Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].I[CH3:16]>CN(C=O)C.C1COCC1>[F:10][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([O:14][CH3:16])[C:4]=1[F:3]
Reactant: CI
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
Step M (4): Sodium hydride (120 mg, 5 mmol) was added to a solution of 2,3-difluoro-5-nitrophenol (250 mg, 1.4 mmol) in DMF/THF (4 mL/4 mL). After 10 min, iodomethane (0.2 mL, 5 mmol) was added. The mixture was heated at 80° C. for 2 h. The reaction mixture was quenched with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1,2-difluoro-3-methoxy-5-nitrobenzene (130 mg, 48% yield).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][C:3]1[C:4]([CH2:7][CH3:8])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1noc(N)c1Br
Product: CCc1noc(NS(=O)(=O)c2ccccc2)c1Br
Yield: 70 %

Procedure:
N-(4-Bromo-3-ethyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-ethylisoxazole and benzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 90-93° C., yield 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:19][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)(=[O:33])=[O:32])[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC1(C)C=Cc2cc(CNc3ccccc3)cnc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(Cc2cnc3c(c2)C=CC(C)(C)O3)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 19a (20 mg, 0.075 mmol) in DCM (1 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (36 mg, 0.150 mmol) and triethylamine (0.021 mL, 0.150 mmol). The reaction was stirred for 24 hours at room temperature. The reaction mixture was washed with water (×2) and the organic layer dried over MgSO4 and concentrated in vacuo. Column chromatography (2:1 hexane/EtOAc) gave a white solid (?? g). Yield: 43%. 1H NMR (CDCl3): δ 1.47 (s, 6H), 3.76 (s, 3H), 3.97 (s, 3H), 4.60 (s, 2H), 5.66 (d, 1H, J=9.6), 6.26 (d, 1H, J=10), 6.93-6.99 (m, 4H), 7.23-7.25 (m, 3H), 7.32-7.36 (m, 2H), 7.63 ppm (d, 1H, J=2.4). HRMS (ESI) m/z calcd for C25H25N2O5S [M+H)+] 467.1641. found: 467.1636. HPLC: ret. time=7.5 min, 99.0%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:27])=[O:26].Cl>C(O)C>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Agent: Cl
Solvent: CCO
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a solution of N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) in ethanol (2.5 ml) was added a solution of HCl (0.25 ml, 1M in diethyl ether), and the reaction was heated to 70° C. After 5 h, the precipitate was filtered off and washed with ethanol and dried to give the title compound as a white solid (104 mg, 87%). 1H NMR (300 MHz, d6-DMSO) δ 10.1 (s, 1H), 8.74 (m, 1H), 7.93 (d, J=6.6 Hz, 1H), 7.60-7.65 (m, 3H), 7.41 (s, 1H), 7.24-7.29 (m, 3H), 5.90 (s, 1H), 4.39 (s, 2H), 4.09 (m, 1H), 3.69 (s, 3H), 3.49 (s, 3H), 2.87 (s, 3H), 1.33 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=480 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li][CH3:15].[NH4+].[Cl-]>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]([OH:13])[CH3:15])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C(C)O)C(C)C1
Temperature: -20 °C
Yield: 94 %

Procedure:
4-Isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (23 g, 130 mmol) was dissolved in diethyl ether (200 ml). The solution was cooled to −20° C. under nitrogen and MeLi (1.6M, 100 ml, 160 mmol) added over 30 min with stirring. The temperature was allowed to rise to −5° C. and the reaction stirred at this temperature for 1 h. The reaction mixture was poured slowly, and under nitrogen, onto a vigorously stirred mixture of sat. NH4Cl (150 ml) and ice (100 g). After stirring for 15 min the phases were separated and the lower aqueous layer extracted with diethyl ether (100 ml). The organic phases were combined, washed with water (100 ml), dried (Na2SO4) and concentrated in vacuo to give 24 g of a light yellow oil. The crude oil was purified by flash chromatography (MTBE/hexane 1:3) to give 4b as a 3:2 mixture of diastereomers (18 g, 72% yield, colorless oil, >99% pure). Subsequent distillation provided 12.5 g of olfactory pure product.
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@@H:2]12.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:6][C@H:4]2[CH2:5][O:1][C@@H:2]3[C@H:9]([OH:10])[CH2:8][O:7][C@H:3]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 2 L flask, 100.0 g (0.684 mol) of (3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (Isosorbide) were dissolved in 600 ml of water and 130, 5 g (0.684 mol) of Tosyl chloride dissolved in 600 ml of Toluene are added at 0° C. 49.5 g (0.751 mol) of potassium hydroxide (86%) in 170 ml of water were added dropwise over ½ h at 0° C. and the reaction was stirred for 1 hr at 0° C. and 5 h at room temperature. The organic phase was extracted, dried, filtered and concentrated under vacuum and after subjecting the crude reaction product to silica gel column chromatography and eluting with a 99/1 mixture of dichloromethane/methyl alcohol, 50.0 g of the product of the title were obtained after concentrating to dryness.
Reaction SMILES: [Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:22]NC.C(Cl)Cl.C=O>C(O)(C)(C)C>[Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:22])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Yield: 5.6 %

Procedure:
A mixture of t-butyl 7α-bromo-3-methyl-3-cephem -4-carboxylate 1,1-dioxide (700 mg, 1.9 mmol), dimethylamine hydrochloride (460 mg, 5.7 mmol), methylene chloride (3 ml) and t-butyl alcohol (50 ml), formaldehyde (0.57 g, 37% w/v) was heated to reflux at 80°-90° C. for 20 hours. t-Butyl alcohol was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 200 mg of crude product which was purified over silica column using methylene chloride as eluant to give 40 mg of pure t-butyl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4](Cl)[C:5]([F:8])([F:7])[F:6])#[N:2].FF.[SH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[K+]>O.C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:14][C:4]([C:5]([F:8])([F:7])[F:6])=[C:3]([C:10]#[N:11])[C:1]=1[NH2:2])=[O:17])[CH3:20]
Reactant: N#CC(C#N)=C(Cl)C(F)(F)F
Reactant: CCOC(=O)CS
Agent: CC(=O)[O-]
Agent: FF
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1N

Procedure:
Combine 1,1-dicyano-2-chloro-2-(trifluoromethyl)ethylene (0.554 mmol) (prepared by the method of Middleton, J. Fluorine Chem., 20, 1982, p 397-418) and ethanol in a 50 ml flask. Add ethyl 2-mercaptoacetate (0.554 mmol) and potassium acetate (0.831 mmol) and heat to 60-70° C. for 30-40 minutes. Cool the reaction and add water. Product crystallizes as yellowish needles. Filter crystals and wash with 1:1 ethanol/water. Dry solid under reduced pressure to give the title compound as light yellow crystals: 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 2H), 4.36 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.0 Hz), MS found (M−1) 262.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].I.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[NH:22])SC)=[CH:14][CH:13]=1)#[N:11]>O.C(O)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[NH:22])[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][CH:17]=1)#[N:11]
Reactant: NCCC(=O)O
Reactant: CSC(=N)Nc1ccc(C#N)cc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(NC(=N)NCCC(=O)O)cc1
Yield: 64.1 %

Procedure:
A mixture of 4.18 g (47 mmol) of β-alanine, of 1,88 g (47 mmol) of sodium hydroxide in 20 cm3 of water and of 15 g (47 mmol) of N-(4-cyanophenyl)-S-methylisothiourea hydroiodide in 100 cm3 of 95% ethanol is heated to reflux for 5 hours. The precipitate formed is filtered, then dissolved in 150 cm3 of 1N aqueous sodium hydroxide solution. The solution obtained is washed with ethyl acetate (3×50 cm3), then neutralized to pH 7 by a concentrated HCl solution. The precipitate obtained is filtered, washed with hot absolute ethanol, then recrystallized in water. 7 g (yield 65%) of N-[4-cyanophenylamino(imino)methyl]-3-aminopropanoic acid, having a melting point of 233°-235° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(-c2nc(C(=O)O)cc3ccccc23)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2ccc(C)cc2)n1
Yield: 53.7 %

Procedure:
Operations are carried out as for Example 7, starting from 5 g of 1-(4-methylphenyl) isoquinoline 3-carboxylic acid, 2.18 g of triethylamine, 2.39 g of ethyl chloroformate and 1.83 g of diethylamine in 190 ml of chloroform. 3.25 g of N,N-diethyl 1-(4-methylphenyl) isoquinoline 3-carboxamide melting at 113° C., are obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[CH2:11][C:12](C)(C)[C:13]([OH:15])=[O:14].Cl.N[C:20]1(CC(OC)=O)C[CH2:21]1>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4][N:3]1[C:11]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:21][CH2:20]1
Reactant: COC(=O)CC1(N)CC1
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Agent: Cl
Product: O=C(O)CC1(N2C[C@H]3CNCCN3C2=O)CC1

Procedure:
Compound 47-A was prepared in analogy to compound Q in Example 19 by using methyl 2-(1-aminocyclopropyl)acetate hydrochloride salt (for its synthesis, refer to: Sandstroem A., et al, Bioorganic & Medicinal Chemistry, 16(10), 5590-5605; 2008) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9]1.[O-]S(C(F)(F)F)(=O)=O.C([Yb+2])C.[O-]S(C(F)(F)F)(=O)=O>ClCCl.C1(C)C=CC=CC=1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([CH:2]([OH:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9]1
Reactant: CCOC(=O)C=O
Reactant: c1ccc2occc2c1
Agent: CC[Yb+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(O)c1coc2ccccc12
Yield: 31 %

Procedure:
Ethyl glyoxylate 50% in toluene (3.72 mL, 18.6 mmol) was added to a solution of benzofuran (2.0 g, 16.9 mmol) and ethyl ytterbium (III) triflate (0.53 g, 0.8 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 48 hours with two additions of an equivalent of ethyl glyoxylate 50% in toluene each day. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane/ethyl acetate 95/05 to 80/20) to provide the desired hydroxyl-ester (20a) (1.15 g, 5.2 mmol, 31%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:11]([N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19])[OH:14])=[O:12].[OH-].[Na+]>CC(C)=O.O>[C:1]([O:14][N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:20])([OH:19])[OH:21])[CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=CN(O)CCCP(=O)(O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=CN(CCCP(=O)(O)O)OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A solution of benzoyl chloride (700 mg) in dry acetone (6 ml) was added dropwise to a solution of sodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (820 mg) in a mixture of water (15 ml) and acetone (15 ml) under ice-cooling, while stirring. During this period, pH of the mixture was kept at around 7.5-7.7 with 1 N aqueous sodium hydroxide solution. The stirring was continued at the same temperature for 10 minutes and then acetone was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 3.5 with 1N hydrochloric acid and ether (40 ml) was added thereto. After removal of the precipitated impurities, the aqueous layer was adjusted to pH 1.6 with 1N hydrochloric acid and extracted three times with ethyl acetate (50 ml, 20 ml×2). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give crystals, which were washed with ether to give crystalline 3-(N-benzoyloxy-N-formylamino)propylphosphonic acid (620 mg). Mp 149°-153° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][NH:13][C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([CH3:20])[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cc2c(s1)SCCc1cc(=O)[nH]nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)SCCc1cc(=O)n(C)nc1-2
Yield: 47.5 %

Procedure:
To a solution of 0.6 g of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 15 ml of N,N-dimethylformamide is added 0.11 g of 60% sodium hydride with stirring under ice-cooling and the mixture is stirred for 10 minutes at room temperature. To the mixture is added 0.39 g of methyl iodide, and the mixture is further stirred for 20 minutes and then poured into ice-cold water. The precipitated crystals are collected by filtration, washed with water and recrystallized from ethanol to give 0.3 g of 9-ethyl-2-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 168°-170° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:24])[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.3 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (195 mg, 0.479 mmol) obtained in Example 126a), potassium carbonate (66.1 mg, 0.479 mmol, 1.0 eq.) and morpholine (0.085 ml, 0.957 mmol, 2.0 eq.) were suspended in acetonitrile (4.0 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with 2% aqueous sodium carbonate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration and crystallized from ethyl acetate. The precipitate was collected by filtration and crystallized from ethanol again to give the title compound as a white powder (142 mg, 0.356 mmol, 74.4%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])(=[O:13])=[O:12].N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17]([C:16]1[CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=1)=[O:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: C=C(C)C(=O)OCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Yield: 84.1 %

Procedure:
With stirring, a solution of 13 g (0.1 mole) of 2-hydroxyethyl methacrylate in 80 ml of tetrahydrofuran is slowly added dropwise at 0° C. to a solution of 23.9 g (0.1 mole) of 3-chlorosulfonylbenzoyl chloride and 7.9 g (0.1 mole) of pyridine in 150 ml of tetrahydrofuran. The reaction mixture is subsequently stirred for 15 hours at room temperature. The precipitated pyridine salt is removed by filtration, and the filtrate is concentrated by evaporation in vacuo. The oily residue is dried under high vacuum, affording 28 g of viscous product.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([NH2:38])[C:26]3[C:30]([CH:31]=2)=[N:29][N:28](C2CCCCO2)[CH:27]=3)[CH:20]=[CH:21][CH:22]=1>C1COCC1>[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[C:25]([NH:38][C:13]([CH:10]3[CH2:12][CH2:11]3)=[O:14])[CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(-c2cc(N)c3cn(C4CCCCO4)nc3c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(NC(=O)C3CC3)c3cn[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (1 ml), DIPEA (0.142 ml, 0.813 mmol) and cyclopropanecarbonyl chloride (34 mg, 0.325 mmol) were added to 6-(3-methylphenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.163 mmol) and the reaction was stirred at RT for 1 h. The solvent was evaporated under a stream of nitrogen and 2 M sodium hydroxide (aq) (3 ml) was added and the reaction stirred for 1 h. DCM (3 ml) was added and the reaction stirred for a further 30 mins. The organic layer was passed through a hydrophobic frit and the aqueous layer extracted with DCM. The combined organic layers were concentrated. The residue was dissolved in MeOH (2 ml) and 4 M HCl in 1,4-dioxane (2 ml) was added. The reaction was stirred for 1 h then the solvent was removed in vacuo. The residue was purified by MDAP (Method A) then freeze dried to give title compound, 17 mg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a mixture of 3.034 g (13 mmol) 3-(4-Trifluoromethyl-phenyl)-propionyl chloride (CAS: 539855-79-3) and 1.4 g (14.1 mmol) N,O-Dimethylhydroxylamine hydrochloride in 55 mLl chloroform, under argon, was added dropwise 2.28 mL (28 mmol) pyridine at 0° C. The solution was allowed to warm to RT and was stirred for 2 hour. The mixture was washed with 1N HCl (50 mL). The organic layer was washed once with 1N NaOH. The organic phases was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified with flash column chromatography on silica gel eluting with a gradient formed from heptane and ethylacetate to provide 2.1 g (63%) of title compound as colorless oil. MS (m/e): 262.0 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3N3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 1.3 h
Yield: 98.7 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.17 g of piperidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for two hours, and then at 80° C. for 1.3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 2-[3-(piperidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 54”).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[CH:7]=1.O.[NH2:22][NH2:23]>>[OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc(CO)c2)cc1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc(CO)c3)cc2)=NN1

Procedure:
Similarly, the reaction of 4-(4-hydroxymethyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(4-hydroxymethyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3g), mp 213.5°-215° C.