Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[OH-].[Na+]>C(O)C.O>[NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])(=[O:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(O)CN)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
0.5 g of ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)-phosphinate is dissolved in 5 ml of ethanol and this solution is added to a solution of 0.14 g of sodium hydroxide in 2 ml of water. This mixture is then heated to 60° for a period of 3 hours, cooled to room temperature and the solvent evaporated under reduced pressure. The oily residue is passed down an Ion Exchange Resin (DOWEX® 50W-X8 H+) using de-ionised water as eluant. Ninhydrin-positive fractions are combined and evaporated to give 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinic acid, m.p. 214°-215° (dec.), 31P-NMR : δ=+30.9 ppm (D2O).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:8])[CH2:5][OH:6].[CH2:27](N(CC)CC)C.Cl[P:35]1(=[O:40])[O:39]CC[O:36]1>C1C=CC=CC=1>[P:35]([O:6][CH2:5][CH2:4][N+:7]([CH3:9])([CH3:27])[CH3:8])([OH:40])([OH:39])=[O:36].[CH3:1][O:2][CH2:3][CH:4]([N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:8])[CH2:5][OH:6]
Reactant: CCN(CC)CC
Reactant: O=P1(Cl)OCCO1
Agent: CCCCCCCCCCCCCCCCCCN(C)C(CO)COC
Solvent: c1ccccc1
Product: C[N+](C)(C)CCOP(=O)(O)O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Compound of the formula Ia wherein R1 =CH3, R2 =C18H37, R3 =CH3, ##STR12## 2 g (5 mmol) of 3-methoxy-2-(N-methyl-octadecylamino)propanol (IIa) and 3 ml of triethylamine were dissolved in 20 ml of dry benzene, and the mixture was cooled to 5° C. under nitrogen circulation. 1 g (7 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphospholane in 4 ml of benzene was added under stirring, and stirring was continued overnight. The amino salt was filtered off and washed with benzene. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of dry methyl cyanide and transferred to a reactor. 20 ml of methyl cyanide, saturated with gaseous trimethylamine, was added, and the mixture was heated at 65° C. for 24 hours. A solid separated on cooling. It was filtered off and chromatographed on silica gel (eluent chloroform:methanol 90:10, then 70:30 by volume, then methanol) to yield 1.1 g (39%) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.O>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.), stirred solution of nitric acid (20 mL) in acetic acid (65 mL) was added 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (5.0 g) and the resulting mixture was allowed to stir at ambient temperature for 1.5 h. The resulting solution was poured into 400 mL of water, the resulting solids filtered and dried to afford the title compound of Step A as a yellow solid, 5.1 g. MS Calc.:425.2; Found: 422.9.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1CSC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CSC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione was prepared as for Example 10 from thiazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C)C=O.O>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:26]=[CH:27][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:10])[C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: CC(C#N)Oc1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C#N)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 130 °C

Procedure:
In a nitrogen atmosphere, add a solution of 4.9 g (0.03 mole) 2-(4-hydroxyphenoxy)propionitrile in 20 cc dimethylformamide to 1.5 g sodium hydride (0.03 mole) in 20 cc dimethylformamide. When the evolution of hydrogen ceases, add 4.9 g (0.03 mole) 2-chloroquinoxaline. Heat at approximately 130° C. until the reaction is complete. Pour into water and extract the product in ether. Dry the ethereal extracts and concentrate to yield the desired nitrile.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]3=[CH:10][S:11][C:6]=2[C:5](C(O)=O)=[C:4]([C:19]([OH:21])=[O:20])[CH2:3]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[C:7]2[N:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]3=[CH:10][S:11][C:6]=2[CH:5]=[C:4]([C:19]([OH:21])=[O:20])[CH2:3]1
Reactant: O=C(O)C1=C(C(=O)O)C2=C(C(=O)C1)N1C=CC=CC1=CS2
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(O)C1=CC2=C(C(=O)C1)N1C=CC=CC1=CS2
Temperature: 230 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A mixture of 6 g of 1-oxo-pyrido[2,1-C][1,4]benzothiazine-3,4-dicarboxylic acid in 60 ml Dow-Therm-A was stirred at 230° C. for 1 hr. (until no more gas was evolved). It was then allowed to cool, filtered, and the precipitate washed with ether giving 4.1 g crude product which was crystallized from 1N NaOH and 1N HCl to give 3.5 g product, m.p. 222° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(N(CC)CC)C>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:21]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Into 50 ml of tetrahydrofuran, were added 3.5 g of 2-amino-4-phenylthiazole and 2.0 g of triethylamine. The mixture was cooled to 0°--5° C. Then, 4.3 g of α-bromopropionylbromide was dropped to the solution mixture. After the completion of the dropwise addition, the solution mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was taken up in chloroform and washed with water. Upon removal of chloroform, a crude reaction product was obtained. It was thereafter subjected to silica gel chromatography and then eluted with a chloroform/methyl alcohol (40:1) mixed solvent. It was then recrystallized from an ether/cyclohexane mixed solvent, thereby obtaining 4.2 g of 2-(α-bromopropionylamino)-4-phenylthiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7](=[O:13])[CH:6]=1.[CH2:18]=O.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CO.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7](=[O:13])[C:6]=1[CH2:18][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1
Reactant: C=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(CN2CCCCC2)=C(Nc2ccccc2Cl)C1
Reaction time: 1 h

Procedure:
12.5 Parts of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one is dissolved in 3o volume parts of methanol under warming and, then, to the resulting solution are added 4.5 parts of a 37 weight % aqueous solution of formaldehyde, 6.05 parts of piperidine hydrochloride and 2 drops of glacial acetic acid. The whole mixture is allowed to stand at room temperature for 1 hour, whereupon a yellow, clear solution is obtained. The methanol is distilled off under reduced pressure, and a small amount of isopropyl ether is added to the resulting residue, followed by cooling, whereupon colorless crystals separate. The crystals are collected by filtration and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-piperidinomethyl-2-cyclohexen-1-one hydrochloride. Melting point: 105°-106° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11](O)[C:5]=2[CH:4]=1.C1C=CC=CC=1.S(Cl)([Cl:30])=O>N1C=CC=CC=1.O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11]([Cl:30])[C:5]=2[CH:4]=1
Reactant: OC1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)C(Cl)Cc1c(Cl)cccc1S2

Procedure:
To the mixture of 0.5 g of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-ol, 5 ml of anhydrous benzene and one drop of anhydrous pyridine were added dropwise with stirring 0.3 g of thionyl chloride with ice-cooling and the resulting mixture was reacted at room temperature for 10 minutes, then refluxed for 20 minutes, and freed of benzene under reduced pressure. To the thus obtained residue was added water and the mixture was extracted with benzene. The extract was washed with water, saturated sodium bicarbonate, then water, dried over anhydrous sodium sulfate and freed of benzene to obtain 2-trifluoromethyl-9-chloro-11-chloro-10,11-dihydrodibenzo[b,f]-thiepin as colorless crystals having a melting point of 88°-90° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[CH:12]([C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=1)=[O:13]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)n1cc(C=O)nc1-c1ccccc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (35 mL) were added potassium carbonate (2.78 g) and methyl bromo(phenyl)acetate (2.53) and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→3:7) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 814 mg, yield 25%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
4,4'-dihydroxybenzophenone (100.0 grams, 0.467 mole) is added to ethanol (300 milliliters) in a 1 liter Erlenmeyer flask and stirred. After dissolution of the 4,4'-dihydroxybenzophenone, a solution of hydroxylamine hydrochloride (48.6 grams, 0.699 mole) and sodium acetate (57.4 grams, 0.700 mole) in deionized water (70 milliliters) is added followed by an additional 100 milliliters of ethanol. This mixture is stirred and heated on a hot plate to a gentle reflux (75° C.). After heating for 4 hours, the solution is allowed to cool to room temperature (25° C.) with stirring and then filtered. The filter cake is washed with ethanol (100 milliliters); then the total filtrant obtained (600.4 grams) is concentrated to a weight of 219.2 grams by evaporation of the ethanol and water. The concentrated solution is placed into a 1 liter Erlenmeyer flask then stirred as 600 milliliters of deionized water is added. The addition of the deionized water induced formation of a white precipitate. After thirty minutes of stirring, the mixture is filtered. The solid 4,4'-dihydroxybenzophenone oxime thus obtained weighed 98.22 grams after drying. 4,4'-Dihydroxybenzophenone oxime (66.0 grams. 0.288 mole) and glacial acetic acid (330 milliliters) are added to a 500 milliliter round bottom flask equipped with a stirrer, water cooled condensor, nitrogen purge and heating mantle. A catalytic amount of p-toluenesulfonic acid (1.85 grams, 0.027 mole) is added and the reaction mixture then heated to 83° C. After heating for approximately two hours, a precipitate formed and the mixture is stirred for an additional two hours at 87° C. After this time, 25 milliliters of deionized water is added to the reactor and after thirty minutes, the contents of the reactor is transferred to a 1 liter Erlenmeyer flask and maintained therein with stirring. Immediately following the transfer, 400 milliliters of deionized water is added to the flask. The mixture is stirred for forty five minutes and then filtered. The filter cake thus obtained is washed with 800 milliliters of deionized water and then dried. The resultant light beige colored solid weighed 54.82 grams. Fourier transform infrared spectrophotometric analysis of a portion of the product confirmed the product structure as that of 4,4'-dihydroxybenzanilide. Differential scanning calorimetry demonstrated a sharp melting point endotherm at 273° C. for the 4,4'-dihydroxybenzanilide product.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C[C:23]([O-:26])([CH3:25])C.[K+].[OH2:28]>C(O)CO.O1CCOCC1>[OH:28][CH2:25][CH2:23][O:26][C:2]1[C:3]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccnc2Cl)CC1
Agent: [K+]
Solvent: OCCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2nccnc2OCCO)CC1
Temperature: 90 °C

Procedure:
To a stirred mixture of tert-butyl 4-(3-chloropyrazin-2-yl)-1,4-diazepane-1-carboxylate (2.5 g, 8.0 mmol; from Step 1) in ethylene glycol (8 mL) and dioxane (25 mL), was added t-BuOK (0.99 g, 8.8 mmol). The mixture was heated at 90° C. with condenser, under N2, overnight. Water (10 mL) was added to the light brown mixture and extracted with dichloromethane (3×20 mL). The organic phase was dried over MgSO4. The solution was filtered and the solvent evaporated. The residue was purified by chromatography on silica gel using toluene/EtOAc (2:3) as eluent. 1H NMR analysis supports the stated structure. Yield: 1.66 g (61%). HPLC purity: 100%. MS m/z 339 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:14]1([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=3)[CH2:8]2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: O=C1CCc2cc(Cl)c(Cl)cc2C1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1cc2c(cc1Cl)CC(N1CCNCC1)CC2
Reaction time: 8 h
Yield: 46.1 %

Procedure:
A mixture consisting of 6,7-dichloro-2-tetralone (4.30 g), piperazine (3.44 g), and 4A molecular sieves (4 g) 100 ml of toluene was stirred overnight under nitrogen and warmed briefly. The sieves were filtered off, and the filtrate was freed of solvent on an evaporator. Seventy-five ml of THF and 6 ml of methanol were added to the residue. The solution was cooled in an ice bath under nitrogen, and 1.24 g of sodium cyanoborohydride was added. Small amounts of gaseous HCl were added periodically until the solution remained acidic. The solution was stirred overnight at ambient temperature, the solvents were evaporated, and the residue was dissolved in dilute HCl. The acidic solution was extracted with three portions of ether and then made basic with sodium hydroxide. The oil which separated was extracted with ether, and the ether solution was dried (Na2SO4). The after evaporation of the ether was dissolved in ethanol, and excess anhydrous HCl was added. The crystalline solid isolated from the ethanol melted at about 272°-275° C. After recrystallization from ethanol there was obtained 1.1 g of the title compound. m.p. 278°-282° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>C(#N)C.C(O)(C)C>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cn1
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc(NCC(O)CO)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.5 g (0.003 mol) 6 and 0.3 g (0.003 mol) triethylamine in 10 ml acetonitrile is added 0.32 g (0.0035 mol) 3-amino-1,2-propanediol (10) in 10 ml iso-propanol. After stirring for 18 hours at room temperature the solvent is removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel eluting with 10% methanol/chloroform. Pure 12 has Rf 0.4 and is a pale yellow solid, m.p. 185°-7°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[S:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[N:15][CH:14]=1>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>[CH3:12][C:13]1[S:17][C:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:15][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ncc(C)s2)c1
Temperature: 90 °C

Procedure:
A mixture of commercially available methyl 2-bromoisonicotinate (2.750 g; 12.70 mmol), 5-methyl-2-(tributylstannyl)thiazole (4.942 g; 12.70 mmol), copper iodide CuI (242 mg; 1.27 mmol), and Pd(PPh3)4 (1.471 g; 1.27 mmol) in anh. DMF (55 ml) was heated to 90° C., under nitrogen, for 18 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the separated solids were washed with AcOEt. The organic layer was washed with water and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-(5-methylthiazol-2-yl)isonicotinate as an orange solid. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 235.10 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:7]C(OCC1C=CC=CC=1)=O)[CH:5]=[CH2:6].S(Cl)([Cl:21])=O>CO>[ClH:21].[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:7])[CH:5]=[CH2:6]
Reactant: C=C[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Reactant: O=S(Cl)Cl
Solvent: CO
Product: C=C[C@H](N)C(=O)OC
Product: Cl
Reaction time: 1 h

Procedure:
Carboxylic acid 62 (0.350 g, 2.56 mmol) was suspended in methanol (10 mL). This was cooled in ice and 20% (v/v) thionyl chloride was added portionwise. The solution was stirred in ice for 1 h and then at rt for 18 h before being concentrated in vacuo to afford a white solid, 0.388 g, (100%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[CH2:12]([O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(C)CCCCCCCO
Product: CC(C)CCCCCCCOC(=O)CC(C)CC(C)(C)C

Procedure:
The preparation from 3,5,5-trimethylhexanoic acid and isodecyl alcohol (mixture of methyl branched primary decanols from Hoechst) was analogous to Example 3; colorless liquid of medium viscosity; B.P. (1.3 mbar)=148°-154° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2].[C:25]([Cu])#[N:26]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([CH2:21][CH2:22][CH3:23])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:25]#[N:26])[CH:16]=[CH:15][C:14]=3[CH3:20])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(Br)c21
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 220 °C
Yield: 87.5 %

Procedure:
5-Bromo-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (1.27 g, 3.22 mmol) and CuCN (0.433 g, 4.83 mmol) was dissolved in N-methyl-2-pyrrolidinone (15 mL) and the solution was divided into the 4 microwave reaction vessels (3.75 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 4 vessels were combined and then diluted with water (30 mL). The crude mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 0.959 g (88%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 9.75 (bs, 1H), 7.33 (d, J=7.52 Hz, 1H), 6.93 (d, J=7.52 Hz, 1H), 4.21 (m, 2H), 4.11 (m, 1H), 4.03 (m, 1H), 3.08 (t, J=5.52, 2H), 2.99 (d, J=4.17 Hz, 2H), 2.57 (s, 3H), 2.06 (m, 2H), 1.42 (m, 1H), 1.26 (t, J=7.16 Hz, 3H), 1.18 (m, 1H), 0.88 (t, J=7.32 Hz, 3H).