Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.C[C:21](C)([O-:23])C.[K+]>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:23][CH3:21])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: O=C1NC(=O)C(c2c(F)cccc2F)O1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cccc(F)c1C1OC(=O)NC1=O
Temperature: 155 °C

Procedure:
5-(2,6-Difluorophenyl)oxazolidine-2,4-dione (2.0 g., 9.4 mmoles) was dissolved in 50 ml. of dimethylsulfoxide. Methanol (5 ml.) and then potassium tert-butoxide (2.11 g., 18.8 mmoles) were then added and the reaction mixture heated in an oil bath maintained at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 200 ml. of 1 N hydrochloric acid and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. The solids were taken up in 1 N sodium hydroxide, and the solution washed with three portions of ethyl acetate and then acidified with 1 N hydrochloric acid to precipitate purified 5-(2-fluoro-6-methoxyphenyl)oxazolidine-2,4-dione (1.32 g., 62%; m.p. 138°-142° C.). For analysis, the product was recrystallized from toluene (930 mg. recovered; m.p. 139°-141° C.)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[CH2:16][CH:17]([OH:32])[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH:17]([OH:32])[CH2:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=2)=[O:33])[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
50 ml of dichloromethane was added to 4.55 g of N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline, and trifluoroacetic acid was added to the mixture at room temperature until no foaming occurred. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 1.21 g of the title compound as white powder.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(O)C.C([N:18]([CH2:21][CH3:22])CC)C>>[N:18]1([CH2:12][C@@H:10]([OH:11])[CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1nccn1C[C@H]1CO1
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1

Procedure:
A solution of 0.3 g (1.8 mmole) of (S)-(-)-2-nitro-1-(2-oxiranyl-methyl)-1H-imidazole, 0.24 g (5.4 mmole) of 1H-aziridine, and 3.5 mL of 99:1 absolute ethanol:triethylamine is heated at reflux for 10 minutes, cooled, and concentrated. The residue is crystallized from 99:1 absolute ethanol:triethylamine to give product, mp 119.5°-121° C. [α]D25 =-28.7° [c1.15, chloroform].
Reaction SMILES: C[O:2][CH:3]=[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:5]>C1COCC1.O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH3:5])[CH:3]=[O:2])[N:7]=1
Reactant: COC=C(C)c1cccnn1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O
Solvent: C1CCOC1
Product: CC(C=O)c1cccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a solution of 1-methoxy-2-(pyridazin-3-yl)propene (0.26 g, 1.72 mmol) in THF (50 ml) and water (10 ml) under nitrogen at ambient temperature was added mercury(II)acetate (1.66 g, 5.2 mmol). This mixture was stirred at room temperature for 2 hours, and was then poured onto potassium iodide solution (7%, 350 ml) and extracted with toluene (2×50 ml). The combined organic phases were washed with potassium iodide (7%, 140 ml) and brine (90 ml), dried (Na2SO4) and evaporated to give the title compound (54 mg, 23%), as an orange gum. The crude aldehyde was used directly without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=CC=CC=2)[CH2:4][CH2:3]1.[ClH:11].[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1)([O-])=[O:13].[N+]([O-])([O-])=O.[K+].[S:30](=O)(=O)(O)O>>[CH3:3][CH:2]([OH:13])[CH3:10].[ClH:11].[ClH:11].[ClH:11].[NH2:24][CH:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([NH:12][C:2]([C:3]3[S:30][CH:10]=[CH:5][CH:4]=3)=[NH:1])[CH:23]=2)[CH2:19][CH2:20]1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc21
Reactant: NC1CCc2ccccc21
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: CC(C)O
Product: N=C(Nc1ccc2c(c1)C(N)CC2)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Nitro-1-aminoindane hydrochloride 1-Aminoindane (10.0 g, 75.08 mmol) was added to concentrated sulfuric acid (40 ml) at 0° C. The mix was warmed to room temperature to aid in solvation then cooled to 0° C. Potassium nitrate (7.60 g, 75.08 mmol) was then added portionwise and the mixture allowed to stir at room temperature for 1 hr before being dumped onto ice/50% NaOH. The aqueous solution was extracted with chloroform (3×100 ml). The combined extracts were washed with water, decolorized with charcoal, dried over magnesium sulfate, filtered, and concentrated to an oil. Treatment with IPA/HCl afforded the sub-titled compound: (6.90 g, 43%); m.p. dec 280° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:19]=O)[CH2:15][C:16](=O)[CH3:17])=[C:10]([O:21][CH3:22])[CH:9]=1.C([O-])(=O)C.[NH4+:28]>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[C:16]([CH3:17])[N:28]=[CH:19]2)=[C:10]([O:21][CH3:22])[CH:9]=1
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
An acetic acid (255 mL) solution of 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoic acid methyl ester (118 g) and ammonium acetate (172 g) was heated under stirring at 140° C. for 1 hour. The reaction solution was neutralized with an ammoniac solution under ice-cooling after the reaction completed. Ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was filtered with a silica gel pad after dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the residue and the deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 68.4 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore, crystallization mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system), and 22.3 g of the title compound was obtained.
Reaction SMILES: N[C@H](C(O)=O)CC[C:5](O)=[O:6].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]>>[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:5][OH:6])[OH:20])[OH:18])[OH:16])[OH:14]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
On the other hand, when the P. ananatis NA1 strain containing pTWVPtac_ccrNXA_Km was cultured with the mixed carbon source of glucose and xylose (MSII-GX medium), the glutamic acid yield was significantly higher as compared to the parent strain (yield: 69.9%). If it is taken into consideration that the parent strain hardly produces glutamic acid from xylose, and it is assumed that the glutamic acid yield from glucose of the strain containing pTWVPtac_ccrNXA_Km is equivalent to that of the parent strain, the yield of glutamic acid produced from xylose via the NXA pathway is about 86%. In fact, when the culture was performed with xylose as the sole carbon source (MSII-Xylose), the strain containing pTWVPtac_ccrNXA_Km produced Glu at a yield of 80% (Table 3).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9]CN)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:23]=[C:24]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1.[CH3:31][N:32](C)C=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:32]([CH2:21][C:22]2[CH:23]=[C:24]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=2)[CH3:31])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Yield: 65.2 %

Procedure:
N-(4-tert-butylbenzyl)methylamine (1.25 g; 7.04 mmol) and potassium carbonate (1.95 g; 14.1 mmol) were added to N,N-dimethylformamide (30 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (1.50 g; 7.04 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 1 hour at room temperature. Reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform), to thereby yield 1.42 g of the target compound as pale yellow oily matter (yield: 65.2%).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[OH:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:24][O:25][CH2:26]Cl.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][O:25][CH3:26])[C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COCCl
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(=O)OC)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
9 g (0.3 mol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 71.6 g (0.25 mol) of methyl 3-(1-adamantyl)-4-hydroxybenzoate in 500 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. 22.8 ml (0.3 mol) of methoxymethyl chloride were then added and the mixture was stirred at room temperature for one hour. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. 67.7 g (82%) of the expected compound were recovered in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:35][CH:36]=5)=[CH:26][CH:27]=4)[CH2:22]C[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB(C2C=CC3C4C(=CC(B5OC(C)(C)C(C)(C)O5)=CC=4)C(=O)C=3C=2)[O:51]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[N:35][CH:36]=5)=[CH:26][CH:27]=4)[C:22](=[O:51])[C:30]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1

Procedure:
Followed the procedure used to prepare compound 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 2,7-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-fluoren-9-one was used instead of 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane. m/z 650.9 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[CH2:9]([S:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH:17]([C:22]([CH3:24])=O)[C:18](OC)=[O:19])=[CH:14][CH:13]=1)[CH3:10].O>CO>[CH2:9]([S:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][C:17]2[C:18](=[O:19])[NH:4][C:2]([CH3:3])=[N:5][C:22]=2[CH3:24])=[CH:14][CH:13]=1)[CH3:10]
Reactant: CC(=N)N
Reactant: CCSc1ccc(CC(C(C)=O)C(=O)OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCSc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a solution of 4-ethylthiobenzyl alcohol (3.7 g) in tetrahydrofuran (80 mL) were added triethylamine (3.0 mL) and methanesulfonyl chloride (1.7 mL) at 0° C., and the mixture was stirred for 30 minutes. After the insoluble material was removed by filtration, the filtrate was added to a suspension of sodium hydride (60%, 0.88 g) and methyl acetoacetate (2.4 mL) in 1,2-dimethoxyethane (100 mL), and the mixture was heated under reflux for 4 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed to give methyl 2-(4-ethylthiobenzyl)-acetoacetate (6.1 g). To a suspension of acetoamidine hydrochloride (0.80 g) in methanol (15 mL) was added sodium methoxide (28% solution in methanol, 1.7 mL), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added a solution of methyl 2-(4-ethylthiobenzyl)-acetoacetate (1.5 g) in methanol (5 mL), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitated crystals were collected by filtration and dried to give 5-(4-ethylthiobenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.33 g).
Reaction SMILES: [O-]CC.[Na+].[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].C(O)C.[C:19](OCC)(=[O:25])[C:20]([O:22]CC)=[O:21]>O>[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][C:19](=[O:25])[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(I)cccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1c(I)cccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Sodium ethoxide solution (35 ml, 44 mmol) in an ice-water bath was added dropwise with a solution of 1-iodo-2-methyl-3-nitro-benzene 74b in ethanol (35 ml, 40 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred until substantial brown precipitates were formed, and added with diethyl oxalate (6 ml, 44 mmol) in one portion. The reaction mixture was refluxed at 100° C. in an oil bath for 0.5 hour, added with water (70 ml) and refluxed for another 1 hour. The reaction mixture was concentrated under reduced pressure to evaporate ethanol, washed with ethyl acetate (50 ml) under base condition, adjusted to pH 3 with hydrochloric acid (1M), and extracted with ethyl acetate (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 3-(2-iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.94 g) as a brown oil to be used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: CCC(=O)Cl
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a stirred solution of (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (45 mg, 0.15 mmol) and triethylamine (0.04 mL, 0.29 mmol) in tetrahydrofuran (1 mL), propanoyl chloride (0.014 mL, 0.16 mmol) was added drop wise at 0° C. The resulting reaction mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate (2×20 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. The residue was taken up in methanol (2 mL), potassium carbonate (25 mg) was added and stirred at room temperature for 10 minutes, concentrated on a rotary evaporator, diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulphate and concentrated on rotary evaporator. N-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]propanamide (7.4 mg, 14%) was isolated by silica gel column chromatography using dichloromethane and methanol gradient as eluent.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].COC(=O)C1C=CC(N[CH:18]2[CH2:24][CH:23]3[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)=C(O)C=1.F[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:31]=1[N+:38]([O-])=O.FC1C=CC=C[C:43]=1[N+:48]([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>>[CH3:37][O:36][C:32]1[CH:33]=[C:34]([CH:35]=[CH:30][C:31]=1[NH:38][CH:18]1[CH2:24][CH:23]2[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]2)[CH2:19]1)[C:43]#[N:48].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC1CC2CCC(C1)N2C

Procedure:
Using an adaptation of Procedure 2, substituting 8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine for the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a, 1-fluoro-3-methoxy-2-nitrobenzene, 1e for 2-fluoronitrobenzene, and cesium carbonate for potassium carbonate, the title compound 3-methoxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile, 1p was obtained as TFA salt and as a mixture of endo and exo isomers after purification via reverse phase HPLC (eluent gradient: 20% to 45% CH3CN in water containing 0.1% TFA). MS m/z=272 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl-].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18][NH3+:19])=[CH:15][CH:14]=1>S(Cl)(Cl)=O>[C:1]([NH:19][CH2:18][C:17]([C:16]1[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:20])(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C[NH3+])cc1
Reactant: O=C(O)c1ccncc1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)CNC(=O)c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Isonicotinic acid (24.93 g., 0.0938 mole) and thionyl chloride (50 ml) was refluxed for 1 hour. The crude acid chloride which remained after removal of excess thionyl chloride at diminished pressure was dissolved in dry pyridine (200 ml) and p-methoxy phenacylammonium chloride (19.00 g, 0.938 mole) was added portion wise to the stirred solution. During the addition, an exotherm occurred which raised the temperature of the stirred mixture to 40° C. After the addition was completed, the reaction mixture was heated and stirred on a boiling water bath for 2 hours and then poured into ice-water to precipitate the product. The solid was collected and dried under reduced pressure to give 12.07 g. (yield 48%) of α-isonicotinamido-p-methoxyacetophenone m.p. 227°-230° C. (with decomposition).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=C[CH:12]=1.CC1OC(C)OC(C)O1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:11][CH:12]1[O:10][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][O:9]1
Reactant: OCC(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC1OC(C)OC(C)O1
Product: CC1OCC(c2ccccc2)O1
Temperature: 20 °C
Yield: 85.3 %

Procedure:
100 g (0.63 mol) of (±)-1-phenyl-1,2-ethanediol (3) (87% pure according to GC) according to Example 1, 200 ml of toluene, 32 g (0.24 mol) of paraldehyde and 1 g of para-toluenesulfonic acid were charged to a 1 l stirrer, heated to boiling (110° C.) and stirred under reflux for a period of 4 h. A total of 10 ml of water were eliminated. After this time, the mixture was cooled to 20° C. and washed until neutral with sodium carbonate solution and water, and the solvent was distilled off under reduced pressure, leaving 103 g of crude product (85.3% pure according to GC). GC conditions see Example 2.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].S(=O)(=O)(O)[OH:11].[N+]([O-])([O-])=O.[Na+].[Cl-].[Na+]>O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O

Procedure:
L-Leu-OH (10.0 g) was dissolved in water (150 ml) containing concentrated sulfuric acid (3.2 ml) at 0° C. To the solution was added dropwise a solution of sodium nitrate (7.9 g) in water (50 ml) over 1 hour. The mixture was saturated with sodium chloride and extracted with ethyl acetate (500 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with hexane to give (2S)-2-hydroxy-4-methylvaleric acid (6.51 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[NH:14][N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[N:14]([CH2:28][CH2:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NNC(=O)SC3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NN(CCOC4CCCCO4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To 200 mg (0.55 mM) of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 4 ml of dimethylformamide are added 91 μl (0.6 mM) of 2-(2-bromoethoxy)tetrahydro-2H-pyran and 533.5 mg (1.64 mM) of caesium carbonate. The reaction medium is then stirred at room temperature for 16 hours. Demineralised water is added and the organic phase is isolated, washed with demineralised water and then dried over anhydrous sodium sulfate. The solvent is then evaporated off under vacuum and the residue is purified by chromatography on silica, using a dichloromethane/acetone mixture (90/10) as eluent, to give 200 mg of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of an oil.