Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:16])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])C>O.CO>[C:10]1([NH:9][C:7](=[O:8])[C:6]([OH:16])=[O:5])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of KOH (1.68 g, 30 mmol) in water (25 mL) and MeOH (25 mL) was added to Intermediate 1 (5.8 g, 30 mmol), and the resulting mixture was stirred for 18 hours at room temperature. The reaction was diluted with water, then extracted with EtOAc. The aqueous layer was cooled in an ice bath, acidified with 1N HCl, extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo to provide 3.8 g (77%) of a colorless solid. 1H NMR (DMSO-d6) δ: 7.1–7.8 (m, 6H), 10.5 (s, 1H); MS ES+m/e 166.0 (p+1), ES−m/e 164.1 (p−1). Anal. Calcd for C8H7NO3: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.99; H, 4.25; N, 8.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([N:32]([C:40]2[CH:45]=[CH:44][C:43](C3C=CC=CC=3)=[CH:42][CH:41]=2)[C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20]([C:43]5[CH:42]=[CH:41][C:40]([N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:29]6[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=6)=[CH:45][CH:44]=5)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3
Reactant: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with 52 g (110 mmol) of bis-biphenyl-4-yl(4-bromophenyl)amine. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 65 g (95 mmol), 88% of theory, purity according to HPLC 99.9%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13]2[C:18]([C:19]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:17][CH:16]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=2.[H-].[Na+].O>CN(C)C=O>[CH:20]1([C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:26]([O:28][CH3:29])=[O:27])=[CH:14][C:13]=3[N:12]3[C:11]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCCCl)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
To a solution of methyl 2-[2-(2-chloroethoxy)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (180 mg, 0.44 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (20 mg, 0.49 mmol) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue. The precipitated solid was collected by filtration, washed with diisopropyl ether and dried in vacuo to give methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (70 mg, yield 42.3%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][NH2:19])([CH3:15])[CH3:14]>>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCN(C(C)C)C(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-diisopropylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[NH:7][C:6]=1[C:18]([O:20]CC)=[O:19])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:25]>O>[ClH:25].[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[S:16][CH3:17])[NH:7][C:6]=1[C:18]([OH:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C(=O)OCC)[nH]c2cccc(SC)c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1c(C(=O)O)[nH]c2cccc(SC)c2c1=O

Procedure:
0.63 g of the product of Step B in 10 ml of a N sodium hydroxide solution was stirred for 2 hours at reflux and the mixture was poured into ice-cooled water, acidified with concentrated hydrochloric acid, separated, washed with water, dried and impasted in 100 ml of ethyl acetate to obtain 495 mg of the desired product melting at 240° C.
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C1CCCc2ccc(-c3ccc(F)cc3)cc21
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (15.5 g), dimethyl carbonate (91 ml) and 7—(4-fluorophenyl)-1-tetralone (13.8 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 3N hydrochloric acid (200 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (90 ml), and to the mixture was added sodium boron hydride (1.36 g) at 0° C. and then was dropwise added methanol (9 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in methanol (80 ml), and to the mixture was added 1N sodium hydroxide (100 ml). The mixture was refluxed for 4 hours and cooled to room temperature. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (50 ml), and to the mixture was added concentrated hydrochloric acid (10 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7—(4-fluorophenyl)-3,4-dihydronaphthalene-2-carboxylic acid (6.01 g) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[N:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COc1nc(Cl)ccc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C(N)=O
Temperature: 110 °C
Yield: 38.6 %

Procedure:
A mixture of 6-chloro-2-methoxy-nicotinamide (7.15 g, 38.3 mmol), 2-bromo-5-hydroxy-benzaldehyde (11.5 g, 57.5 mmol) and K2CO3 (15.9 g, 115 mmol) in dimethylformamide (60 mL) was heated to 110° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with H2O (800 mL) and extracted with ethyl acetate (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (50-80% ethyl acetate/hexanes) to give the title compound as a light brown solid (5.19 g, 39% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:17][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]#[N:29]>>[C:27]([CH2:28][NH:29][C:19](=[O:20])[C@@H:18]([NH:17][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:22][CH:23]([CH3:24])[CH3:25])#[N:26]
Reactant: N#CCN
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F)C(=O)O
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F)C(=O)NCC#N

Procedure:
Using the procedure mentioned in the Step 4 of Example 19, (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methyl-pentanoic acid was coupled with amino acetonitrile to give (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methylpentanoic acid cyanomethylamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:13]([O:12][C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([O:19][CH3:18])=[O:29])=[CH:7][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 94.5 %

Procedure:
tert-Butyl 2-(4-hydroxyphenyl)ethylcarbamate (3.534 g, 14.9 mmol), 2-bromomethyl-benzoic acid methyl ester (3.582 g, 15.6 mmol) and potassium carbonate, anhydrous (3.087 g, 22.3 mmol) were mixed in acetonitrile (50 ml). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 5.427 g the desired product, yield 94.5%.
Reaction SMILES: O[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH:3]=[CH2:4].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Cl:22][CH2:4][CH:3]=[C:2]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:5]
Reactant: C=CC(C)(O)c1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=CCCl)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 12.0 grams (0.056 mole) of 3-hydroxy-3-(2,5-dichlorophenyl)-1-butene and 4.7 grams (0.056 mole) of pyridine in 85 mL of methylene chloride is cooled in an ice-water bath, and 6.6 grams (0.056 mole) of thionyl chloride is added dropwise. Upon completion of addition, the reaction mixture is stirred for about one hour. After this time the reaction mixture is diluted with 50 mL of methylene chloride and about 50 grams of ice. The mixture is stirred until the ice melts, and then the organic layer is separated. The organic layer is washed in turn with two 50 mL portions of an aqueous 0.5M solution of hydrochloric acid, two 50 mL portions of an aqueous solution saturated with sodium bicarbonate, two 50 mL portions of water, and two 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 5.5 grams of 1-chloro-3-(2,5-dichlorophenyl)-2-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])[CH:9]=[C:8](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC/C=C/c1cc(/C=C/COC)cc(C(=O)NC2CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1

Procedure:
An EtOAc (0.15 M) solution of N-cyclopropyl-3,5-bis[(1E)-3-methoxyprop-1-en-1-yl]benzamide (1 eq.) from the previous step was eluted through an H-Cube hydrogenation apparatus equipped with a 10% palladium over carbon cartridge at a rate of 1 mL/min with EtOAc as the eluent. The hydrogenation was carried out using full hydrogen setting at RT. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:18]1[CH2:17][CH2:16][CH:15]([N:14]2[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:20][CH2:19]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of {(S)-1-[1-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester (1.80 g, 5.22 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo affording (S)-1-[1-(Tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethylamine as a light yellow solid (415 mg, 32%). LCMS: RT 0.27 min [M+Na]+ 268.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cl:15][CH2:16][C:17]([CH3:19])=[CH2:18]>>[Cl:15][CH2:16][C:17]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:19])[CH3:18]
Reactant: C=C(C)CCl
Reactant: COc1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc(C)cc1C(C)(C)CCl
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To a yellow solution of 20 g of 4-methylanisole and 1.7 mL of concentrated sulfuric acid was added dropwise 19.17 mL of 3-chloro-2-methylpropene. The reaction became warm and turned dark purple and after 20 minutes a precipitate formed. The reactions was monitored by TLC indicating a new less polar product. After 18 hours, the reaction was poured onto ice and extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to leave an oil. The residue was diluted with hexanes, cooled to −78° C., and the solids collected by filtration to afford 14 g of 2-(2-chloro-1,1-dimethylethyl)-1-methoxy-4-methylbenzene which melted upon warming to room temperature. The filtrate was concentrated in vacuo to afford 15.5 g of product and starting anisole (4:1 mixture).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([O:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(Cl)ncc1F
Temperature: -10 °C
Reaction time: 21 h
Yield: 7.4 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (515 mg, 3.08 mmol) was weighed into a 150 mL RBF, and was suspended in THF (5.0 mL). The stirring suspension was cooled to −10° C. NaOMe (250 mg, 4.63 mmol) was added in one portion at −10° C. An additional 0.5 eq of NaOMe were added and the suspension was stirred at RT for 21 h. The suspension was diluted with MeOH, and the solvents were removed in vacuo. The crude material was purified by flash chromatography (eluting with 100% DCM) to give 2-chloro-5-fluoro-4-methoxypyrimidine (37 mg, 0.228 mmol, 7.38%) as an amorphous white solid. MS (ESI, pos. ion) m/z: 162.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J=2.7 Hz, 1H), 4.04 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.CC([O-])(C)C.[K+]>CC(N(C)C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccc(N)cc2)c1

Procedure:
4-Aminophenol was reacted with 4-methoxy-2-chloropyridine in the presence of KOtBu/8-Crown-6/DMA at 150° C. for 5 hrs to give 2-(4-aminophenoxy)-4-methoxypyridine. The product was purified by chromatography.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:23][O-:24].[Na+]>C(OCC)(=O)C.[Cu]Br>[CH2:8]([C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[C:2]=1[O:24][CH3:23])[CH3:9]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1OC

Procedure:
7.20 g (20 mmol) of 5-bromo-6-ethyl-4-(cis-4-phenylcyclohexylamino)pyrimidine (DE-A-42 08 254) and 0.44 g (3 mmol) of copper(I) bromide were heated under reflux for 12 hours in 10 ml of 30% methanolic sodium methylate solution, to which 0.70 g of ethyl acetate have been added. For working up, the solvent is stripped off, the residue is taken up in ethyl acetate, this mixture is subjected to extraction by stirring with water, and the organic phase is dried and concentrated. For purification, the crude product is chromatographed on silica gel using ethyl acetate/petroleum ether (8:2). 3.7 g (60% of theory) of a colorless oil were obtained which gradually solidified.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 6-hydroxycarbostyril (50 g) and 1-bromo-3-chloropropane (120 ml) in dimethylformamide (600 ml) is added potassium carbonate (65 g) in portions at room temperature. The mixture is stirred at room temperature for three days, and the insoluble materials are collected by filtration and washed with n-hexane. The resulting crystals are further washed successively with water, acetone and n-hexane, and dried to give 6-(3-chloropropoxy)carbostyril (50.7 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:16]=1)=[O:8]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(S(=O)(=O)CCO)c1
Reaction time: 8 h

Procedure:
To 2,4-dichlorophenoxyacetic acid (110.6 mg, 0.5 mmol), 2-(3-amino-benzenesulfonyl)-ethanol (151.0 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (102.1 mg, 0.75 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative (CH2CH2:MeOH=30:1) to give 2-(2,4-dichloro-phenoxy)-N-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-acetamide as a yell foam (21.5 mg, 10.6% yield).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[C:12]=3[CH3:28])[O:5][CH2:4]2)[CH2:2]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:2]1[C:3]2([CH2:4][O:5][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]4[NH:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[O:37])[C:12]=3[CH3:28])[O:7][CH2:8]2)[CH2:1]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
The 2-(((4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (629 mg, 1.58 mmol) obtained by the step (2e) was mixed with methanol (5 ml) and toluene (15 ml) and the mixture was cooled to −50° C. Then, 3-chloroperbenzoic acid (378 mg, 1.42 mmol as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9) to obtain the title compound (623 mg, yield: 95.4%) as a colorless foam.