Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Si]([O:13][CH2:14][C:15]([CH3:45])([CH3:44])[CH2:16][N:17]1[CH:26]=[C:25]([CH2:27]O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:29]3[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=3[CH3:41])[C:32]([NH:34][CH:35]3[CH2:37][CH2:36]3)=[O:33])[CH:23]=2)[C:18]1=[O:43])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH3:53][C@H:54]1[NH:59][CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]1>C(Cl)Cl>[CH:35]1([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[N:17]([CH2:16][C:15]([CH3:44])([CH3:45])[CH2:14][OH:13])[CH:26]=[C:25]4[CH2:27][N:59]3[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]3[CH3:53])[C:40]([CH3:41])=[C:39]([F:42])[CH:38]=2)[CH2:37][CH2:36]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCNC[C@H]3C)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
Methanesulfonyl chloride (0.55 mL) was added to a solution of 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 3.65 g) and triethylamine (1.79 mL) in DCM (10 mL) at −20° C. After 30 min the solution was warmed to 0° C. and tert-butyl (3R)-3-methylpiperazine-1-carboxylate (2.58 g) was added. The reaction was stirred for 18 h at room temperature, evaporated and the residue purified (SiO2 chromatography, elution with 20 to 80% ethyl acetate in isohexane). Fractions containing product were evaporated, dissolved in THF (100 mL) and treated with 4 M HCl in dioxane (5 mL), stirred at room temperature for 60 h, evaporated to dryness and the residue purified (SiO2 chromatography, elution with 5 to 10% 7N NH3/methanol in DCM) to give the title compound (1.53 g) as a solid.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:11][CH:10]=2.[OH-].[Na+]>C(O)(=O)C>[CH3:3][N:4]([CH3:1])[CH2:5][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:16]([O-:18])=[O:17])[NH:8][C:7]=1[CH3:6]
Reactant: CNC
Reactant: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1[nH]c2cccc([N+](=O)[O-])c2c1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an acetic acid (5 mL) solution of an aqueous 370% formaldehyde solution (271 mg), an aqueous 50% dimethylamine solution (317 mg) was slowly added dropwise under ice cooling and the mixture was stirred at room temperature for 30 minutes. Furthermore, an acetic acid (1 mL) solution of 2-methyl-4-nitro-1H-indole [Tetrahedron 1, 1999, 5395-5398] (310 mg) was added and the mixture was stirred at room temperature for 24 hours. The pH of the reaction mix was adjusted to 9 using an aqueous 5M sodium hydroxide solution, followed by extraction with dichloromethane three times. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was washed with diisopropyl ether to obtain the titled compound having the following physical properties (303 mg).
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)[C:3](O)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.O.[NH2:30][NH2:31]>CO>[CH3:1][C:2]1[C:3](=[O:4])[NH:30][N:31]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CC(=CC(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccc(-c3ccc(F)cc3)cc2)n[nH]c1=O
Reaction time: 6 h

Procedure:
28.4 g of 2-methyl-4-(4'-fluoro-4-biphenylyl)-4-oxo-2-butenoic acid is dissolved in 100 ml of methanol; 15.4 g of K2CO3 is added and the mixture is stirred for 6 hours at 20°. It is then acidified with hydrochloric acid, 5.4 ml of hydrazine hydrate is added and the batch is boiled for 2 hours. Thereafter, it is again acidified; the solution is concentrated and cooled; and the 4-methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one obtained is filtered off and washed with water. m.p. 247°-248°.
Reaction SMILES: [OH-].[K+].O[C:4]([CH3:10])([CH2:8][OH:9])[C:5]([OH:7])=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[CH3:20]N(C=O)C>C(OCC)(=O)C>[CH2:11]([O:7][C:5](=[O:6])[C:4]([CH3:10])([CH3:20])[CH2:8][OH:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)(CO)C(=O)O
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Add potassium hydroxide (486.7 mmol, 32.1 g) over a solution of 2,3-dihydroxy-2-methyl-propionic acid (423.2 mmol, 50 g) in 300 mL of DMF. Stir for 1 hour at 100° C. Then add benzyl bromide (584.04 mmol, 69.46 mL) and stir overnight. Cool down the mixture and dilute with ethyl acetate. Wash organic layer with water. Wash aqueous layer with ethyl acetate several times. Combine organic layers and dry over sodium sulfate, filter and concentrate under reduced pressure. 1H NMR (CDCl3, 300 MHz): δ ppm :7.36-7.32 (m, 5H), 5.1 (s, 2H), 3.5 (s, 2H), 1.21 (s, 6H).
Reaction SMILES: [N+]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[C:5]=1[C:14]([O:16][CH3:17])=[O:15])([O-])=O.[CH3:18][O-:19].[Na+]>CN(C)P(=O)(N(C)C)N(C)C.O>[C:14]([C:5]1[C:4]([O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1c(OC)cccc1C(=O)O
Reaction time: 44 h
Yield: 77.3 %

Procedure:
Dimethyl 3-nitrophthalate (4.8 g, 20 mmol) was added to a cold solution of sodium methoxide (2.61 g, 48.3 mmol) in dry hexamethylphosphoric triamide (75 ml). The resulting dark solution was gradually brought to room temperature and the reaction mixture was stirred for 44 hrs. It was then diluted with water (125 ml) and extracted with benzene. (This extract contained a variable quantity of dimethyl 3-methoxyphthalate. The aqueous layer was acidified with hydrochloric acid and extracted with benzene. The combined organic layers were washed with water (5×30 ml) and then brine (1×15 ml), dried over sodium sulfate, filtered and evaporated to give 3.25 g (75%) of 2-carbomethoxy-3-methoxybenzoic acid, mp 140°-141° C. (benzene). Identity was confirmed by mixture mp, co-chromatography and spectroscopic comparison with an authentic sample. 1H NMR (CDCl3) δ 3.86 (3H, s, ArCO2CH3), 3.93 (3H, s, ArOCH3), 7.13 (1H, dd, J=8,2 Hz, ArH4), 7.43 (1H, t, J=8 Hz, ArH5), 7.68 (1H, dd, J=8,2 Hz, ArH6, 10.50 (1H, broad s, ArCO2H); IR (KBr) 3200 (br), 2960, 1740, 1690, 1585, 1475, 1310, 1050 cm-1 , etc.; mass spectrum m/e (rel. intensity) 211 (m+ +1,5%), 210 M+, 30%), 193 (M+ -OH, 2%), 180 (M+ -2CH3, 100%), 179 (M+ -OCH3, 10%), etc.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([CH:15]([SH:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:16][CH:15]([S:17][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(S)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(SN1C(=O)CCC1=O)c1ccccc1
Yield: 36.8 %

Procedure:
To a suitable reactor equipped with temperature controlling means and stirring means, there are charged, while maintaining the temperature at about room temperature, N-chlorosuccinimide (about 0.30 mole) in 400 ml of benzene and 1-phenylethanethiol (about 0.30 mole) in 50 ml of benzene. After stirring the reaction mixture 10 minutes, triethylamine (0.32 mole) in 50 ml of benzene is added dropwise. The benzene mixture is stirred one hour and then filtered. The filtrate is washed three times with 250 ml portions of water and then subjected to vacuum with heating to strip off volatile components. A crystalline residue is recrystallized from ethanol to give 26 grams of N-(α-methylbenzylthio)succinimide, m.p. 121-125°C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10]Br>>[Cl:22][C:12]1[CH:13]=[C:14]([S:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:15]=[C:6]([Cl:5])[C:7]=1[O:8][CH2:9][CH2:10][NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCN
Reactant: FC(F)(F)CSc1cc(Cl)c(OCCBr)c(Cl)c1
Product: CCCNCCOc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
5 g of n-Propylamine were added to 2.38 g of 2-[2,6-dichoro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl bromide, and the mixture was stirred at room temperature for 8 hours and then under reflux for 3 hours. The excess of n-propylamine was evaporated. To the residue were added 20 ml of water, 20 ml of a 5% aqueous solution of potassium hydroxide and 100 ml of toluene. The mixture was stirred, and the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Low-boiling compounds were evaporated under reduced pressure. There were obtained 2.16 g of crude N-{2-[2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl}-N-(propyl)amine having a refractive indes of nD2O=1.5210, which were used without further purification) for the preparation of compound No. 1 shown above.
Reaction SMILES: [C:1]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15]C)=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:13]([C:8]12[CH2:11][CH2:12][C:5]([C:1]([OH:3])=[O:2])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2)([OH:15])=[O:14]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C12CCC(C(=O)O)(CC1)CC2
Yield: 98 %

Procedure:
A stirred solution of 1,4-dicarbomethoxybicyclo[2.2.2]octane (31.7 g, 0.14 mole) in tetrahydrofuran (200 mL) and isopropanol (70 mL) was treated with a solution of lithium hydroxide hydrate (17.7 g, 0.42 mole) in water (200 mL), and the mixture was heated to 6°-70° C. for 2.5 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was filtered, then the filtrate was cooled on an ice bath and acidified with concentrated hydrochloric acid (40 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 27.19 g (98%) of subject material as a white solid. No MS could be obtained. 1H NMR (d6-DMSO) δ 12.09 (br s, 2H), 1.66 (s, 12H).
Reaction SMILES: S(Cl)(C)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:20]O)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.[Cl-:29].[Na+]>CN(C=O)C>[Cl:29][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC2CCl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 882.2 %

Procedure:
27.9 ml (0.36 mol) of mesyl chloride were added dropwise to a solution of [1-(4-nitrophenyl)pyrrolidin-2-yl]methanol (66.7 g, 0.03 mol), 300 ml of anhydrous DMF and 58.5 ml (0.42 mol) of anhydrous triethylamine, cooled in an ice bath. The temperature was allowed to rise to 20° C. over one hour with stirring. 35.2 g (0.6 mol) of sodium chloride were added and the mixture was heated at 100° C. for one hour. The reaction medium was poured into 1.4 l of ice-water. The precipitate was filtered off, washed with water, dried and recrystallized from isopropanol. 63.7 g of a yellow powder (1) were thus obtained.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[SH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: CC(=O)SCc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CS)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-(acetylthiomethyl)benzoic acid (16.4 g, 78.10 mmol, 1.00 equiv) in methanol (150 mL), and a solution of potassium carbonate (26.9 g, 194.93 mmol, 2.50 equiv) in water (70 mL). The resulting solution was stirred for 4 h at 60° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of water and adjusted to pH 3 with 10% hydrochloric acid. The resulting solution was extracted with 3× (100/20 mL) of ethyl acetate/tetrahydrofuran and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 12 g (91%) of 3-(mercaptomethyl)benzoic acid as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:22][C:20]1[C:19]([CH:25]2[CH2:27][CH2:26]2)=[CH:18][C:11]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(C3CC3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N)c(C3CC3)cc12
Yield: 114.3 %

Procedure:
To a solution of ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8 g, 18.2 mmol) in ethyl acetate (450 mL) was added 10% palladium on carbonate (1.83 g), 1N HCl solution (2.5 mL), and stirred with under 0.4 MPa of hydrogen at room temperature for 8 hrs. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum to give ethyl 6-amino-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate as a brown solid (7.4 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-methylacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: Cl[C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2.O.[NH2:18][NH2:19]>C(O)C>[NH:18]([C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2)[NH2:19]
Reactant: COc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1nc2ccc([N+](=O)[O-])cc2nc1NN
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 3.4 g (14.2 mmol) of 3-chloro-2-methoxy-6-nitroquinoxaline and 1.65 g (33 mmol) of hydrazine hydrate in 150 ml of ethanol was stirred at room temperature over night. The precipitate was collected and washed with water and cold ethanol to give 3.13 g (94%) of crude product.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][OH:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:40][O:41][CH2:2][O:3][CH3:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Yield: 97.1 %

Procedure:
Chloro(methoxy)methane (0.201 mL, 2.65 mmol) was added dropwise to a solution of 6-(N-(4-bromo-3-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.724 g, 1.06 mmol) and DIEA (0.555 mL, 3.18 mmol) in tetrahydrofuran (10 mL) under N2. The mixture was heated to 50° C. overnight. Cooled down to room temperature and aqueous NaHCO3 was added, the aqueous layer was extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4. The crude residue was purified by chromatography on silica gel eluted with 0-50% EtOAC in hexane to give the product (0.65 g, 97%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (dd, J=8.78, 5.27 Hz, 2H) 7.64 (s, 1H) 7.57 (d, J=2.73 Hz, 1H) 7.50 (d, J=8.78 Hz, 1H) 7.47 (s, 1H) 7.18-7.26 (m, 3H) 5.79 (d, J=4.49 Hz, 1H) 4.74 (s, 2H) 4.61 (s, 2H) 3.39 (s, 3H) 3.25 (s, 3H) 3.01 (d, J=4.88 Hz, 3H) 2.08-2.18 (m, 1H) 0.75-1.14 (m, 3H) 0.58 (br. s., 1H). LCMS (m/z, ES+)=633 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.Br>C(#N)C>[Br-:10].[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[CH:4]1)([OH:18])=[O:17]
Reactant: O=C(O)CCCCCBr
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCCn1c[n+](Cc2ccc3ccccc3c2)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 6-bromohexanoic acid (1.44 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: Clc1ncccn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ncccn1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=584.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][C:13]([O-])([CH3:15])[CH3:14].[K+].[OH2:18]>C1COCC1>[CH3:12][C:13]1([CH3:15])[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:14]1=[O:18].[CH3:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Br)ccc2C1=O
Product: CC1Cc2cc(Br)ccc2C1=O
Reaction time: 3 h
Yield: 43 %
Yield: 13 %

Procedure:
A solution of 5-bromo-1-indanone (3.75 g, 17.76 mmol) in 18 ml of anhydrous THF is brought to −20° C. under an atmosphere of argon and with magnetic stirring. A 1M solution of t-BuOK in THF (18 ml, 18 mmol) is added with a syringe and the stirring continued for 3 hours at ambient temperature. At 0° C., 10 ml of distilled water is added and the mixture then extracted with ether (4×75 ml), dried over MgSO4, filtered and evaporated to obtain a raw product that is incorporated onto silica and purified by flash chromatography on silica (eluent ether:petroleum ether=2:98 up to 5:95). In order of elution, one obtains 1.85 g of a yellowish oil, 2,2-dimethyl-5-bromo-1-indanone (yield=43%), 0.50 g of a white solid 2-methyl-5-bromo-1-indanone (yield=13%) and 1.20 g of a white solid (32%) the starting material, 5-bromo-1-indanone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2cccnc2)CCCc2cccnc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1cccnc1)CCCc1cccnc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
4-[4-(3-Pyridyl)-1-(3-pyridyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (59) (0.3754 g; 0.78 mmol) is dissolved in methylene chloride (6 mL) at ambient temperature. Trifluoroacetic acid (6 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (50 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×10 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.1704 g) as a yellow oil. ESMS:MH+ 382.4 (base).