Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light grey solid (93 mg, 98%), MS (ISP) m/z=380.3 [(M+H)+], mp 305.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[NH:30][CH:31]=[CH:32][C:22]=3[C:21]=2[CH:20]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]>CN(C)C=O>[C:8]1([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[NH:25][C:24](=[O:29])[C:23]4[NH:30][CH:31]=[CH:32][C:22]=4[C:21]=3[CH:20]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:33]([C:35]([O-:37])=[O:36])[CH3:34]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccccc3)cc2c2cc[nH]c12
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
62 μL (0.44 mmol) of triethylamine and then 31 μL (0.24 mmol) of benzenesulfonyl chloride are added to 60 mg (0.22 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The solution is stirred for 1 h at 40° C. The solvent is evaporated and the raw product obtained is purified by recrystallization from methanol to give 51 mg (57%) of 8-benzenesulfonylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[CH:12]1([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(N(CC)CC)C>[CH:1]([O:4][C:5](=[O:11])[CH2:6][C@@H:7]([C:8]([OH:10])=[O:9])[NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:3])[CH3:2]
Reactant: NCCCNC1CCCCC1
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C[C@H](NCCCNC1CCCCC1)C(=O)O
Yield: 81.9 %

Procedure:
In a manner analogous to that of Example 1, 400 ml of triethylamine are added to 350.2 g (2.0 mols+10% excess) of maleic acid-monoisopropyl ester, and the mixture is subsequently reacted with 311.3 g (2.0 mols) of 3-cyclohexylamino-1-propylamine at 59°-85° C. for 35 minutes. The reaction mixture is further processed in the manner described in Example 1 to yield 515 g (82.2% of theory) of the desired aspartic acid derivative, which decomposes at 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)Br)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1C[O:18]CC1.O>[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:18])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1C(Br)Br
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
Combine 4-bromo-1-(dibromomethyl)-2-(trifluoromethyl)benzene (6.66 g, 16.8 mmol), silver nitrate (14.8 g, 87.3 mmol), THF (250 mL), and water (35 mL) in a 500 mL flask equipped with a magnetic stir bar, reflux condenser, and N2 inlet. Reflux the mixture while stirring for 2.5 hours then cool to room temperature. Filter the reaction through Celite®, add ethyl acetate (250 mL) and wash with water (2×200 mL) then saturated aqueous sodium chloride solution (1×200 mL). Dry over anhydrous magnesium sulfate, concentrate to an orange oil, and purify the crude product via silica gel chromatography eluting with hexanes to afford 3.46 g (81%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 10.35-10.33 (m, 1H), 8.0 (d, 1H, J=8.3 Hz), 7.93 (d, 1H, J=1.4 Hz), 7.86 (dd, 1H, J=1.2 Hz, J=8.3 Hz).
Reaction SMILES: BrC1C=C(C=O)SC=1.N1C=CN=C1.N1(C2C=C(C=O)SC=2)C=CN=C1.[N:26]1([C:31]2[CH:32]=[C:33]([C:36](=O)[CH2:37][CH2:38][C:39]([OH:41])=O)[S:34][CH:35]=2)[CH:30]=[CH:29][N:28]=[CH:27]1.O.[NH2:44][NH2:45]>>[N:26]1([C:31]2[CH:32]=[C:33]([C:36]3[CH2:37][CH2:38][C:39](=[O:41])[NH:44][N:45]=3)[S:34][CH:35]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1cc(-n2ccnc2)cs1
Agent: O=Cc1cc(-n2ccnc2)cs1
Agent: O=Cc1cc(Br)cs1
Agent: c1c[nH]cn1
Solvent: O
Product: O=C1CCC(c2cc(-n3ccnc3)cs2)=NN1

Procedure:
4-Bromo-thiophen-2-aldehyde is reacted with imidazol to 4-(imidazol-1-yl)-thiophen-2-aldehyde which is reacted with the necessary acid nitrile to 4-[4-(imidazol-1-yl)-thien-2-yl]-4-oxo-butyric acid nitrile which is hydrolized to 4-[4-(imidazol-1-yl)-thien-2-yl]-4-oxo-butyric acid. This compound is reacted with hydrazine hydrate to yield 4.5-dihydro-6-[4-(imidazol-1-yl)-thien-2-yl]-3-(2H)-pyridazinone which is subsequently dehydrogenated with 3-nitrobenzolsulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:16][C:17]([NH2:19])=[O:18].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([O:6][CH2:16][C:17]([NH2:19])=[O:18])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Reactant: NC(=O)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)COC(=O)c1c(Cl)ccc(Cl)c1Cl

Procedure:
This compound was prepared in the manner of Example I, using 15.0 grams (0.066 mole) of 2,3,6-trichlorobenzoic acid, 4.4 grams (0.066 mole) of potassium hydroxide, 6.2 grams (0.066 mole) of 2-chloroacetamide, and 1.8 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 300 ml of dry toluene and 200 ml of dimethylformamide. The crude product was purified by liquid chromatography, followed by recrystallization from ethyl acetate. The yield was 0.9 gram of (aminocarbonyl)methyl 2,3,6-trichlorobenzoate; mp 158°-160°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:15][NH:16][CH2:17][C@H:18]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:12])=[CH:5]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Product: Cl
Reaction time: 1 h
Yield: 119.5 %

Procedure:
The compound (170 mg) obtained in Example 94 was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (2 ml) was added at room temperature to stir the mixture for 1 hour. After concentrating the reaction mixture, chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added. The resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography on silica gel (chloroform:methanol:water=7:3:1 under layer). A methanol solution of hydrochloric acid was added to the resultant intended product to obtain the title compound (90 mg) as a hydrochloride (NMR was measured in the form of a free base).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH:31][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:30])[O:26][N:25]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncco3)c2)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc(C)no3)cc(-c3ncco3)c2)nc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 109.9 %

Procedure:
To a solution of hydrochloride salt of 3-(5-methylpyridin-2-yl)-5-(1,3-oxazol-2-yl)benzoic acid (103 mg, 0.292 mmol) in N,N-dimethylformamide (4 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride salt (72 mg, 0.437 mmol), EDC (168 mg, 0.875 mmol), HOBT (134 mg, 0.875 mmol) and N,N-diisopropylethylamine (204 μL, 1.17 mmol). The reaction mixture was stirred at 20° C. for 16 h. The mixture was purified by reverse-phase HPLC gave the hydrochloride salt of the title compound (125 mg). HRMS 390.1560 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.82-8.78 (m, 2H); 8.74 (t, J=1.7 Hz, 1H); 8.61 (d, J=8.2 Hz, 1H); 8.52 (s, 1H); 8.42 (d, J=8.3 Hz, 1H); 8.13 (d, J=0.9 Hz, 1H); 7.43 (d, J=0.8 Hz, 1H); 5.50 (q, J=7.2 Hz, 1H); 2.65 (s, 3H); 2.39-2.35 (m, 3H); 1.75 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>C1(C)C=CC=CC=1.C(OCC)C>[ClH:1].[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:14]1
Reactant: O=C(CCCl)Cc1cccs1
Reactant: CC1CCCNC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1CCCN(CCC(=O)Cc2cccs2)C1
Product: Cl

Procedure:
18.85 g (0.10 mol) of 4-chloro-l-(2-thienyl)butanone are run, over a periodof 30 min, into a solution, maintained at 100° C., of 21.8 g (0.22 mol) of 3-methylpiperidine in 35 ml of toluene, and the mixture is heated to reflux for 2 hours. The reaction medium is diluted with ethyl ether andthe mixture is washed with water. The organic phase is extracted with dilute hydrochloric acid solution which, after alkalinisation with sodium hydroxide, is in turn extracted with ethyl ether. The organic phase is dried over dry sodium sulphate and treated with a solution of hydrogen chloride in isopropanol.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)(=O)C.[NH2:10][C:11]1[N:12]=[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:14][C:15]=1[C:16]#[N:17].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl>[CH2:18]([C:13]1[NH:14][C:15]([C:16]#[N:17])=[C:11]([N:10]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[N:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc(N)c(C#N)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nc(-n2cccc2)c(C#N)[nH]1
Temperature: 25 °C

Procedure:
A solution of potassium acetate (5.0 g), acetic acid (22 mL) and 4-amino-2-butyl-5-cyanoimidazole (Example 7, 1.45 g) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (1.25 mL). The reaction was held at reflux for 1 minute then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated at reduced pressure then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (90:10 to 80:20). Evaporation of solvents gave a gum that was redissolved in dichloromethane and evaporated once again. The residual oil was held under a vacuum overnight to afford a waxy solid. 1H-NMR (CDCl3) δ 9.9 (br, 1H), 7.4 (s, 2H), 6.3 (s, 2H), 2.7 (t, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>ClCCl>[ClH:3].[Cl:3][CH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCN2CCC[C@H]2CCO)cc1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC[C@H]2CCCl)cc1
Product: Cl

Procedure:
Thionyl chloride (2ml) was added slowly to a solution of (S)-2-(2-hydroxyethyl)-1-(4-methoxyphenethyl)pyrrolidine (see Preparation 9) (3.0 g) in dichloromethane (30 ml). The mixture was heated under reflux for 2 hours and evaporated under reduced pressure to give the title compound as a brown oil, (4.15 g), which was characterised by NMR and used directly in Example 5 without further purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][C:19]=2[F:50])[CH2:16][CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][C:19]=2[F:50])[CH2:14][CH2:15][CH2:16]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.58 g), sodium hydrogen carbonate (2.39 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclobutyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.56 g, 52%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Cl:8][C:7]1[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cc1cc(Nc2ncnc3ccc(Oc4ncccc4Cl)cc23)n[nH]1

Procedure:
The compound of Example 116 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, 3-amino-5-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:36][NH2:37]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:37][N:36]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-2-morpholinecarboxamide (302 mg, 0.66 mmol) and hydrazine monohydrate (0.41 mL, 13.18 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. in a sealed tube for 18 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by flash chromatography (60 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (239 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.6 Hz, 3H), 2.77-3.02 (m, 4H), 3.78 (d, J=11.2 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 4.02 (dd, J=11.2, 2.9 Hz, 1H), 4.27-4.41 (m, 2H), 4.41-4.85 (bs, 2H), 5.39 (s, 2H), 6.51-6.72 (m, 2H), 7.19-7.38 (m, 5H), 7.62 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.99 (s, 1H), 8.54 (t, J=6.2 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: NC1C=C(C(O)=[O:8])C(O)=CC=1.[OH:12][CH:13]1[O:32][C@H:31]([CH2:33][OH:34])[C@@H:18]([O:19][C@@H:20]2[O:28][C@H:27]([CH2:29][OH:30])[C@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]2[OH:22])[C@H:16]([OH:17])[C@H:14]1[OH:15].[CH3:35][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH2:37].[Na+].[Cl-]>CO>[CH2:29]([OH:30])[C@H:27]1[O:28][C@@H:20]([O:19][C@H:18]2[C@H:16]([OH:17])[C@@:13]([OH:12])([CH2:14][OH:15])[O:32][C@@H:31]2[CH2:33][OH:34])[C@H:21]([OH:22])[C@@H:23]([OH:24])[C@H:25]1[OH:26].[OH2:8].[CH3:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH2:35]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: C=C(C)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O
Product: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
5-Aminosalicylic acid (5-ASA), MgO for neutralization, and the additive were mixed in a mortar and made to prepare tablets. The tablets were coated with 11 wt % of a 10 w/v % methanol solution of Eudragit E100 by means of a Hicoater. Then tablets of lactulose were prepared and coated with 11 wt % of a 10 w/v % methanol solution of Eudragit RS100/triacetin (5/1). Each one of the tablets 1 and the tablets 2 and 200 mg of lactose were put in a #1 gelatin capsule. The capsule was coated first with a methanol dispersion of Eudragit RS100L/NaCl (particle size: 75 to 355 μm) (½) and then with 12 wt % of Eudragit L100/castor oil (5/1) to obtain the preparation of the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[C:8]([NH:18][CH2:19][CH3:20])=[N:9][C:10]([CH:13]([O:16]C)OC)=[CH:11][CH:12]=1)=[O:6].[ClH:24].[CH3:25][C:26](C)=[O:27]>>[Cl:24][CH2:25][C:26]([N:18]([C:8]1[C:7]([C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=[C:10]([CH:13]=[O:16])[N:9]=1)[CH2:19][CH3:20])=[O:27]
Reactant: CC(C)=O
Reactant: CCNc1nc(C(OC)OC)ccc1C(=O)c1cccc(Cl)c1
Reactant: Cl
Product: CCN(C(=O)CCl)c1nc(C=O)ccc1C(=O)c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To an acetone solution of 3-(3-chlorobenzoyl)-6-dimethoxymethyl-2-ethylaminopyridine was added 6M hydrochloric acid, and the whole was reacted at room temperature for 5 hours. After removal of the solvent by evaporation, propylene oxide and chloroacetyl chloride were added to the product obtained by a usual liquid-separation treatment in methyl t-butyl ether, and the whole was stirred at 60° C. for 14 hours. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-chloro-N-[3-(3-chlorobenzoyl)-6-formylpyridin-2-yl]-N-ethylacetamide as a yellow oily substance. NMR1: 10.1 (1H, d, J=0.6 Hz), 7.95 (2H, brs), 1.0-1.5 (3H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:30][CH2:31][CH2:32][CH2:33][N:34]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O.[CH:40](O)([CH3:42])[CH3:41]>>[ClH:38].[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:34][CH2:33][CH2:32][CH2:31][N:30]=2)=[CH:19][CH:18]=1)[C:13]([O:15][CH:40]([CH3:42])[CH3:41])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)O
Reactant: O=C(CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Product: CC(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Product: Cl
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
23.88 g (0.04 mol) of the compound of Example 1 (as trifluoroacetic acid salt) were suspended in 400 ml of isopropanol. To this suspension was added at −15° C. under an inert gas atmosphere a previously prepared solution of thionyl chloride in isopropanol (for the preparation of this solution 10.4 ml of thionyl chloride had been added dropwise at −10 to −15° C. and unter an inert gas atmosphere within 5 min to 160 ml of isopropanol and the mixture had been stirred at −10° C. for further 20 min). After completion of the addition the temperature rose within 30 min to room temperature. Then, the meanwhile clear solution was heated at 60° C. under stirring for 7 hours. Stirring was continued without heating overnight. By TLC control, the reaction exhibited to be completed. Solvents were removed by rotary destination in vacuo. The residue was suspended in 100 ml of isopropanol and the isopropanol was removed in vacuo. The solid residue was triturated with diethylether and separated by suction filtration. The raw product was suspended in 120 ml of isopropanol, heated to reflux with 2.4 g of charcoal and filtered. After cooling, the colourless product was separated by filtration. Yield: 16.2 g of an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[F:56]C1C=C(S(Cl)(=O)=O)C=CC=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:56])[CH:27]=3)(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.0 mmol) and 3-fluorobenzenesulfonyl chloride (0.60 mL, 4.5 mmol) the title compound of Step A was obtained (1.46 g, 2.99 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.48-7.65 (m, 4H), 7.37 (t, J=7.7 Hz, 1H), 7.20-7.28 (m, 3H), 6.97 (d, J=5.1 Hz, 1H), 3.30-3.37 (m, 1H), 1.38 (d, J=7.0 Hz, 6H). MS (ESI): 489.1 [M+H]+.