Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[C:13]([C:19](=O)[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=1)[O:8][C:7]([CH3:22])=[CH:6][C:5]2=[O:23].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>CC(O)C>[C:27]([C:26]1[CH:12]([C:10]2[CH:11]=[C:2]([F:1])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:22])=[CH:6][C:5]3=[O:23])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:20])[NH:24][C:25]=1[C:29]([F:32])([F:31])[F:30])#[N:28]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CCOC(=O)C(=Cc1cc(F)cc2c(=O)cc(C)oc12)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C#N)C1c1cc(F)cc2c(=O)cc(C)oc12

Procedure:
A solution of 230 mg (0.72 mmol) of ethyl 2-[(6-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)-methylene]-3-oxobutanoate in 10 ml of 2-propanol is mixed with 98.34 mg (0.72 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 12.2 mg (0.11 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). The resulting crystals are purified further by preparative HPLC. 27.4 mg (8.69% of theory) of the title compound are obtained as yellow crystals.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C@@H:5]1[C:10](O)=[O:11].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:10]([C@H:5]1[CH2:6][CH2:7][C:8](=[O:9])[NH:4]1)=[O:11])[CH3:2]
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CCC(=O)N1
Temperature: 30 °C

Procedure:
To a flask containing anhydrous ethanol and D-pyroglutamic acid at ambient temperature (˜23° C.) was slowly added trimethylsilyl chloride while maintaining a reaction temperature NMT 30° C. After stirring at ambient temperature for a period of time, the reaction solution was concentrated under reduced pressure to give a yellow oil. The product was dissolved in toluene and concentrated under reduced pressure to give a yellow oil. The crude product was dissolved in dichloromethane and stirred with the slow addition of aqueous saturated sodium bicarbonate solution until a pH of 7-8 was reached. The organic layer was isolated, and the aqueous layer was extracted further with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give product, (R)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester, as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:41][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38]CC)=[O:37])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)[CH2:41][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)Cc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylmethyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted with 5N hydrochloric acid to pH 7 and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[CH3:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16])=[CH:8][C:9]=2[CH3:15])[CH3:14])=[CH:23][C:22]=1[CH3:29]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
A mixture of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine (643 mg, 2.6 mmol, 1.2 eq) and 4-formyl-2-methyl-benzoic acid methyl ester (380 mg, 2.1 mmol), acetic acid (252 mg, 4.2 mmol, 2.0 eq.), sodium triacetoxyborohydride (890 mg, 4.2 mmol, 2.0 eq.) in 1,2-dichloroethane is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the resulting residue is partitioned between EtOAc (50 mL) and 5% NaHCO3 (40 mL). The organic. phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography eluting with a gradient of EtOAc/Hexane to afford the title compound as a syrup (1.0 g, 95%). LC-ES/MS m/e 414.3 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]>C(OCC)(=O)C>[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][C:27]=1[Br:1])[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(NC(C)=O)cc1O
Temperature: 72.5 °C
Yield: 44.4 %

Procedure:
N-Bromosuccinimide (0.94 g, 5.3 mmol) was added to an N,N-dimethylformamide (8 ml) solution of methyl 4-acetylaminosalicylate (I-248) (1.1 g, 5.0 mmol), followed by stirring with heating under reflux at 70 to 75° C. for 2 hours and a half. After cooling to room temperature, ethyl acetate was added, followed by washing twice with saturated brine and drying over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform/methanol (100:1) gave the entitled compound (0.64 g, 45%) as a pale red solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[C:16]([NH2:18])=[O:17])#[N:14]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(F)cc1[N+](=O)[O-])C(N)=O
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A mixture of 4-fluoro-2-nitrobenzaldehyde (8.70 g., 51.5 millimoles), 2-cyanoacetamide (4.7 g., 54.4 millimoles), piperidine (0.032 g., 0.37 millimole) and ethanol (80 ml.) is stirred at room temperature for 28 hours. The solid which formed is separated by filtration, washed with ethanol (45 ml.) and dried. Yield = 10 g. (83.5%) of the title acrylamide as light tan crystals M.P. 278°-279° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][OH:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.C[N+]1([O-])CCOCC1.CCOC(C)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CO)c21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(C=O)c21
Reaction time: 1.5 h

Procedure:
To a suspension of (5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (675 mg, 1.889 mmol), 4-methylmorpholine 4-oxide (443 mg, 3.78 mmol), and molecular sieves (337 mg, 1.889 mmol) in dichloromethane (10 mL) at room temperature was added tetrapropylammonium perruthenate (19.9 mg, 0.057 mmol). After 1.5 h, the crude reaction mixture was loaded directly onto a pre-conditioned column of silica gel (silica gel/dichloromethane). The solvent was then switched directly to 12% EtOAc/Hex and the column run in that solvent system to give 565 mg (84%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 10.31 (s, 1H), 8.11 (d, J=1.8, 1H), 8.05 (s, 1H), 8.03 (d, J=1.8, 1H), 6.04 (s, 2H), 3.45 (m, 2H), 0.81 (m, 2H), −0.12 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 188.9, 135.4, 135.0, 134.2, 130.0, 129.3, 123.0, 114.0, 81.2, 66.4, 17.8, −1.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([O:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc(Nc3nc(Oc4ccccc4)nc4c3CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 13 h

Procedure:
The title compound was prepared following a published procedure in the literature (D'Angelo, N. D. et al. Tetrahedron Letters, 2006, 47, 5045-5048). A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]cyclobutane carboxylic acid methyl ester (0.45 g, 1.26 mmol), phenol (0.23 g, 2.5 mmol), copper powder (0.010 g) and cesium carbonate (1.25 g, 3.8 mmol) in anhydrous dimethylformamide (3 mL) was stirred at a temperature in the range of 10° C. to 100° C. for 6 to 20 hours. The mixture was cooled to about 20 to 35° C. and diluted with water. The organics were extracted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel) to afford white solid (43% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[S:4]([OH:7])(=[O:6])=[O:5].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.Cl>O>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:12][C:10]3[CH:9]=[CH:8][C:3]([S:4]([OH:7])(=[O:5])=[O:6])=[C:2]([Cl:1])[CH:11]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Agent: Cl
Solvent: O
Product: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1Cl

Procedure:
9.9 Grams of 2-chloro sulphanilic acid and 9.4 grams of 4,7-dichloroquinoline were suspended in 200 milliliters of water and concentrated hydrochloric acid added until the solution was just acid. The mixture was refluxed for 4 hours when a solid began to precipitate. After cooling the solid was collected, washed with water and dried to give 15.8 grams of 4-(7-chloro-4-quinolylamino)-2-chlorobenzenesulphonic acid. Melting point 280°-285°C with decompostion.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[C:23]2=[C:24]3[C:13]([C:14]4[C:25]5[C:22]2=[CH:21][CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=5[C:17]([C:29](O)=[O:30])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:32](=N)[OH:33])[C:9]3=[C:8]([C:35](=N)[OH:36])[CH:7]=1>>[CH:15]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]4[C:32]([O:2][C:35](=[O:36])[C:8]5[C:9]=4[C:24]=3[C:23](=[CH:6][CH:7]=5)[C:22]3[C:25]=2[C:18]2[C:19]([C:26]([O:28][C:29](=[O:30])[C:17]=2[CH:16]=1)=[O:27])=[CH:20][CH:21]=3)=[O:33]
Reactant: N=C(O)c1ccc2c3ccc(C(=O)O)c4c(C(=O)O)ccc(c5ccc(C(=N)O)c1c25)c43
Reactant: O=S(=O)(O)O
Product: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Temperature: 220 °C

Procedure:
800 g of 95% strength sulfuric acid are initially taken and 200 g of 89.4% strength perylene-3,4,9,10-tetracarboxylic acid diimide are introduced at room temperature. The temperature of the mixture is then raised to 220° C., and this temperature is maintained for two hours. The mixture is then allowed to cool to room temperature and the precipitate which has been formed is filtered off with suction and washed first with 280 g of 80% strength sulfuric acid and then with water until it is neutral. Drying at 80° C. gives 174.3 g of crude perylene-3,4,9,10-tetracarboxylic dianhydride. This is introduced, with exclusion of light, into a solution composed of six liters of water and 140 g of 85% strength potassium hydroxide. While blanketed with nitrogen, the solution is heated to 80°-90° C., and stirring is continued for a further 90 minutes at this temperature. The mixture is then allowed to cool to 25° C., the pH is adjusted to a value of 8-9 and the solid residue is filtered off with suction and washed with 100 ml of water. (The residue is 38.7 g of perylene-3,4,9,10-tetracarboxylic acid diimide which has only been half-saponified, i.e. perylene-3,4,9,10-tetracarboxylic acid monoanhydride-monoimide, and this is expediently added to the next batch.) 60 g of 85% strength potassium hydroxide and 60 g of animal charcoal are introduced into the filtrate, with exclusion of light, and the mixture is then blanketed with nitrogen. After a further hour's stirring at 25° C., a solution of 48.8 g of copper carbonate and 600 ml of water is added dropwise, the mixture is stirred for a further hour at 25° C. and is clarified, and the filtrate is then added dropwise to 600 g of concentrated hydrochloric acid, the mixture is kept at 80°-90° C. for one hour and the precipitate is filtered off with suction, washed with water until it is neutral and dried at 80° C. This gives 133.7 g of perylene-3,4,9,10-tetracarboxylic dianhydride having the following extinction values:
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:37][NH:38][CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1>C(Cl)Cl>[CH3:37][N:38]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1)[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)(=[O:14])=[O:15]
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: CNC1CCOc2cc(CN3CCCCC3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (100 mg, 0.268 mmol, 1.0 eq) and DMF (one small drop) in CH2Cl2 (2.5 mL) was added oxalyl chloride (68 mg, 0.536 mmol, 2.0 eq). The reaction was stirred at 0° C. for 1 h. It was warmed to RT and stirred at RT for additional 15 min. Solvent was removed with a rotary evaporator. The newly formed acid chloride was dissolved in CH2Cl2 (2 mL) and the solution was cooled down to 0° C. A solution of methyl-(7-piperidin-1-ylmethyl-chroman-4-yl)-amine (70 mg, 0.268 mmol, 1.0 eq) in CH2Cl2 (0.95 mL) was added slowly. The resulting mixture was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred at this temperature for additional 20 min. The reaction was quenched with saturated Na2CO3 (60 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-4% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 616 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10]>O1CCCC1.S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([O:11][CH2:17][CH2:3][CH2:2][CH2:20][CH3:19])=[O:10]
Reactant: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCOC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
First, 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid (compound b-1) is dissolved in tetrahydrofuran, to which thionyl chloride is added under stirring, and the mixture is heated and stirred under reflux. After left for cooling and the subsequent concentration, the residue is dissolved in tetrahydrofuran (hereinafter referred to as solution A). Tetrahydrofuran is added to 1-pentyl alcohol, to which solution Aid added and pyridine is then added. After stirring at room temperature, 2% aqueous hydrochloric acid is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to give pentyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate (compound b-19).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:11]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:8]=[CH:9]2)([CH3:18])[CH3:17])=[CH:20][CH:21]=1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride (0.65 g) in dichloromethane (20 ml). The solution was cooled to 0° C. and benzenesulphonyl chloride (0.27 g) in dichloromethane (10 ml) was added dropwise with stirring. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 3 hours. The mixture was washed with water, sodium bicarbonate solution and then dried, filtered and evaporated to give a yellow oil which was dissolved in alcohol and treated with ethereal hydrogen chloride. The resulting salt was hygroscopic and so was converted back to the free base by treatment with aqueous sodium hydroxide solution to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]-propyl}imidazol-4-yl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH2:11][CH2:10]1.Cl>C(O)C>[CH:12](=[C:11]1[C:1](=[O:8])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:9][CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)COc2ccccc21

Procedure:
(66) To a solution of benzaldehyde (430 mg, 4.05 mmol) and 4-chromanone (500 mg, 3.37 mmol) in 8.4 ml of ethanol heated almost to boiling was added 1.7 ml of concentrated hydrochloric acid dropwise. After refluxing for 2 days, the solution was cooled overnight, and a precipitate formed. The precipitate was recrystallized from ethanol to afford 367 mg (46.1%) of white flakes: mp 111.8-113.4° C. (lit. mp 112° C., Powell, J. Am. Chem. Soc., 1923, 45, 2708-2711). 1H NMR (250 MHz) δ 8.06-8.02 (dd, 1H), 7.90 (s, 1 H), 7.54-7.31 (m, 6 H), 7.09 (t, 1 H), 7.00-6.96 (d, 1 H), 5.37 (s, 2 H); 13C NMR (62.7 MHz) 182.4, 161.3, 137.7, 136.1, 134.6, 131.1, 130.2, 129.7, 128.9, 128.1, 122.1, 118.1, 67.8 ppm.
Reaction SMILES: B(Br)(Br)[Br:2].S(O[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24]C)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)[CH3:26])(C)(=O)=O.O>C(Cl)Cl>[Br:2][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCOS(C)(=O)=O)cc1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(c2ccc(O)cc2)CCc2cc(O)ccc2C1CCCCBr
Temperature: -60 °C

Procedure:
A molar solution of boron tribromide in methylene chloride (27.6 ml.) was added to a stirred solution of (1RS,2RS)-1,2,3,4-tetrahydro-1-(4-mesyloxybutyl)-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene (Example 1; 2.3 g.) in methylene chloride (30 ml.) which was cooled to -60° C. under an atmosphere of argon, and the mixture was allowed to warm up to laboratory temperature and then poured into iced water. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluent. There were thus separately obtained the (1RS, 2RS)- and (1RS,2SR)-isomers of 1-(4-bromobutyl)-2-p-hydroxyphenyl- 2-methyl-1,2,3,4-tetrahydronaphth-6-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccccn1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
A solution of 19.8 g (95 mmol) of 2-(N-(t-butyloxycarbonyl)aminomethyl)pyridine in anhydrous tetrahydrofuran was cooled under N2 atmosphere to 0° C. and treated with 4.95 g (124 mmol) of sodium hydride (60% dispersion in oil). The solution was stirred for 15 min, treated dropwise with 7.1 ml (114 mmol) of methyl iodide, stirred at ambient temperature for 2 h, and quenched cautiously with water. The resulting mixture was partitioned between ether and water, dried over Na2SO4, and concentrated in vacuo. Chromatography on silica gel provided 14.9 g (70%) of the desired compound as a colorless oil.