Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C([O-])(=O)C.[Na+].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(O)(=O)C>[OH:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(O)c2c1NC(=O)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(O)c2c1NC(=O)CC2
Yield: 54.1 %

Procedure:
5.0 g of 8-amino-5-hydroxy-3,4-dihydrocarbostyril was suspended in 30 ml of acetic acid, and 4.0 g of sodium acetate was added to the suspension while stirring. 3.5 g of methanesulfonyl chloride was then added to the mixture followed by heating for 7 hours while refluxing. After completion of the reaction, 100 ml of water was added to the reaction mixture which was then concentrated to dryness under reduced pressure. The resulting residue was added to 200 ml of water, and the mixture was stirred. The crystals formed were recovered by filtration, washed with water and recrystallized from methanol to obtain 3.89 g of 5-hydroxy-8-methanesulfonylamino-3,4-dihydrocarbostyril as colorless amorphous crystals having a melting point of 269.4°-269.8° C.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ncccc1Br
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: C1CCOC1
Solvent: COCCOC
Product: O=Cc1ncccc1-c1cccs1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (126 mg, 0.675 mmol) and 2-thiopheneboronic acid (91.6 mg, 0.716 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (39 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. for 4 h. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (2×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 80:20) gave 3-thiophen-2-yl-pyridine-2-carbaldehyde (81 mg, 63%) as a yellow oil. 1H NMR (CDCl3) δ 7.13-7.22 (m, 2H), 7.48-7.57 (m, 2H), 7.92 (dd, 1H, J=7.9, 1.9 Hz), 8.82 (dd, 1H, J=6.0, 1.5 Hz), 10.23 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH2:10]([O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:27][N:26]=2)=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)nc2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (400 mg, 3.39 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (2.50 g, 9.03 mmol) under nitrogen atmosphere at room temperature. Triethylamine (1.89 mL, 13.6 mmol) was then added dropwise thereto, and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:2) to obtain the title compound (315 mg, 26%).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC(C)=CC=1)C.O=O>>[CH3:9][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8]
Reactant: CC(C)c1ccccc1
Agent: O=O
Solvent: CCc1ccc(C)cc1
Product: C=C(C)c1ccccc1

Procedure:
This example illustrates the dehydrogenation of cumene and p-ethyltoluene using a diluent comprising steam and nitrogen. Three and three-tenths grams of the catalyst prepared in Example II, ground to 18 to 40 mesh, was employed in the reactor described in Example II. Initially p-ethyltoluene was flowed into the reactor at 0.38 liquid hour space velocity, 11:1 diluent to p-ethyltoluene ratio (8:1 steam and 3:1 nitrogen) at 588° C., yielding a relatively poor conversion and selectivity. The catalyst was decoked with 5% oxygen and nitrogen for about 1 hr. Cumene was then run at 0.38 liquid hour space velocity, 11:1 diluent ratio (8:1 steam and 3:1 nitrogen) at 588° C. providing 40% conversion to alphamethylstyrene and 88% selectivity. The feed was then switched from cumene to p-ethyltoluene using the same diluent dilution and conditions providing 22% conversion to p-methylstyrene and 93% selectivity. Conditions were then changed to 0.72 liquid hour space velocity, 10:1 diluent ratio for the p-ethyltoluene (8:1 steam and 2:1 nitrogen) at 598° C., yielding 40% conversion and 92% selectivity to p-methylstyrene.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([CH:15]3[CH2:17][CH2:16]3)[OH:14])[O:11][C:10]([CH3:19])([CH3:18])[N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[O:11][C:10]([CH3:19])([CH3:18])[N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@H](O)C2CC2)OC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A mixture of 500 mg (1.36 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclopropylhydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 750 mg (1.77 mmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one in 10 ml of methylene chloride is stirred at room temperature for 3 hours. Thereafter, 50 ml of ether and 20 ml of 2N sodium hydroxide solution are added and the mixture is stirred at room temperature for 1 hour. The organic phase is separated, washed with 20 ml of 2N sodium hydroxide solution, dried over sodium sulphate and evaporated. There are obtained 400 mg of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-(cyclopropylcarbonyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a yellow oil; MS: 366 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Nc1cccnc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncccc1N

Procedure:
A mixture of 3-aminopyridine-2-carboxylic acid (6.4 g, 46.3 mmol) in 26 mL of EtOH and 8 mL of concentrated sulfuric acid is heated to reflux for 2 days. After cooling, the mixture is concentrated to about 15-20 mL and poured into 20 g of ice. The mixture is basified to pH 8-9 with concentrated NH4OH while cooling in an ice bath. The resulting brown precipitate is filtered off, and the filtrate is extracted with ether (4×60 mL). The combined ether extracts are washed with brine (4×60 mL), dried (Na2SO4), filtered, and evaporated to give a yellow/brown solid. This solid is combined with that from the above filtration and the whole is triturated with cold ether to give the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, m), 7.21 (1H, m), 7.03 (1H, m), 5.74 (2H, bs), 4.44 (2H, q, J 7.2, 6.9), 1.45 (3H, t, J 6.9).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH2:6])=[CH2:4].[C:7]1(=[O:12])[CH2:11][CH2:10][CH:9]=[CH:8]1>C1(C=CC(O)=CC=1)O>[CH3:1][O:2][C:3]1[CH2:4][CH:10]2[CH:11]([CH2:6][CH:5]=1)[C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: C=CC(=C)OC
Reactant: O=C1C=CCC1
Agent: Oc1ccc(O)cc1
Product: COC1=CCC2C(=O)CCC2C1
Yield: 21.7 %

Procedure:
2-Methoxybutadiene (69.9 g), 2-cyclopentenone (68.22 g) and hydroquinone (0.2 g) were heated together at 190° C. for 2 hours. The product was then distilled in vacuo, to give 3-methoxybicyclo[4,3,0]non-3-en-7-one (30 g), b.p. 74°-92° C./1.5 mmHg.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([S-:6])=[S:5].[K+].[NH2:8][C:9]1[N:14]=[C:13]([CH2:15]Cl)[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1>C(O)C.O>[NH2:8][C:9]1[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([CH2:15][S:5][C:4]([O:3][CH2:2][CH3:1])=[S:6])[N:14]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=S)SCc1cc(OC)nc(N)n1

Procedure:
16.0 g of potassium ethylxanthogenate and 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the reaction solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (87% of theory) of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine, m.p. 91°-93° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2OC)(=[O:12])[CH3:11]>O.C(O)CCC>[ClH:1].[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[NH:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: NCc1ccccc1
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(=O)Nc1ccc2nc(C)cc(NCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 96 h
Yield: 70.6 %

Procedure:
A warm solution of benzylamine hydrochloride (1.5 g, 10.4 mmol) in water (2 mL) was added to a mixture of 6-acetamido-4methoxy-2-methylquinoline (2.0 g, 8.7 mmol) in n-butanol (20 mL). The mixture was stirred for 4 days at 100° C., cooled in an ice bath, and the resulting precipitated solid was filtered, washed with ether, and dried by suction to afford 2.1 g (71%) of 6-acetamido-4-benzylamino-2-methyl-quinoline hydrochloride. This material was heated in 25% hydrochloric acid (33 mL) for 5 h at 90° C. After cooling, the separated solid was filtered, washed with ether, and dried by suction. The solid was dissolved in water, made basic (pH >10) with 5N sodium hydroxide to afford a yellow solid that was filtered, washed with water, and dried. 6Amino-4-benzylamino-2-methyl-quinoline was obtained in 43% yield (0.98 g). 0.5 Grams (1.9 mmol) of this material was dissolved in glacial acetic acid, and the solution was treated with oxalyl chloride (0.17 mL) for 1 h at room temperature with stirring. Ether was then added (25 mL) and the mixture stirred for 30 min. The solid was filtered, washed with ether, and dried by suction. It was dissolved in water (25 mL) and warm ethanol (200 mL) with additional water added to achieve complete solution. After cooling to room temperature, 5N sodium hydroxide was added to give a yellow precipitate that was filtered, and dried under high vacuum to yield 0.46 g (41%) of the title compound; m.p. 292-294° (dec.); MS (FAB): m/z 581 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]([Cl:17])[C:15]([OH:22])([C:18]([F:21])([F:20])[F:19])[O:14][N:13]=2)=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[Cl:17][CH:16]1[C:15]([OH:22])([C:18]([F:19])([F:20])[F:21])[O:14][N:13]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[C:7]([N+:1]([O-:4])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: OC1(C(F)(F)F)ON=C(c2ccc(Cl)cc2)C1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C2=NOC(O)(C(F)(F)F)C2Cl)ccc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
At 5° C., 1.81 ml of a mixture of 0.46 ml of 98% strength nitric acid and 1.35 ml of concentrated sulfuric acid were added dropwise to 2.4 g of 3-(4'-chlorophenyl)-4-chloro-5-hydroxy-5-trifluoromethylisoxazoline in 20 ml of concentrated sulfuric acid. The reaction mixture was stirred at 5° C. for 1.5 hours and then poured into 300 ml of ice-water. The organic phase was subsequently separated off, dried over sodium sulfate and finally concentrated. Yield: 2.5 g.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[C:18]([CH3:19])=[CH:17][N:16]([CH3:20])[C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:20][N:16]1[CH:17]=[C:18]([CH3:19])[C:14]([NH:13][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[C:15]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1c(N)c(C)cn1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])c(C)cn1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
The solution of ethyl 3-amino-1,4-dimethyl-1H-pyrrole-2-carboxylate in dimethyl formamide obtained in Example 19 is cooled to 0° C.; 3.0 g of 80% sodium hydride and 14.1 g of 2-fluoronitrobenzene are added thereto with stirring. After removing the ice-bath, the temperature rises to 40° C. and, simultaneously, an evolution of gas can be observed; this evolution subsides after 3 hours. The mixture is stirred overnight, cooled to 0° C.; 100 g of ice and 100 ml of water are then added. The precipitate formed is filtered off and is washed thoroughly with cold (0° C.) methanol. 13.5 g (87%) of the title compound of m.p. 114° C. (from ethanol) are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O.Cl>CN(C)C=O>[C:21]1(=[O:31])[N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12
Reactant: O=C(O)CCCCCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 142.5 %

Procedure:
2 g of 17-bromoheptadecanoic acid are added to 2.14 g of potassium phthalimide in 40 cm3 of N,N-dimethylformamide and the mixture is heated for 6 hours at a temperature in the region of 80° C. The solution is cooled to about 20° C., it is poured into 100 cm3 of distilled water and 10 cm3 of 2N hydrochloric acid are added dropwise. The solid formed is separated by filtration. 5.13 g are obtained of a residue which is chromatographed on a column with a diameter of 4 cm containing 250 g of silica (0.020-0.045 mm) eluted with a 95/5 (by volume) mixture of methylene chloride and methanol. The first 4 fractions are discarded, the following 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 3.39 g of 17-phthalimidoheptadecanoic acid are thus obtained in the form of a white solid.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:13]=1)=O>CO>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[C:7](=[CH:10][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=3)[CH:13]=2)[C:8](=[O:9])[NH:1]1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: N#Cc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Solvent: CO
Product: N#Cc1ccc(Cn2cc(C=C3C(=O)NC(=O)NC3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of barbituric acid (1.28 g; 0.01 mol) and 4-((3-formyl-1H-indol-1-yl)methyl)benzonitrile (2.60 g; 0.01 mol) in methanol (50 ml) were stirred at room temperature. After 10 min the reaction mixture became a solid suspension and the color of reaction mixture changed to yellow color solid suspension. The suspension continued to stir at room temperature for 5 hrs. Solid product was separated by filtration and washed several times with cold methanol (3×5 ml). The isolated yellow solid recrystallized from methanol gave (1) as a yellow crystalline product; m.p. >300° C.; 1H NMR (DMSO-d6): δ 5.81 (s, 2H), 7.33-7.36 (m, 2H), 7.43-7.45 (d, 2H), 7.61-7.64 (m, 1H), 7.82-7.84 (d, 2H), 7.90-7.93 (m, 1H), 8.68 (s, 1H), 9.63 (s, 1H), 11.07 (bs, 1H), 11.15 (bs, 1H); 13C NMR (DMSO-d6): δ 49.7, 109.4, 110.5, 110.8, 111.8, 117.9, 118.4, 123.0, 123.8, 128.0, 129.6, 132.6, 136.1, 141.7, 141.8, 142.6, 159.2, 162.9, 164.1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:16][C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[NH2:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][C:17]1[C:22]([F:23])=[C:21]([Br:8])[C:20]([F:24])=[CH:19][C:18]=1[NH2:25])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)cc(F)c1OCc1ccccc1
Solvent: ClCCl
Product: Nc1cc(F)c(Br)c(F)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NBS (1.60 g, 9.01 mmol) in methylene chloride (20 mL) at 0° C. is added a solution of 2-benzyloxy-3,5-difluorophenylamine (2.12 g, 9.01 mmol) and the mixture is stirred at 0° C. for 30 min then at RT for 30 min. The Mixture is washed with water and the solvent evaporated under reduced pressure. The residue is purified by column chromatography to give the title compound: MS (M−H)−=313.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 50 °C
Yield: 65 %

Procedure:
1 g of the thus-obtained ester was dissolved in 20 ml of ethanol and treated with a solution of 1.6 g of potassium hydroxide in 10 ml of water. After heating to 50° C. for 2 hours, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted repeatedly with ethyl acetate. The crystalline residue obtained after evaporation was recrystallized from acetic acid. There was obtained 0.6 g of p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-yl)propenyl]benzoic acid, m.p. 255°-257° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=O)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]2([CH:22]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23]3)[CH2:2][CH2:1]2)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(C(=O)C1CCN(Cc2ccccc2)C1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37.7 %

Procedure:
A stirred solution of ethylmagnesium bromide (3.0 M in ethyl ether, 2.1 mL, 6.3 mmol) in THF (17.0 mL) was cooled to −78° C. To this solution was added a solution of titanium (IV) isopropoxide (0.76 mL, 2.6 mmol) in THF (1.7 mL) dropwise with the temperature below −70° C. After stiring for three minutes, the solution of 4-[(1-benzyl-pyrrolidine-3-carbonyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol) in THF (1.7 mL) was added. The resulting solution was slowly warmed to room temperature, heated at reflux for one hour and then cooled to 8° C. Ethylmagnesium bromide (3.0 M in ethyl ether, 1.8 mL, 5.4 mmol) was added followed by a solution of titanium (IV) isopropoxide (0.66 mL, 2.2 mmol) in THF (1.0 mL) rapidly. The reaction mixture was stirred at room temperature for one hour and partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (60% ethyl acetate in hexane with 0.5% triethylamine) to give pale yellow oil (390 mg, 38%). ESI MS m/z 414.3 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:29]4[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1(F)CCNC1
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclo hexyl methyl)-amide, and 3,3-Difluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.71 (bs, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.55-7.62 (m, 2H), 7.03 (d, J=9.3 Hz, 1H), 4.67 (s, 1H), 3.96-4.03 (m, 2H), 3.76-3.80 (m, 2H), 3.37-3.39 (m, 2H), 2.54-2.61 (m, 2H), 1.88-2.08 (m, 4H), 1.68-1.76 (m, 4H). m/z: 460.2 [M+H]+
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:3][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:24]=1)[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1

Procedure:
18.7 g (0.092 mole) of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione are mixed with 17.5 g (0.092 mole) of 3-(1-piperidinylmethyl)-phenol and the resulting mixture heated for 10 minutes to 130° C. After cooling, the reaction mixture is dissolved in 200 ml of chloroform and the organic phase is washed three times in succession with 30 ml of 1N NaOH-solution, then with 30 ml of water and finally with 30 ml of saturated aqueous NaCl-solution. After the organic phase has been dried over Na2SO4, it is concentrated in vacuo. The residue contains the title compound in the form of a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])[CH3:6])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:6])([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)C(C)S(=O)(=O)c1cccs1
Reactant: BrCc1ccccc1
Product: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1cccs1

Procedure:
2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2-sulfonyl)- propionic acid ethyl ester (3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil; MS 339.1 (M+H).