Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:12]([O:14]CC)=[O:13])([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[OH-].[K+].O>C(O)C>[O:1]1[CH2:2][CH2:3][C:4]([C:7]([OH:9])=[O:8])([C:12]([OH:14])=[O:13])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred solution of diethyl oxane-4,4-dicarboxylate (40.0 g., 173 mmol) in ethanol (100 mL) was added a solution of potassium hydroxide (21.4 g, 382 mmol) in ethanol (300 mL). After the completion of the addition, the reaction mixture was stirred for 15 min at ambient temperature and then refluxed for 2.5 h. Water (40 mL) was added to the thick, white suspension, and then the solvent was removed by rotary evaporation. Water (40 mL) was added to the remaining residue and the resulting mixture then acidified with concentrated sulfuric acid (20 mL). The acidic solution was extracted with diethyl ether (3×300 mL) and the combined organic layers were dried (Na2SO4). Removal of solvent by rotary evaporation yielded the product (27.3 g, 90.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Solvent: O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of succinic acid (0.59 g) in 2-propanol (35 ml) and water (5 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 167.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(=O)C1C(=CC=CC=1)O>[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(N)C(=O)O
Agent: C[C@H](NC(=O)c1ccccc1)C(=O)O
Solvent: O=Cc1ccccc1O
Solvent: O
Product: CC(C)[C@H](N)C(=O)O
Temperature: 95 °C
Reaction time: 48 h

Procedure:
Twenty four grams of DL-valine and 19.3 g of N-benzoyl-L-alanine were suspended in 200 mL of deionized water. The suspension was heated to 95° C. to form a clear solution, to which 0.2 g of salicylaldehyde was added. The solution was cooled slowly to room temperature and stirred for another 48 hours at 25° C. The precipitated crystals were then separated by filtration, washed with 50 mL of deionized water, and dried to obtain 29.2 g of crystalline L-valine N-benzoyl-L-alanine complex (L-valine to N-benzoyl-L-alanine molar ratio of 1:1).
Reaction SMILES: Cl[CH2:2][Si:3]([O:6][CH3:7])([CH3:5])[CH3:4].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:8]([O:11][CH2:2][Si:3]([O:6][CH3:7])([CH3:5])[CH3:4])(=[O:10])[CH3:9]
Reactant: CO[Si](C)(C)CCl
Reactant: CC(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CO[Si](C)(C)COC(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 230.4 kg (1.662 kmol) of (chloromethyl)-methoxydimethylsilane and 11.8 kg (34.8 mol) of tetrabutylphosphonium bromide was heated up to 90° C. and admixed during 3 h with 150 kg (1.828 kmol) of sodium acetate (anhydrous) in 6 portions of 25 kg each such that the temperature did not exceed 114° C. The mixture was subsequently stirred without additional heating for 1 h and then at 115-122° C. for a further 2 h. Thereafter, the product was distilled out through a column at 18-30 mbar (head), 50-53° C. (head) and 84-120° C. (pot), while 150 kg of Hydroseal G 400 H were metered into the residue during the distillation to ensure stirrability. The product (acetoxymethyl)methoxydimethylsilane (249.2 kg, 1.536 kmol, 92% of theory; purity 99.6% (GC area %)) was obtained as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOCCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCCOC(=O)C(=C)C
Temperature: 120 °C
Yield: 72.5 %

Procedure:
To a three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a Dean-Stark apparatus were added methacrylic acid (137.7 g, 1.6 moles), ethyleneglycol monoallylether (80.7 g, 0.8 moles), p-toluenesulfonic acid (0.76 g, 4.0 mmole) and toluene (650 mL). The mixture was heated to 120° C. for 5 hours with exclusion of water. Another portion of p-toluenesulfonic acid (0.12 g) and the mixture was heated to 120° C. for 6 hours. The other portion of p-toluenesulfonic acid (0.1 g) was added and the mixture was heated to 120° C. for 9 hours. During the reaction, the consumption of methacrylic acid and ethyleneglycol monoallylether were monitored by liquid chromatography and the conversion reached 98%. The mixture was neutralized by addition of aq. NaHCO3 and the layers were separated. The aqueous layer was extracted with toluene and the combined organic layers were dried over CaCl2 and concentrated under reduced pressure. Distillation of the crude material (60° C. at 2 mmHg) yielded 2-allyloxyethyl methacrylate (98.7 g, 73%) shown below.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([O:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11].[N-]=C=O.Cl>O.CN(C)C(=O)C>[C:9]([O:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [N-]=C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(O)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Into a 1 liter fask 500 g of N,N-Dimethyl acetamide and 173.5 g (1.6 mole) of p-aminophenol were added. This mixture was placed in cold bath and 234.9 g (1.5 mole) of methacryloyl oxyethyl isocyanate was added over a period of 1 hour. After the addition was complete, stirring was continued for 5 hours at room temperature. The mixture was tested for isocyanate functionality using IR spectroscopy. 30 ml of concentrated HCl was added to the mixture and was stirred for 15 minutes. The mixture was poured into 4.5 liter of water. The deposit was filtered, washed and dried to produce 370 g of 2-(N′-(4-hydroxyphenyl)ureido)ethyl methacrylate.
Reaction SMILES: [Cl-].[Cr+3:2].[Cl-].[Cl-].[NH2:5][C@@H:6]([CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13])[C:7]([OH:9])=[O:8]>O>[Cr:2].[NH2:5][C@@H:6]([CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13])[C:7]([OH:9])=[O:8]
Reactant: [Cr+3]
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: O
Product: [Cr]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
One gram (3.7 mmole) of chromium chloride (CrCl3) was dissolved in 40 ml of deionized water to get a green solution. 4.6 g (15 mmole) of glutathione (GSH) was dissolved in 40 ml of deionized water were added, the pH of the reaction mixture adjusted to 6, and the reaction mixture was stirred for 3 hours at 40° C. until the solution turned violet. The absorbance peaks for Cr-GSH are 410 and 550 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-L-alanine (6.5 g, 28.5 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 36.2 mmol), and N-hydroxybenzotriazole (4.8 g, 34.8 mmol) were dissolved in THF (32 mL) and cooled to 0° C. under N2. Diisopropylethylamine (12.3 mL, 71.3 mmol) was slowly added, maintaining the temperature below 25° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.0 g, 36.2 mmol) was then added slowly, maintaining the temperature at 15-25° C. The slurry was stirred overnight at room temperature, and then cooled to 0° C. 1N Aqueous HCl (36 mL) was added slowly, and the mixture was warmed to room temperature and extracted with EtOAc. The combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, and then concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=O>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: O=[Se]=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 3.33 parts of selenium dioxide was refluxed in 35 parts of xlene for eight hours. The reaction mixture was cooled, ether was added and the insoluble inorganic products were removed by filtration. Evaporation of the volatile components of the filtrate gave a brown residue which crystallised from light petroleum (b.p. 40°-60°C) to give 1.54 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: [O-][n+]1cc(F)cc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cnc2[nH]ccc2c1Cl

Procedure:
4-Chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine can be obtained as in example 4 stage 4(b) but starting from 1.7 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide in 10 cm3 of phosphorus oxychloride. In this way, 1.3 g of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine is obtained as a solid with the following characteristics:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].ClC1C=CC(Cl)=CC=1Cl.[Cl-].[Cl-].[Cl-].[Al+3]>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Acetanilide (13.94 g), propionyl chloride (14.31 g) and 1,2,4-trichlorobenzene (100 ml) were warmed to 60° C. and aluminium trichloride (40.0 g) was added over 15 minutes. The mixture was heated at 100° C. for 90 minutes, cooled at 40° C. and ethanol (200 ml) was added dropwise keeping the temperature below 60° C. by means of an ice-water bath. After stirring for 30 minutes at 40° C. a homogeneous system was obtained. This was quenched with water (100 ml) at 25°-30° C. and stirred for 15 minutes. Dichloromethane (300 ml) and water (200 ml) were added and the organic layer was separated and washed with water (2×200 ml). The organic layer was evaporated to about half-volume (about 150 ml), and petroleum ether (60° C.-80° C.) (150 ml) was added at 50° C. A solid precipitated and was collected after 60 minutes of stirring to afford p-acetamidopropiophenone (15.12 g; 79%), m.p. 169°-70° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].[C:32]([O:36][C:37]([NH:39][C@@:40]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:45]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[C@H:44](O)[C@@H:43]2[C@H:41]1[C@H:42]2[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:38])([CH3:35])([CH3:34])[CH3:33].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)C>[C:32]([O:36][C:37]([NH:39][C@@:40]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:45]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[C@@H:44]([O:28][C:27]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)=[O:29])[C@@H:43]2[C@H:41]1[C@H:42]2[C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Triphenylphosphine (12.66 g, 48.26 mmol) and 4-nitrobenzoic acid (8.19 g, 48.26 mmol) are added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (14.20 g, 24.13 mmol) and tetrahydrofuran (241.28 mL, 2.97 moles) at room temperature. Cool the mixture in an ice bath. Diisopropyl azodicarboxylate (9.57 mL, 9.76 g, 48.26 mmol) in tetrahydrofuran (20 mL) is added and the reaction mixture is gradually warmed to room temperature overnight. Dilute with diethyl ether, and then wash with aqueous sodium carbonate. Extract the aqueous layer again with diethyl ether. Combine all ether extracts, wash with water, brine, dry over magnesium sulfate, and concentrate under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 10-100% ethyl acetate in hexanes to give the title compound (9 g, 12.2 mmol, 51%): MS (m/z): 759 (M+1).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
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: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) (30 mg, 0.10 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70 min, MH+ 350. NMR: δH [2H6]-DMSO 9.11, (1H, s), 8.84, (1H, t), 8.48, (1H, d), 8.31, (1H, dd), 7.88, (1H, s), 7.81, (1H, d), 7.70, (1H, d), 7.41, (1H, d), 3.20, (1H, t), 2.86, (1H, m), 2.37, (3H, s), 1.06, (1H, m), 0.69, (2H, m), 0.57, (2H, m), 0.46, (2H, m), 0.26, (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C1COCC1.C(Cl)Cl>[N:42]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dissolve 3-nitro-5-trifluoromethyl-benzoic acid (2.9 g, 12.6 mmol) and 1-hydroxy-7-azabenzotriazole (25 mL of 0.5 M solution in DMF) in THF. Add 1,3-dicyclohexylcarbodiimide (2.6 g, 12.6 mmol) and morpholine (1 g, 11 mmol). Stir the mixture for 48-72 hours at room temperature. Dilute the resulting suspension with DCM and quench with saturated aqueous ammonium chloride. Wash the organic layer further by aqueous saturated sodium chloride and water, dry (MgSO4) and concentrate to a yellow-white residue. Purify by silica gel column chromatography, with a gradient from 100% hexane to 50% hexane in ethyl acetate, yielding the title compound as 2.5 g white solid (75% yield). LCMS (ES), m/z 305 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CN(C)C(=O)Cl
Product: Cc1cc(OC(=O)N(C)C)nc(C(Cl)(Cl)Cl)n1

Procedure:
The pyrimidinyl carbamate compounds of the present invention may be prepared by reacting trichloroacetamidine with the corresponding acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carbamoyl chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with methylacetoacetate to form 4-hydroxy-6-methyl-2-trichloromethylpyrimidine. In equation (B), the 4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with dimethylcarbamoyl chloride to form 6-methyl-2-trichloromethyl-4-pyrimidinyl dimethylcarbamate. ##STR3##
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with triethylamine (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous bicarbonate (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry acetonitrile (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product as a brown solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH2:15](O)[CH3:16]>>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1cncc(Br)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82 %

Procedure:
20 ml (27 mmol) of thionyl chloride are added dropwise, at room temperature, to a solution of 10 g (49 mmol) of 5-bromonicotinic acid in 250 ml of ethanol. The reaction medium is stirred at room temperature for 4 days and then evaporated under vacuum. The residue is taken up in dichloromethane and washed with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 9 g (82%) of ethyl 5-bromonicotinate are obtained.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10 but in the presence of (S)-phenylethylamine (2.29 mmol) instead of NaOH as a base, 5 g (11.48 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in 37 ml methanol/dichloromethane (3:2) in the presence of 0.93 mg of [Ru(OAc)2((S)-TMBTP)] (S/C molar ratio 10'000) under 30 bar of hydrogen for 4 h at 40°, then 2 h at 60° h to reach 99.9% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 91.8% ee with 99.4% purity (HPLC area). In analogy to example 13, the experiments described in table 1 have been carried out with different substrate-to-catalyst ratios.