Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:21]([C:25]1[N:26]=[N:27][C:28](Cl)=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH3:24].O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[N:27]=[N:26][C:25]([CH2:21][CH2:22][CH2:23][CH3:24])=[C:30]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:35][CH:36]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (94.2 mmol, 18.97 g) in THF (100 mL) at room temperature was added potassium tert-butoxide (87.0 mmol, 9.76 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (72.5 mmol, 25.0 g) in THF (100 mL). The reaction mixture was allowed to slowly attain room temperature while stirring overnight. The reaction was poured into a mixture of water (300 mL) and ethyl acetate (300 mL). The mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 330 g SiO2 cartridge using an ethyl acetate/hexanes gradient to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[CH:12][CH:13]=1.[Cl:14][CH2:15][CH:16]1[O:18][CH2:17]1>FC(F)(F)CO>[Cl:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[CH:12][CH:13]=1
Reactant: CN1C(=O)c2ccc(N)cc2C1=O
Reactant: ClCC1CO1
Solvent: OCC(F)(F)F
Product: CN1C(=O)c2ccc(NCC(O)CCl)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.3 %

Procedure:
Twenty-five grams (g) (0.142 mole) 4-amino-N-methylphthalimide [Flitsch, Chem. Ber. 94:2494(1961)] and 20.7 g (0.21 mole) 1-chloro-2,3-epoxypropane were added to 150 ml 2,2,2-trifluoroethanol and the reaction mixture was heated to reflux with stirring for 48 hours. Seventy to eighty ml of 2,2,2-trifluoroethanol was removed by distillation and a heavy yellow precipitate formed when the remaining solution cooled to room temperature. This precipitate was triturated with ethyl acetate, collected by filtration and dried to give 29.5 g (77% yield) of the desired phthalimide intermediate m.p. 136°-138.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1.O>CO.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:4][N:3]=1
Reactant: Brc1cnc(C#CCCn2ccnn2)cn1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: Brc1cnc(CCCCn2ccnn2)cn1

Procedure:
2-Bromo-5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrazine (2.50 g, 9.0 mmol) is dissolved in methanol (700 ml) and hydrogenated for 2 h at r.t. in the presence of platinum(IV) oxide ×H2O (0.840 g, 3.40 mmol). The reaction mixture is filtered and concentrated in vacuo to yield 2-bromo-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrazine as a colorless solid. Yield 1.63 g (64%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:16])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:16])[CH2:10][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CN1CCOCC1)NC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
To a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (23 mmol) in CH3CN (20 mL) was added morpholine (28 mmol) and K2CO3 (23 mmol) at room temperature. The reaction mixture was brought to 50° C. and kept at the same temperature overnight. The reaction mixture was cooled and solvent was removed under reduced pressure, and the residue was treated with CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to afford (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester as viscous liquid, yield: 62%. MS (M+H)=245.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(=O)C1C=CC=CC=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[CH2:46]([OH:48])[CH3:47]>C1COCC1>[C:46]([C:42]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:36][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)[C:3]([OH:43])=[O:2])(=[O:48])[C:47]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COC(=O)C(Cc1ccc(OCC=Cc2ccc(-c3ccccc3)cc2)cc1)(Nc1ccccc1)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1N[C@@H](Cc1ccc(OC/C=C/c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-(S)-2-(2-Benzoyl-phenylamino-3-[4-(3-biphenyl-4-yl-allyloxy)-phenyl]-propionic acid methyl ester (example 1) (400 mg, 0.7 mmol) was dissolved in a mixture of ethanol (15 ml) and THF (15 ml). 1N NaOH (3 ml) was added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated in vacuo. Water (5 ml) and ethyl acetate (10 ml) was added. The mixture was neutralised with 1N HCl. The aqueous phase was isolated and extracted with ethyl acetate (×2) The organic layers were combined, washed with water, dried (MgSO4) and evaporated to give 400 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH3:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33]C(O)[CH2:31][C:30]1([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH:17]3[CH2:33][C:34]([CH3:36])([CH3:35])[N:29]([CH3:28])[C:30]([CH3:39])([CH3:38])[CH2:31]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Product: CN1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccc(Cl)cc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C

Procedure:
Methyl 3-(5-chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (10.0 g, 0.026 mol) and 1,2,2,6,6-pentamethyl-4-hydroxypiperidine (3.98 g, 0.023 mol) are reacted together according to the procedure of Example 1. The title compound is obtained in a yield of 3.23 g (26%) as an off-white solid, melting at 150-158° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,092 l/mole cm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[CH:19][CH:18]=[CH:17]1)[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1ccccc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino benzoic acid ethyl ester (20 g; 121 mmol) in acetic acid (35 mL) was added 2,5-dimethoxytetrahydrofuran (19 g; 174 mmol). The reaction mixture was stirred for two hours at reflux. After evaporation of the solvent, the crude product was purified by flash column chromatography (methylene chloride) to give compound 2-pyrrol-1-yl-benzoic acid ethyl ester as a yellow oil. Rf=0.63 (methylene chloride); (22.2 g; 103 mmol; 85%)
Reaction SMILES: [Na].[Br:2][CH:3]([CH2:13][C:14](Br)([Br:16])[Br:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl>C(O)C>[Br:2][CH:3]([CH:13]=[C:14]([Br:15])[Br:16])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Br)(Br)Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C)(C)C(Br)C=C(Br)Br
Reaction time: 2 h
Yield: 52 %

Procedure:
Two millileters of an ethanolic solution containing 92 mg (4 mmoles) of sodium was added dropwise to a cold solution of 1.95 g (4 mmoles) of ethyl 4,6,6,6-tetrabromo-3,3-dimethylhexanoate in 10 ml of absolute ethanol. The cooled mixture was stirred for 2 hours, then poured into chilled 1N hydrochloric acid. The acidic mixture was extracted with diethyl ether, and the extract was washed successively with saturated aqueous sodium bicarbonate and sodium chloride. The washed extract was dried over magnesium sulfate and distilled to give 846 mg (52% yield) of ethyl 4,6,6-tribromo-3,3-dimethyl-5-hexenoate, b.p. 130°-133°/0.3 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:28])[CH:26]=[O:27])[CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:28])[CH:26]([OH:27])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: CCCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-hexan-2-one (40.36 mmol, 11.4 g), oxo-acetic acid ethyl ester solution in toluene (30 mL, 50% solution in toluene) and triethylamine (15 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with water (3×100 mL), and the organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography eluting with 30% ethyl acetate in hexanes to provide 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester.
Reaction SMILES: C[O-].[Na+].CO.Cl.[NH2:7][C:8]([NH2:10])=[NH:9].Cl[C:12]([C:14]1[C:18]([CH3:19])=[CH:17][N:16]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:13]>COCCOC.C(Cl)(Cl)Cl>[NH:9]([C:12]([C:14]1[C:18]([CH3:19])=[CH:17][N:16]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:13])[C:8]([NH2:10])=[NH:7]
Reactant: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
1.4 g (25.5 mmol) of sodium methoxide is added at a temperature in the region of 20° C. under an argon atmosphere to 25 mL of methanol. After complete dissolution, 2.5 g (26.2 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 25 mL of 1,2-dimethoxyethane and then again concentrated to dryness. The residue is suspended in a mixture of 75 mL of tetrahydrofuran and 50 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere, and then 1.07 g (3.97 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole, dissolved in 25 mL of chloroform, are added thereto. After stirring at a temperature in the region of 20° C. for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 mL of water. After filtering, a gum is obtained, which gum is triturated in 50 mL of methanol and filtered. The filtrate is partially concentrated to a volume of 5 to 10 mL and is then purified by silica gel chromatography [eluent: chloroform/methanol (75/25 by volume)]. After concentrating the fractions under reduced pressure and triturating in ethyl ether, 0.64 g of 3-guanidinocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of an off-white solid melting at 215° C. Mass spectrum (EI): m/e 293 (M+.), m/e 234.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH:15]1([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:21])[C:3]([OH:22])=[O:2])=[CH:10][CH:9]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)C(=O)c1ccc(OCCOC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOC2CCCCC2)cc1
Yield: 89.8 %

Procedure:
A mixture of 4-[[2-(cyclohexyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in methanol (10 mL) and 0.5N sodium hydroxide (7 mL) was treated as in Example 19. Extraction with diethyl ether provided material which was crystallized from diethyl ether-hexane to give 0.6 g of colorless 4-[[2-(cyclohexyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid, mp 96°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][CH:27]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:28]([CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1)=O>C(O)C>[CH3:25][O:26][CH:27]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:28]1[C:30]2[CH2:31][O:32][CH2:33][CH2:34][C:35]=2[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COC(C(=O)C1COCCC1=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(C(OC)c4ccccc4)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 2.7 %

Procedure:
A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.300 g, 0.81 mmol) and potassium carbonate (0.337 g, 2.44 mmol) in ethanol (5 mL) was stirred at 50° C. for 5 minutes. 3-(2-methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (0.161 g, 0.65 mmol) in ethanol (0.5 mL) was added dropwise to the reaction mixture and the resulting mixture was stirred at 50° C. overnight. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The combined organic layer was dried over MgSO4, filtered, concentrated and purified by preparative HPLC yielding 4-(methoxy(phenyl)methyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (8.00 mg, 2%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:12]([C:11]1[C:2]([CH:26]([C:24]#[N:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:3]([F:23])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2=[O:22])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.8 g of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl cyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are metered in at room temperature. The mixture is stirred overnight and then ice-water is added. It is rendered acidic using HCl and extracted using methylene chloride. The organic phase is dried and concentrated. The residue is stirred once more with water and the solid is isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5](=[O:12])[N:4]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@H:15]([CH2:20][OH:21])[O:14]2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:22])=[O:9])[C:5](=[O:12])[N:4]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][OH:21])[O:14]2)[CH:3]=1
Reactant: COC(=O)c1nc(Cl)cn([C@@H]2O[C@@H](CO)[C@@H](O)[C@H]2O)c1=O
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(Cl)cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Temperature: 0 °C

Procedure:
In 4 mL of methanol was dissolved 0.26 g of methyl 6-chloro-4-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. While cooling the solution with ice, gaseous ammonia was introduced until saturation. The reaction mixture was stirred at an ice-cooled temperature for one hour and then the solvent was removed under reduced pressure. By purifying the residue thus obtained by column chromatography [eluent: chloroform:methanol=7:1], 0.06 g of 6-chloro-4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained as a light yellow-colored solid product.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([CH3:31])[CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][C:25]=2[CH3:31])=[C:25]([CH3:31])[CH:24]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: Cc1cc(Br)ccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1COCCOCCOCCOCCOCCOCCOCc1ccc(Br)cc1C
Yield: 88.1 %

Procedure:
To a solution of 354 mg (3.85 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (20 ml) was added 1.00 g (3.54 mmol) of hexaethylene glycol, and the mixture was reacted at 40°-50° C. for 30 min. Then, 2.06 g (7.79 mmol) of 4-bromo-2-methylbenzyl bromide was added, and the mixture was allowed to react at room temperature for 17 hours. To the reaction solution at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetate-hexane (1:4) yielded 2.02 g (3.12 mmol) of 1,21-bis(4-bromo-2-methylphenyl)-2,5,8,11,14,17,20-heptaoxaheneicosane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:4][CH2:3]1.[C:21]([C:23]1[O:27][C:26]([C:28](Cl)=[O:29])=[CH:25][CH:24]=1)#[N:22].CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:28]([C:26]3[O:27][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[O:29])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1N
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 35.8 %

Procedure:
1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60 mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg 5% Pd—C in MeOH (5 mL) under H2 (1 atm) for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 40 mg (72%) of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in the presence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.13 (s, 3H), 2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8 Hz), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7 Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H), 8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H), found 407.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=O)=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=C(F)[N:15]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[N:15]=2)=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: O=CNc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(Nc2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
Sodium hydride (1.2 g, 30.9 mmol) was added to a solution of N-(4-chloro-phenyl)-formamide (4 g, 25.7 mmol) in N,N-dimethylformamide (40 mL) and stirred for 15 minutes. 2,6-Difluoropyridine (2.96 g, 25.7 mmol) was added, the reaction mixture was stirred at 70° C. overnight and poured into a stirred ice-water solution. The resulting participate was filtrated off and dried to give (4-chloro-phenyl)-(6-fluoro-pyridin-2-yl)-amine (5.95 g) as the crude product. The crude product was used without further purification.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][O:9][C:10]1[C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=1[S:23](=[O:26])(=[O:25])[NH2:24].[C:27](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:27][O:21][C:20]([C:13]1[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:10]([O:9][CH3:8])=[C:11]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:12]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COc1c(S(N)(=O)=O)cc(C(=O)O)c2c1OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Yield: 96.5 %

Procedure:
396 g of methanol were introduced into a balloon flask provided with a condenser and then 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added while cooling. The mixture was heated under reflux and then poured into 485 cm3 of water and 40 g of sodium carbonate. The precipitate was dried off, washed and dried. 110.5 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 202°-203° C.; yield: 92%).