Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH2:34]([NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1)[CH3:35].CN1CCCC1>C(O)C>[CH2:34]([NH:36][CH:37]1[CH2:40][N:39]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:38]1)[CH3:35]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CCNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-(ethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 107 mg of the title compound as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]([F:18])([F:17])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][CH:12]([F:18])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Reaction time: 3 h
Yield: 29.4 %

Procedure:
3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere. After stirring at 60°-65° C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether. The aqueous layer was extracted three times with ether. The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38%). mp 83°-85° C.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:6])(=O)C.P([O-])([O-])([O-])=O>C(Cl)(Cl)Cl>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CC(=O)OC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Yield: 88.6 %

Procedure:
15 g of benzyl (-)-4'-(1-acetoxyethyl)-4-biphenylcarboxylate, 10 ml of chloroform, 400 ml of 0.2 M phosphate buffer and 3 g of Amano swine liver esterase were mixed and reacted at 30°-35° C. for 30 hours. The reaction solution was extracted with chloroform. The chloroform layer was concentrated and the residue was column-chromatographed to give 11.8 g of (-)-benzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (V-26).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22]C)[C:3]=1[I:24].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[I:24]
Reactant: COc1c(I)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.006 mole) of 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1 H,3H)-pyrimidinedione in 75 mL of methylene chloride was cooled in a dry ice/acetone bath and 22.0 mL (0.022 mole) of 1 M boron tribromide (in methylene chloride) was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature were it stirred for about one hour. At the conclusion of this period, the reaction mixture was poured into 200 mL of water and extracted with two 50 mL portions of methylene chloride. The combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:21][C:22]1[CH:23]=[C:24]([N:27]=[C:28]=[O:29])[S:25][CH:26]=1>C(N(CC)CC)C.C(Cl)Cl>[CH2:14]([N:13]([C:28](=[O:29])[NH:27][C:24]1[S:25][CH:26]=[C:22]([CH3:21])[CH:23]=1)[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1csc(N=C=O)c1
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)Nc1cc(C)cs1

Procedure:
The equipment was the same as in Example 26 above. 3.0 g (0.01 mole) 1,3-di-n-heptyl-2-S-ethyl isothiourea was mixed with 25 ml of methylene chloride. Two drops of triethylamine and 1 drop of dibutyltindilaurate were added and then 1.65 g (0.01 mole) 4-methyl thiophenyl isocyanate was added. The temperature rose from 23° to 33°. The reaction mixture was then vacuum evaporated to remove the methylene chloride to produce 4.65 g (100 percent of theory yield) of a yellow liquid having a nD30 of 1.5340. The liquid solidified on standing into a semi-solid. The product was identified as the title product by IR and NMR spectra analyses. Compound No. in Table 47 in Table I.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][N:36]=[CH:35]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:40]5[CH:39]=[C:38]6[C:34]([CH:35]=[N:36][NH:37]6)=[CH:33][CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cn[nH]c4c3)cc2)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.186 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 9.80 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (50 mg, 0.205 mmol)) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.7 mL, 1.400 mmol) was stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was adjusted to pH˜6-6.5 using 1N aq HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-90% acetonitrile/water+0.1% NH4OH) provided the title compound as a white solid (20 mg, 26%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: F[C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([NH:15][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: NS(=O)(=O)c1ncccc1F
Solvent: ClCCl
Product: C=CCNc1cccnc1S(N)(=O)=O

Procedure:
5.28 g of 3-fluoropyridin-2-ylsulfonamide and 18.03 ml of allylamine are stirred for 6 hours in a pressurised vessel at a temperature of 125° C. The reaction solution is subsequently concentrated, the crystallisate obtained is dissolved in methylene chloride and a little acetonitrile, the mixture is purified by chromatography using methylene chloride/ethyl acetate (4:1) as the eluent mixture and silica gel as the carrier material. 5.1 g of 3-allylaminopyridin-2-ylsulfonamide (intermediate No. 2.002) of a melting point of 134°-135° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=1.[OH-].[Na+]>O>[CH3:24][C:23]1[C:18]([CH2:17][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: Cc1cnc(CCl)c(C)c1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c(C)c1

Procedure:
6.54 g of 5-(trifluoromethyl)-2-benzimidazolethiol are suspended in 400 ml of alcohol and treated with 5.76 g of 2-chloromethyl-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 800 ml of methylene choride. The solution is washed firstly with 200 ml of 1.5N sodium hydroxide solution and then 3×with 250 ml of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 110 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[(3,5-dimethyl-2 -pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 137°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:12]O)[S:10][C:3]=12.CCOC(C)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:3]=12
Reactant: ON=Cc1cc2nccc(Cl)c2s1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2nccc(Cl)c2s1
Reaction time: 48 h
Yield: 71.1 %

Procedure:
A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2 ml) was set to reflux for 3 h and then at 90° C. for 48 h. The acetic anhydride was removed under reduced pressure and the residue was partitioned between a cold aqueous K2CO3 solution and EtOAc. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and remained solid was purified by column chromatography, eluents 25% EtOAc/hexane (25:75), then 100% EtOAc, to afford the title compound 126 (65 mg, 71% yield). MS (m/z) 195.1/197.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH3:33])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:29]C(=O)C)=[C:17]([CH:28]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH3:33])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:29])=[C:17]([CH:28]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Yield: 48.6 %

Procedure:
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-fluoroaniline (0.068 g, 0.145 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.030 g, 0.0705 mmol, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].[CH3:12]CCCC.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH2:12]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CCCCC
Solvent: CCOCC
Product: Fc1cc(C2CO2)cc(F)c1F

Procedure:
Following General Procedure EC and using 3,4,5-trifluorobenzaldehyde (Strem), the title compound was isolated after flash chromatography with 10:1 pentane/diethylether.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15][CH3:16])[CH:7]=1.[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>ClCCl>[F:17][CH:2]([F:1])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:14]=[CH:13][C:11]([N:12]=[C:18]=[S:19])=[CH:10][C:9]=2[O:15][CH3:16])[CH:7]=1
Reactant: COc1cc(N)ccc1-n1cnc(C(F)F)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
Step N (5): Dichloromethane (100 mL) was added to a flask charged with 4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyaniline (2.5 g, 10.45 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.43 g, 10.5 mmol). The resulting mixture was stirred for 18 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (0-2% EtOAc/chloroform, linear gradient) to afford 4-(difluoromethyl)-1-(4-isothiocyanato-2-methoxyphenyl)-1H-imidazole (2.26 g, 77% yield). LC-MS (M+H)+ 282.1.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: OC1CCNCC1
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-hydroxypiperidine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>C1C=CC=CC=1>[C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: c1ccccc1
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Reaction time: 2.5 h
Yield: 42.9 %

Procedure:
Into a reaction vessel equipped with a stirrer, a cooler, an nitrogen gas introducing inlet and a dropping funnel, benzene (288.5 ml) and methacrylamide (49.1 g; 0.577 mol) were charged, and the resulting mixture was heated with reflux. Refluxing and bubbling with nitrogen gas were continued, during which ethoxalyl chloride (78.5 g; 0.577 mol) was dropwise added thereto in 2.5 hours. After the dropwise addition was completed, refluxing was continued for 5 hours. The benzene was distilled off, hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (45.8 g). Yield, 43%. B.P., 110°-115° C./0.3 mmHg. Refractive index, 1.473.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:16](=[O:36])[CH2:17]3)(=[O:23])=[O:22])=[CH:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)CC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (115 mg) were added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give crude crystals of 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride. A mixture of the obtained 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride and chloropyridine hydrochloride (85 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1 N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane: methanol containing 10% ammonia solution 10:1) to give colorless solid of the title compound (42 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.O>O1CCCC1>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]([N:11]2[C:12](=[O:14])[C:13]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[CH2:10]2)[CH2:16][C:17]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:18])=[CH:21][C:22]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(CC(=O)N2CCOCC2)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (300 mg, 0.67 mmol) in tetrahydrofurane was added carbonyldiimidazole (130 mg, 0.80 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added morpholine (0.1 ml, 1.0 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile: water=45:55) to give N-{2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-3-morpholin-4-yl-3-oxo-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (250 mg, 72%): mp, 164-166° C.; 1HNMR (CDCl3): 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 3.04 (dd, J=6, 10 Hz, 1H, CHHCO), 3.54-3.72 (m, 9H, morpholine ring+CHHCO), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.27 (d, J=17 Hz, 1H, CHHN), 4.44 (d, J=17 Hz, 1H, CHHN), 5.54-5.59 (m, 1H, CHN), 6.85 (t, HH-F=75 Hz, 1H, OCF2H), 6.94-7.16 (m, 3H, Ar), 7.14 (d, J=8 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.60 (s, 1H, NHCO). 13C NMR (CDCl3): 15.3, 25.6, 36.5, 42.8, 46.9, 49.8, 54.7, 65.5, 67.2, 67.4, 112.6, 114.1, 116.7, 117.6, 118.3, 118.4, 119.9, 120.8, 123.5, 133.9, 138.5, 140.5, 142.2, 151.5, 166.7, 169.7, 170.4; Anal. Calcd. for C26H29F2N3O6: C, 60.34; H, 5.65; N, 8.12. Found: C, 60.04; H, 5.71; N, 8.19.
Reaction SMILES: C([NH:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[N:13]=1)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:8][CH:9]1[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]1=[O:16]
Reactant: CN1C(=O)N=C(NCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1C(=O)NC(N)C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
To a solution of 5-benzylamino-3-methyl-imidazole-2,4-dione (Example 1.3, Part B) (400 mg, 1.84 mmol) in ethanol/ethyl acetate (50 mL, 1:1) was added 10% Pd/C catalyst (195 mg, 0.18 mmol). The flask was evacuated and filled with hydrogen three times and then stirred at room temperature for 23 h. After this period, the reaction mixture was filtered through celite and the filtrate was evaporated to give the product as a colourless solid (214 mg, 90%), mp 122-125° C. δH (300 MHz, CD3CN) 6.31 (br s, 1H, NH), 4.68 (d, J 1.5 Hz, 1H, CH), 2.87 (s, 3H, CH3). δH (300 MHz, D2O) 4.95 (s, 1H, CH), 2.96 (s, 3H, CH3). δC (75 MHz, D2O) 175.6, 158.5, 64.0 (CH), 24.3 (CH3).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)o1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Br)o1

Procedure:
21.0 g of 5-bromo-2-furancarboxylic acid were suspended in 650 ml of toluene and 40 ml of thionyl chloride and the suspension was heated to reflux for 2 hours. The reaction solution was thereafter concentrated, whereby 5-bromo-2-furancarboxylic acid chloride was obtained as the residue.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[C:29]([CH3:30])=[N:28][C:27]([CH3:31])=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[C:29]([CH3:30])=[N:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1cnc(Cl)c(C)n1
Product: Cc1cnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)c(C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-3,5-dimethyl-pyrazine. MS (ESI) mass calcd. for C25H26N4O, 398.50; m/z found, 399.2 [M+H]+.