Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH:17]=[O:18])[C:5]([NH:7][C:8]1[S:9][C:10]([S:13][CH3:14])=[N:11][N:12]=1)=[O:6])[CH2:2][CH3:3].Cl>O>[CH3:14][S:13][C:10]1[S:9][C:8]([N:7]2[CH:17]([OH:18])[CH2:16][CH2:15][N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[O:6])=[N:12][N:11]=1
Reactant: CCCN(CCC=O)C(=O)Nc1nnc(SC)s1
Agent: Cl
Solvent: O
Product: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]O)[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[I:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(I)cc1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Ic1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.4 %

Procedure:
40% DEAD/toluene (2.5 mL) was added to a THF (30 mL) solution of 4-iodophenol (1.0 g), 2-morpholinoethanol (0.72 g) and triphenylphosphine (1.4 g) under ice cooling, and the mixture was stirred for 17 hours at room temperature. After the solvents were distilled off, the resulting residue was purified by NH type silica gel chromatography (gradient elution with hexane/ethyl acetate=90/0→60/40) to obtain 4-[2-(4-iodophenoxy)ethyl]morpholine (colorless oil) (1.4 g, 93%).
Reaction SMILES: I(C1C=CC=CC=1)=O.B(F)(F)F.C[Si](C)(C)[O:15][C:16]([C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)=[CH2:17].[CH3:30][OH:31]>>[CH3:30][O:31][CH2:15][C:16]([C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: C=C(O[Si](C)(C)C)c1ccnc2ncccc12
Reactant: CO
Agent: FB(F)F
Agent: O=Ic1ccccc1
Product: COCC(=O)c1ccnc2ncccc12
Temperature: 25 °C

Procedure:
To a suspension of iodosobenzene (347 mg, 1.57 mmol), in MeOH (7.2 ml) in an ice bath was added borontrifluoride diethyletherate (0.200 ml, 1.57 mmol) followed by 4-(1-trimethylsilanyloxy-vinyl)-[1,8]-naphthyridine from Step 1 (350 mg, 1.43 mmol) in minimum amount of MeOH. The reaction mixture was warmed to RT overnight and then quenched with solid NaHCO3 and diluted with water. Iodobenzene was extracted with EtOAc and the desired material re-extracted with DCM 2×. The organic layers were dried over Na2SO4 and concentrated to an orange oil (110 mg), which consisted of a 2:3 mixture of starting material and desired title compound. MS (ESI+) for m/z 203 (M+H)+.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][C@H:18]3[CH2:34][C@@H:21]4[O:22]C(C5C=CC(OC)=CC=5)[O:24][CH2:25][C@@H:20]4[CH2:19]3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.CC(O)=O>C1COCC1>[C@@H:1]1([NH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([CH2:17][C@H:18]3[CH2:34][C@H:21]([OH:22])[C@H:20]([CH2:25][OH:24])[CH2:19]3)[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](Cc4cc(N[C@H]5CCc6ccccc65)ncn4)C[C@@H]3O2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OC[C@@H]1C[C@@H](Cc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 60 h
Yield: 91.8 %

Procedure:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-6-{[(4aS,6S,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]methyl}pyrimidin-4-amine (0.280 g, 0.61 mmol) was dissolved in THF (2 mL), water (2 mL) and AcOH (6 mL, 0.106 mmol) were added. The mixture was stirred under an atmosphere of argon for 60 h. The mixture was concentrated under reduced pressure and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (0.190 g, 91%). LC/MS: Rt=1.29 min, ES+ 340 (AA standard).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[BH4-].[Na+]>CO>[Cl:3][C:4]1[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH2:1][NH2:2]
Reactant: CN
Reactant: CCCOc1c(Cl)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(Cl)cccc1CCN
Reaction time: 72 h
Yield: 96 %

Procedure:
A solution of methylamine (8.5 mL of a 2.0 M solution in MeOH, 17 mmol) was added to 3-chloro-2-propoxybenzaldehyde (0.425 g, 2.14 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (8.5 mL) and treated with NaBH4 (0.080 g, 2.1 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (10 mL). The mixture was extracted with Et2O (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.441 g, 96%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.31 (m, 2H), 7.08 (t, J=7.7 Hz, 1H), 3.85 (t, J=6.4 Hz, 2H), 3.67 (s, 2H), 2.26 (s, 3H), 2.04 (br s, 1H), 1.82-1.70 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17]C)[CH:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:17])[CH:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)CC2
Reactant: BrCc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(=O)n(Cc3ccccc3)cc21
Temperature: 60 °C
Reaction time: 40 h
Yield: 63.6 %

Procedure:
A mixture of 5-methoxy-2,3-dihydro-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (0.065 g, 0.26 mmol), benzyl bromide (0.053 g, 0.31 mmol), sodium iodide (0.077 g, 0.52 mmol) and acetonitrile (2 mL) was stirred at 60° C. for 40 h. The mixture was poured into a mixture of water (10 mL) and saturated aqueous sodium thiosulfate (10 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography (SiO2; gradient elution with 0-100% EtOAc in petrol) gave the title compound (0.054 g, ˜64%) as a colourless oil. MS: [M+H]+=327.
Reaction SMILES: [NH2:1][N+:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH:29]=O.[OH-].[K+]>O1CCOCC1.O>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[C:29]1[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][N:2]2[N:1]=1
Reactant: COC(=O)c1ccc(N)[n+](N)c1
Reactant: Cc1cccc(C)c1C=O
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3c(C)cccc3C)nn2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a solution of methyl 1,6-diaminopyridin-1-ium-3-carboxylate; 2,4,6-trimethylbenzenesulfonate (6.0 g, 16.3 mmol) in 1,4-dioxane (50 mL) is added 2,6-dimethylbenzaldehyde (1.72 g, 13.00 mmol) and the reaction mixture is heated at 90° C. for 2 hours. The reaction mixture is cooled to room temperature, 1 N KOH solution (15 mL) is added, and the mixture is stirred overnight at room temperature. The reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts are washed with water (100 mL) and saturated brine solution (100 mL), dried over sodium sulphate, filtered, and concentrated. The crude material is purified by silica gel chromatography (combiflash) eluting with 12% EtOAc in hexanes to give the title compound as a yellow liquid (0.35 g, 16%). LCMS m/z 282 (M+H)+.
Reaction SMILES: [CH2:1]([CH:6]1[CH:10]([C:11]#N)[CH2:9][CH2:8][C:7]1=[O:13])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH2:14].Cl.[CH3:16][OH:17]>>[CH2:1]([CH:6]1[C:7](=[O:13])[CH2:8][CH2:9][CH:10]1[C:11]([O:17][CH3:16])=[O:14])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O
Reactant: CO
Reactant: CC(C)CCC1C(=O)CCC1C#N
Agent: Cl
Product: COC(=O)C1CCC(=O)C1CCC(C)C

Procedure:
In a 0.5-L three-necked flask fitted with a reflux condenser, a mechanical stirrer, and a gas inlet tube, is placed a solution of 17.9 g of 2-iso-pentyl-3-cyanocyclopentanone and 2 ml of water in 200 ml of absolute methanol. Dry hydrogen chloride is passed through the refluxing solution for a period of 2 hours. The reaction mixture is maintained at reflux temperature for an additional hour. The methanol is distilled off at a reduced pressure and the residue is diluted with 300 ml of cold water. The organic layer is separated and the water phase is extracted with pentane. The combined organic layer and pentane extract are washed with sodium carbonate solution and water and dried over anhydrous sodium sulphate. The solvent is distilled off at atmospheric pressure and the residue is distilled through a short Vigreux column. Methyl 2-iso-pentyl-3-oxo-cyclopentanecarboxylate is collected at 94.5° C/0.7 mm, yield 14 g (67%), nD20 1.4561.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][Cl:15]
Reactant: COc1cccc(OC)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(OC)c1CCl
Temperature: 25 °C

Procedure:
0.43 g (2.56 mmol) of 2,6-dimethoxybenzyl alcohol was dissolved in 5 ml of benzene, and the resultant solution was added with 0.40 g (3.36 mmol) of thionyl chloride at a room temperature. The mixture was then stirred for an hour at a room temperature to facilitate the provided compounds to react. The reacted solution was then condensed under reduced pressure to obtain a crude product of 2,6-dimethoxybenzyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:21])[C:10]2[CH:16]=[N:17][C:18]([Cl:20])=[N:19][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1CCN(Cc2ccccc2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.144 g (0.0005 mole) of 9-benzyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-22), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.134 g of 9-benzyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-22) as an yellow solid.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:20][NH:21][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: CN
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
A slurry of methyl isophthalate (5.10 g, 0.028 mol) in CH2Cl2 (100 ml) at room temperature was treated with oxalyl chloride (6.0 ml) followed by DMF (3 drops). The resultant mixture was stirred under reflux (90 mins). The resultant mixture was cooled to room temperature, the solvent removed by evaporation and the residue azeotroped with CH2Cl2. The resultant mixture was dissolved in THF (100 ml), cooled to 0° C. and treated with a solution of methylamine (2M, 28 ml, 56 mmol) in THF. The mixture was allowed to warm to room temperature overnight, solvent removed by evaporation and resultant mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer separated and washed with sat aq NaHCO3, sat aq brine, and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the desired product (white solid, 4.60 g, 79%). 1H NMR (CDCl3) δ 3.00 (d, 3H), 4.00 (s, 3H), 6.30 (s, br, 1H), 7.50 (t, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.40 (s, 1H). LRMS m/z=211.1 (M+18)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:23])[C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C(C)(C)C)=[O:17])=[N:14][CH:15]=1.CCOCC.[OH-].[Na+]>ClCCl>[F:23][CH:9]([F:8])[C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cnc(C(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cnc(C(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of t-butyl 5-difluoromethylpyrazine-2-carboxylate (175 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature for five hours. Ether and 5 N sodium hydroxide were added to the reaction solution. The aqueous layer was separated and made acidic with 5 N hydrochloric acid. Ethyl acetate was added to the aqueous layer, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated to obtain the title compound (100 mg).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[N:5]([C:14](Cl)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[N:6][C:7](Cl)([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8].O.[N-:22]=[C:23]=[S:24]>C(O)(C)C.CCCCC>[N:5]([C:14]([N:22]=[C:23]=[S:24])([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[N:6][C:7]([N:3]=[C:2]=[S:1])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(Cl)CC(C)C
Reactant: N#C[S-]
Reactant: [N-]=C=S
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCCCC
Product: CC(C)CC(C)(N=C=S)N=NC(C)(CC(C)C)N=C=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 19.2 grams (0.22 moles) of sodium thiocyanate in 120 ml of 75% aqueous isopropanol in a 250 ml erlenmeyer flask was added 26.7 grams (0.1 mole) of 2,2'-azobis(2-chloro-4-methylpentane) (from Example XXIXA) over 40 minutes while holding the temperature below 20° C. with a water bath. After the addition was complete the reaction mixture was stirred an additional 60 minutes at room temperature, poured into 300 ml water and extracted with pentane. The pentane extract was washed with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave a yellow semi-solid. The semi-solid was slurried in cold pentane and filtered. The filter cake was dried and weighed 8.0 grams (25% crude yield). This material was the undesired 2,2'-azobis(2-thiocyanato-4-methylpentane) and had a sharp band at 2170 cm-1 in its infrared spectrum. The pentane filtrate was stripped under reduced pressure to leave 11.0 grams (34% crude yield) of a yellow liquid. The infrared spectrum of this liquid had a strong broad band at 2000-2130 cm-1 in its infrared spectrum which is indicative of the isothiocyanate isomer.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[N:12][C:13]([O:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[CH:14][CH:15]=3)=[C:7]([C:24]([NH:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1.[C:34]([O-])([O-])=O.[K+].[K+].CI>CS(C)=O.O>[Br:1][C:2]1[C:3]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:31])=[O:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[N:12][C:13]([O:16][C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[CH:14][CH:15]=3)=[C:7]([C:24]([NH:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 20 °C
Yield: 19.5 %

Procedure:
To a degassed solution of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.187 mmol) and K2CO3 (53 mg, 0.374 mmol) in DMSO (2 mL) was added MeI (27 mg, 0.187 mmol) under N2. The mixture was heated at 20° C. for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. It was washed with H2O, brine and dried over Na2SO4. After concentrated, the residue was purified by column chromatography (PE:EA=2:1) to give the product of 5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.63 (d, J=2.8 Hz, 1H), 8.21˜8.24 (m, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.06˜7.08 (m, 3H), 6.98 (d, J=8.8 Hz, 1H), 5.77 (d, J=8.8 Hz, 1H), 3.27 (s, 3H), 3.03 (s, 3H), 2.96 (d, J=4.8 Hz, 3H). MS (M+H)+: 548/550.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:67][O:68][C:69](=[O:78])[C@H:70]([CH2:72][CH2:73][C:74]([O:76][CH3:77])=[O:75])[NH2:71].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:71][C@@H:70]([CH2:72][CH2:73][C:74]([O:76][CH3:77])=[O:75])[C:69]([O:68][CH3:67])=[O:78])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CC[C@H](NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)C(=O)OC
Temperature: 60 °C

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (55 mg, 0.26 mmol). The mixture was heated at 60° C. for another 20 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate as white solid. Yield: 126 mg, 94%.
Reaction SMILES: [C:1](=O)([O-:3])[O-:2].[Ca+2].[C:6]([OH:11])(=[O:10])[CH:7]([CH3:9])[OH:8]>>[C:6]([O-:11])(=[O:10])[CH:7]([CH3:9])[OH:8].[C:1](=[O:3])=[O:2]
Reactant: CC(O)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Product: CC(O)C(=O)[O-]
Product: O=C=O

Procedure:
Isobutyl L-chloropropionate is advantageously prepared starting from D-lactic acid which can be prepared, for example, by a biotechnological process disclosed in EP-A 069 291. This entails a mixture of aqueous glucose solution, yeast autolysate, vitamins, catalytic amounts of phosphoric acid and a buffer for the lactic acid produced, e.g. calcium carbonate, being fermented at about 45° C. with the addition of lactic acid bacteria. The pH of the fermentation broth is preferably 4-6. A lactate is produced with evolution of carbon dioxide and is converted into D-lactic acid by adding an acid, preferably concentrated aqueous sulfuric acid. The D-lactic acid is subsequently extracted with isobutanol. The resulting D-lactic acid solution is then concentrated. Part of the lactic acid is esterified even during this. The remaining amount of lactic acid is esterified with acid catalysis, sulfuric acid being an example of a suitable acid (cf., for example, EP-A 287 426, DE-A 32 14 697 and DE-A 34 33 400). The water formed in the reaction is subsequently removed by distillation together with unreacted isobutanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].ClC1C=CC(N)=CC=1.[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH:45]=1.[OH-].[K+]>CN(C)C=O.CO.O>[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH:44]=[CH:19][C:16]4[CH:15]=[CH:14][C:13]([C:6]5[N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=5)=[CH:18][CH:17]=4)=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH:45]=1
Reactant: Cc1ccc(-c2nc3cc(C)ccc3o2)cc1
Reactant: CCOc1cc(OCC)nc(-c2ccc(C=O)cc2)n1
Agent: Nc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)nc(-c2ccc(C=Cc3ccc(-c4nc5cc(C)ccc5o4)cc3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
3.82 g of the Schiff's base of the formula ##STR77## which is obtained from 4,6-diethoxy-2-(p-formylphenyl)-pyrimidine and p-chloroaniline and has a melting point of 129.5°-130° C., 2.23 g of 5-methyl-2-(p-tolyl)-benzoxazole of the formula ##STR78## and 3.75 g of potassium hydroxide powder with a water content of about 10% are stirred in 80 ml of dimethylformamide under nitrogen. The reaction mixture is warmed to 60° C. in the course of 15 minutes and is stirred for a further one hour at 60°-65° C. After adding 400 ml of methanol, the mixture is cooled to -10° C. and the product which has precipitated is filtered off with suction, washed with 100 ml of methanol and dried. 2.64 g (55.3% of theory) of 2-[4'-(5-methyl-benzoxazol-2-yl)-stilben-4-yl]-4,6-diethoxy-pyrimidine of the formula ##STR79## are obtained in the form of a pale yellow powder with a melting point of 233°-234° C. After twice recrystallising from toluene, and with the aid of bleaching earth, 2.12 g (44.4% of theory) of small, pale greenish-tinged yellow, matted needles are obtained, which melt at 236°-237° C.
Reaction SMILES: C(O[C:4]([CH:6]([C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])C.[C:22]([CH2:24][CH2:25][NH:26][NH2:27])#[N:23]>C(O)(=O)C>[C:22]([CH2:24][CH2:25][N:26]1[C:4]([OH:5])=[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=2)[C:17]([CH:18]([CH3:19])[CH3:20])=[N:27]1)#[N:23]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Reactant: N#CCCNN
Solvent: CC(=O)O
Product: CC(C)c1nn(CCC#N)c(O)c1Cc1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
15 g of compound 45 are dissolved in 100 ml of glacial acetic acid. 7.4 ml of 2-cyanoethylhydrazine are added, and the solution is heated at 100° C. for 2 h. The mixture is added to ice-water and extracted several times with ethyl acetate. The organic phase is extracted with 20% strength ammonium chloride solution and saturated sodium chloride solution and dried over sodium sulfate. 2.40 g of the desired compound 46 crystallize out with the ethyl acetate phase. The mother liquor is concentrated and chromatographed on silica gel (dichloromethane:methanol:glacial acetic acid=100:10:1). A further 1.10 g of compound 46, plus 7.0 g of reisolated precursor 45, are obtained. C17H19N3O3 (313.4); MS (ESI+): 314.2 (M+H)+, tR=0.97 min (Gradient 2).