Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:28]([O:29][CH3:30])[CH3:27])=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C1=C(C(=O)c2ccc3c(c2Cl)S(=O)(=O)CCC3(C)C)C(=O)CCC1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
0.5 g (1.25 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one was dissolved in 10 ml of tetrahydrofuran, and 0.13 g (1.37 mmol) of N,O-dimethylhydroxylamine hydrochloride and 0.28 g (2.74 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 25 hours, stirred into water and extracted with ethyl acetate, the organic phases were extracted with 1N hydrochloric acid and dried and the solvent was removed. This gave 0.4 g of beige crystals.
Reaction SMILES: O[Li].O.[Si]([O:11][C@H:12]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[CH:18]=2)[C@@H:14]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[CH2:13]1)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.O>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[C@H:14]1[CH2:13][C@@H:12]([OH:11])[CH2:16][N:15]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3F)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 8 h

Procedure:
1M aq. solution of LiOH.H2O (0.4 mL) was added to a stirred solution of ethyl 5-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Isomer-I) (Int-60) (0.07 g, 0.14 mmol) in EtOH (5 mL) and the stirring was continued at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with citric acid solution, filtered the solid precipitated to afford 5-((2R,4R)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (Int-62) as yellow solid. MS (ESI): m/z 360(M+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:31])=[C:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:11]([O:18][CH:19]([F:21])[F:20])=[N:12]2)[CH3:5].CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][C:10]1[C:11]([O:18][CH:19]([F:20])[F:21])=[N:12][C:13]2[C:8]([C:9]=1[CH3:31])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:32])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(Cc2ccc(Cl)cc2Cl)c(OC(F)F)nc2c(F)ccc(O[C@@H](C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-[3-(2,4-dichlorobenzyl)-2-difluoromethoxy 8-fluoro-4-methylquinolin-5-yloxy]propionic acid methyl ester (0.070 g), methanol (3.0 mL), water (0.1 mL) and 5.0 M aqueous lithium hydroxide solution (0.060 mL) was stirred at room temperature for 18 hours. The mixture was acidified by the addition of glacial acetic acid and concentrated under reduced pressure. The residue was triturated with water to afford title compound as a white solid, 0.067 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53](O)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.Cl.[NH:66]1[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]1>C(Cl)Cl>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([N:66]3[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]3)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: O=S1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCS(=O)CC1
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.27 mmol) and DIPEA (0.286 mL, 1.64 mmol) at room temperature and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-6-(1-oxo-1,4-thiazinane-4-carbonyl)chromen-4-one (87 mg, 57%) as a pale beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLi (0.0022×1.1 mol) was added to the solution, followed by stirring the solution for about 10 minutes. After 0.60 g (0.0022×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccccc1CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccccc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine (0.130 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 211 mg. To a solution of tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((2-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((2-Methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 40 mg; 13C-NMR (CD3OD, rotamers): δ 26.1, 27.4, 40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5, 54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84, 114.0, 114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1, 127.3, 127.7, 128.8, 129.8, 130.0, 130.08, 130.14, 156.5, 157.0, 159.0, 159.1, 173.2, 173.8.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:28])[CH2:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)(O)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]=[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]([F:18])([F:16])[F:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
After adding 5.34 g of toluene to 1.78 g (4.12 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.98 g (8.25 mmol) of thionyl chloride and 0.65 g (8.25 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.33 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.69 g of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 99.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=1)=[O:4].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.O>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH:9]=[C:8]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reactant: Sc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperature was added TiCl4 (670.0 mg, 3.55 mmol). Thereafter a solution of thiophenol (430.0 mg, 3.90 mmol) and Et3N (730.0 mg, 7.20 mmol) in 10 mL THF was added. The resulting brown mixture was stirred for 6 h before H2O was carefully added to quench the reaction. The pruduct was extracted into Et2O and the combined organic layers washed with saturated aqueous NaCl and dried over MgSO4. Removal of the solvents under reduced pressure afforded a solid from which the title compound was isolated as a yellow solid by column chromatography (5% EtOAc-hexanes).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:23][CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reactant: COCCN
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COCCNc1ccc([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)cc1

Procedure:
The title compound, MS: m/e=551.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(4-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, 2-methoxy-ethylamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C1COCC1>[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH2:8][CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: O=Cc1ccc(F)cc1Br
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 511.7 %

Procedure:
Add (1,3-dioxan-2-ylethyl)magnesium bromide (0.5 M in THF, 40 mL, 20 mmol) to a solution of 2-bromo-4-fluoro-benzaldehyde (3 g, 15 mmol) in THF (20 mL) at 0° C. under N2. Continue to stir the mixture for 48 h at RT. Quench the reaction mixture with 1 N HCl, followed by the basification with diluted ammonium hydroxide to ˜pH 9. Extract the product with chloroform/IPA (3/1). Dry the organic layer over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% methanol in DCM) to give the title compound as a yellow oil (24.5 g, 95%). MS (ES) m/z 319/321 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:23])[CH3:22])[CH:27]([CH3:28])[CH3:29]
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)[Si](OCCOc1cc(F)ccc1F)(C(C)C)C(C)C

Procedure:
The stirred mixture of 0.80 g of 2,5-difluorophenol, 0.82 g of potassium carbonate, 1.98 g of (2-iodoethoxy)triisopropylsilane and 10 ml of acetone is kept at reflux over 3 hours. The reaction mixture is cooled, poured onto water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine (1×80 ml) dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.63.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: OB(O)c1cncnc1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(-c2cncnc2)c2occc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 898.3 %

Procedure:
Pd(PPh3)4 (240 mg, 209 mmol) was added to 7-iodo-5-nitro-1-benzofurane (1.00 g, 3.45 mmol) in DME (11 mL) and the resulting mixture was stirred for 10 min. The color went from dark red to mustard yellow. Pyrimidine-5-boronic acid (0.24 g, 0.21 mmol) and 1 M Na2CO3 (5 mL) were added and the reaction mixture was refluxed at 100° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was dissolved in 1 M HCl (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was made basic (pH 8), by addition of K2CO3, and extracted with chloroform (3×). The combined organic layers were dried with K2CO3, filtered and concentrated to afford 0.455 g (55%) of a yellow solid. HPLC 100%, RT: 1.870 min (System A; 10-97% over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 7.06 (d, J=2.47 Hz, 1H) 7.90 (d, J=2.23 Hz, 1H) 8.45 (d, J=2.23 Hz, 1H) 8.63 (d, J=2.23 Hz, 1H) 9.28-9.31 (m, 3H). LC-MS 242 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([Cl:18])[C:12]=1[Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(Cl)cc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 54.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,3,5-trichlorophenylboronic acid (Aldrich; 751 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-methyl-N′-(2,3,5-trichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (592 mg, 53%) as a colorless oil that solidified on standing.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[C:17](/[CH:19]=[C:20]4/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/4)[CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:29][C:30]([NH2:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:25]=[C:23]1[N:22]([CH2:29][C:30]([NH2:32])=[O:31])[C:21](=[O:26])/[C:20](=[CH:19]/[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)[N:18]=2)/[S:24]1
Reactant: NC(=O)CBr
Reactant: Cc1ccc(N2CCN(c3nccc(/C=C4\SC(=O)NC4=O)n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(c3nccc(/C=C4\SC(=O)N(CC(N)=O)C4=O)n3)CC2)cc1
Temperature: 55 °C
Yield: 34.8 %

Procedure:
To 10 mg of (Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was added 4 mg of 2-bromoacetamide, 4 mg of potassium carbonate, and 0.5 mL of DMF. The reaction mixture was heated to 55° C. for 4 h, concentrated under reduced pressure, and purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient using trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide (4 mg, 11.5 mg theoretical, 35%). LC-MS m/z: 439 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)([OH:12])[CH2:8][CH2:7]1)=O)C.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2([O:12][CH3:26])[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.0 g) was dissolved in dimethylformamide and the mixture was cooled to 0° C. Sodium hydride (250 mg) was added thereto, and the mixture was stirred for 30 min. Then, methyl iodide (0.4 ml) was added, and the mixture was further stirred for 30 min and warmed to room temperature. Water was added thereto, and the mixture was extracted three times with methylene chloride. The organic layer dried over magnesium sulfate and the solvent was evaporated under reduced pressure. Ethanol (20 ml) and a 6N aqueous sodium hydroxide solution (15 ml) were added to the obtained residue, and the mixture was heated under reflux for hr. The reaction mixture was allowed to cool to room temperature, neutralized with 12N aqueous hydrochloric acid, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-methoxypiperidine (1.56 g, yield 93%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][C:14](=[O:21])[CH2:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([O:25][C:26](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:22][O:25][CH:26]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)[C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(OCCN3CCOCC3)ccc2C(=O)N1
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(OCCN3CCOCC3)cc21

Procedure:
A mixture of 6-(2-morpholin-4-yl-ethoxy)-4H-isoquinoline-1,3-dione (390 mg, 1.34 mmole), 10 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.1 mL, 10.1 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the residue treated with 2:1 hexanes/ethyl acetate, the product is collected by filtration, a yellow solid, 230 mg, (52%), MS (ES+): m/z 333.2 (M+H), used as is in the next step.