organic phases are dried on sodium sulfate, filtrated and the solvent is removed in vacuo. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 7:3). The product is obtained as a solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)#[N:4].Cl>CO.C(OCC)C>[OH:12][CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]#[N:4])[CH2:6][CH2:7]1
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#C[C@H]1CC[C@H](CO)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A suspension of 829 mg of sodium borohydride in 20 ml of methanol/diethyl ether (vol. 9:1) was treated dropwise within 5 minutes at 0° C. with a solution of 3.0 g of trans-4-cyanocyclohexanecarboxaldehyde in 30 ml of methanol/diethyl ether (vol. 9:1). The reaction mixture was stirred for a further 2 hours at 10° C., then treated with 10 ml of dilute hydrochloric acid and partitioned in methylene chloride/water. The aqueous phase was extracted three times with methylene chloride. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. There were obtained 3.0 g (98%) of trans-4-(hydroxymethyl)cyclohexanecarbonitrile as a colourless oil.
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:13])[C@@H:6]([F:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([OH:21])=[O:20])=[O:13])[C@@H:6]([F:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](F)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)O)[C@@H](F)C(=O)OC
Reaction time: 2 h

Procedure:
To methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-fluoropropionate G-4 (2.3 mmol) was added 4 N HCl in dioxane (10 mL), the solution stirred for 2 h, then evaporated to dryness to afford 2.3 mmol of methyl 3-(S)-n-butyl-3-[2-(S)-carboxypyrrolidin-1-yl-carbonyl)-2-(R)-fluoropropionate G-5 (quant.). To intermediate G-5 (0.15 mmol) in dioxane (1 mL) was added an amine (0.15 mmol), DIEA (0.38 mmol), and HATU or other coupling reagent (0.15 mmol) and the solution stirred for 8 h. The reaction was cooled to 0° C., aqueous 50% hydroxylamine was added (0.5 mL) and the reaction stirred for 4 h. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(S)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-fluoropropionamide G-6.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Brc1nccs1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2nccs2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 40.2 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-bromothiazole (0.040 mL, 0.44 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 45.8 mg of the title compound as a colorless oily substance (40%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:17]([S:21]([NH2:23])=[O:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1/[CH:5]=[N:23]/[S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-bis trifluoromethyl benzaldehyde (10.0 g, 41.3 mmol), tert butyl sulfinamide (4.5 g, 37.2 mmol) and anhydrous CuSO4 (13.1 g, 82.6 mmol) in DCM (100 ml) was stirred at room temperature overnight. The fine suspension was diluted with water and extracted with DCM. The extracts were washed with water, dried (MgSO4) and evaporated in vacuo to afford the desired N-{(1E)-[2,4-bis(trifluoro methyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as an off white solid (7.62 g, 53%), with no further purification. 1H NMR δ (ppm)(CDCl3): 8.99 (1 H, d, J=1.9 Hz), 8.35 (1 H, d, J=8.2 Hz), 8.02 (1 H, s), 7.92 (1 H, d, J=8.2 Hz), 1.28 (9 H, d, J=4.6 Hz); m/z (ES+) 346 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:17]Cl)[OH:16])=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a stirred suspension of 3.4 parts of a sodium hydride dispersion 78% in 90 parts of N,N-dimethylformamide are added portionwise, during a 5 minutes-period, 6.9 parts of 1H-1,2,4-triazole. After stirring for 10 minutes at room temperature, there are added 19.1 parts of 4-chloro-α-(chloromethyl)benzenemethanol. The whole is stirred and refluxed for 8 hours. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from methylbenzene, yielding 17.3 parts (77%) of α-(4-chlorophenyl)-1H-1,2,4-triazole-1-ethanol; mp. 119° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1Cl)[CH3:5]>CO>[CH2:4]([O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[O:2][CH3:1])[CH3:5]
Reactant: C[O-]
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccnc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly to a solution of ethyl-2-chloronicotinate (11.14 g 60 mmol) in anhydrous methanol (60 mL). The reaction mixture was stirred under reflux for 15 h, then cooled to room temperature. The methanol was removed in vacuo. The residue was dissolved in EtOAc (200 mL) and sat. ammonium chloride solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate (8.58 g, 79%) as yellow oil. Sodium hydride (0.21 g, 60% in mineral oil, 5.16 mmol) was mixed with anhydrous DMF (5 mL). A solution of 3′-bromo-4′-methoxyacetophenone (0.99 g, 4.3 mmol) in anhydrous DMF (3 mL) was added drop-wise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 5 min. and then at room temperature for 30 min. The mixture was cooled to 0° C. A solution of ethyl 2-methoxy nicotinate (1.81 g, 10 mmol) in anhydrous DMF (3 mL) was added slowly. The ice bath was removed and the stirring continued at room temperature under nitrogen for 20 hours. Water (20 mL) was added and the mixture was extracted with EtOAc (2×1.00 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent gave a dark solid. Triturating with ether gave a yellow solid (1.329 g, 84%). The solid (1.31 g, 3.6 mmol) and pyridinium hydrochloride (6.24g, 54 mmol) were mixed together and stirred at 190° C. for 3 h, The reaction mixture was then cooled to room temperature, followed by the addition of water (200 mL). The solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 5:4:1 hexanes, EtOAc and methanol as an eluent) to give 2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridinone (0.453 g, 40%) of as yellow solid. MS (ES) m/z: 317.84, 239.9; Mp. 267-272° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C(O)(=O)C.[N+:27]([O-])([OH:29])=[O:28]>O>[N+:27]([C:13]1[CH:12]=[C:11]([O:14][CH3:15])[C:10]([O:16][CH3:17])=[CH:9][C:8]=1[C:6]([C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.93 g (9.7 mmol) of 3,3',4,4'-tetramethoxybenzophenone (prepared according to Example 1), 9 g of glacial acetic acid and 1.88 g (19.4 mmol) of 65 percent strength nitric acid was stirred at room temperature for 7.5 h. 22 ml of water was then added dropwise, and the resulting precipitate was filtered off, washed 2×6 ml of water and dried to give 2.41 g of a beige solid. The yield of the product was 71.5 percent of theory. Further data concerning the product was:
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[C:17]1([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution (40 ml) of methyl 3-[chloro(hydroxyimino)methyl]benzoate (1.42 g) and ethynylbenzene (1.0 ml) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.5 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 3-(5-phenyl-3-isoxazolyl)benzoate. (2.43 g, yield 96%) as colorless crystals. melting point: 99–100° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:8].[CH3:19][N:20]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]1[C:28](Cl)=[O:29]>CO.C(Cl)Cl.[Pd]>[CH3:17][N:10]1[CH:11]=[C:12]([NH:14][C:28]([C:21]2[N:20]([CH3:19])[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=2)=[O:29])[CH:13]=[C:9]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])=[O:8]
Reactant: CN(C)CCCNC(=O)c1cc([N+](=O)[O-])cn1C
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
N-[3-(Dimethylamino)propyl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (0.241 g, 0.95 mmol; see step (i) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (55 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.179 g 0.95 mmol; see Preparation 1(ii) above) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound (0.239 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1-c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of crude 4-(2-bromo-phenyl)-1H-imidazole (73.5 g, 0.33 mol) and triethylamine (45.8 ml, 0.33 mol) in dry dimethylformamide (750 ml) at 0° C. was added a solution of trityl chloride in dry dimethylformamide (850 ml) dropwise over 40 min. When the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 1.5 h. Then the reaction mixture was poured into a stirring mixture of ice water (ca. 2.0 L). A light orange solid precipitated. After stirring for 20 min the solid was filtered and dried to give a light amber solid. This solid was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].C([O-])(=[O:29])C.[Na+].C(OO)(=O)C.OS([O-])(=O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]([OH:29])=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: CC(=O)OO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (5.0 g; see Example 12, Step 6) and sodium acetate (0.89 g) in acetic acid (90 mL) was added peracetic acid (28 mL). The mixture was then heated at 50° C. overnight. The mixture was cooled to 5° C. and saturated NaHSO4 (17 mL) added, keeping the temperature at less than 25° C. The mixture was concentrated to 50% original volume and partitioned between tert-butyl methyl ether (100 mL) and water (50 mL). The organic phase collected and the volatiles evaporated. The residue was dissolved in toluene (50 mL) and volatiles evaporated, the residue dissolved in toluene (50 mL) and evaporation repeated. Finally the residue was dissolved in toluene (20 mL). Acetic anhydride (3.9 mL) was added and the mixture heated at reflux until complete by HPLC analysis. The mixture cooled to ambient temperature and sodium ethoxide in ethanol (20 mL) was added. The reaction mixture stirred overnight. 2N HCl (31 mL) was added and the title product isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[S:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:16][C:17](=[O:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[C:17](=[O:25])[CH2:16][S:13][C:12](=[NH:14])[CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(CBr)C(F)(F)C(F)(F)F
Reactant: Cc1cc(CC(N)=S)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(CC(=N)SCC(=O)C(F)(F)C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 73.8 %

Procedure:
2-(3-Methyl-4-nitrophenyl)-thioacetamide (1.00 g), 1-bromo-3,3,4,4,4-pentafluoro-2-butanone (1.15 g) and potassium carbonate (0.79 g) were stirred in DMF (10 ml) at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 2-(3-Methyl-4-nitro-phenyl)-thioacetimidic acid 3,3,4,4,4-pentafluoro-2-oxo-butyl ester (1.30 g).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine)palladium(II) (70 mg; 3 mol %), copper iodide (12 mg), N,N-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:20]([OH:24])(=[O:23])[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:7]([O:6][C:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH:22]=[CH:21][C:20]([OH:24])=[O:23])=[O:5])[CH3:8]
Reactant: C=CC(=O)O
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1C=CC(=O)O
Temperature: 110 °C
Yield: 103 %

Procedure:
To a solution of ethyl o-bromobenzoate (20.0 g), P(o-tol)3 (2.66 g), triethylamine (17.6 g) and acrylic acid (12.6 g) in toluene (70 mL) was added palladium acetate (980 mg) under nitrogen atmosphere, and the mixture was heated at 110° C. for one hour. The reaction solution was filtered, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried, filtered, and concentrated to give 3-(2-ethoxycarbonylphenyl)acrylic acid (19.8 g, 103%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14](Cl)=[O:15]>O1CCOCC1.O.C(OC(=O)C)C>[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)Cl
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.5g (0.015m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 3.93g (0.015m) of N-methyl-N-(2-benzoyl-2-propanesulfenyl)carbamoyl chloride in 100 ml of dioxane was added 1.5g (0.015m) of triethylamine. After stirring at room temperature for 16 hours, the reaction mixture was diluted with water and the product isolated in ethylacetate. Recrystallized from isopropyl ether. Weight of the product 1.3g, m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2F)CC1
Yield: 94 %

Procedure:
Heat a mixture of 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in 1,4-dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2M NH3 in methanol, evaporate and purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give 94 mg of the title compound: mass spectrum (electric spray) m/z=396 (M+1); 1H NMR (CDCl3): 7.96 (m, 1H), 7.84 (br s, 1H), 7.05 (m, 1H), 6.79 (m, 3H), 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]CC=C)=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[CH:28]=CC=C[C:24]=1Cl>>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[C:17]([CH2:28][CH:23]=[CH2:24])[C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc2c(CCc3ccccc3)csc2c1
Product: C=CCc1c(O)ccc2c(CCc3ccccc3)csc12
Temperature: 50 °C

Procedure:
The product from Step F (4.373 grams), dissolved in 1,2-dichlorobenzene (45 mL) was refluxed under nitrogen for 8.5 hours. The solution was cooled to approx. 50° C. High vacuum was applied and the solvent removed until the residue solidified. The solid was dissolved in CH2Cl2 (100 mL), recovered, re-evaporated and chromatographed over silica gel (CH2Cl2). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid.