Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[CH:7]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:8]1[CH:7]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1sc(NC(=O)NN)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of ethyl 5-(hydrazinecarboxamido)-3-methylthiophene-2-carboxylate (12.80 g, 52.61 mmol), trimethyl orthoformate (6.33 mL, 57.86 mmol) and p-toluenesulfonic acid monohydrate (0.260 g, 1.367 mmol) in ethanol (130 mL) was stirred at reflux for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, and kept at +5° C. for 16 h. The resulting solid was filtered and washed with ethyl acetate. The filtrate was concentrated, and the residue was triturated with ethanol. The combined material was dried to afford the title compound as a cream solid in 70% yield (9.37 g): 1H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.66 (s, 1H), 7.27 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 254.2 (M+1).
Reaction SMILES: Cl.CCOCC.[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24](/[CH:30]=[CH:31]/[C:32]([NH:34][O:35]C4CCCCO4)=[O:33])[CH:25]=3)[O:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24](/[CH:30]=[CH:31]/[C:32]([NH:34][OH:35])=[O:33])[CH:25]=3)[O:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2)NO
Yield: 83.4 %

Procedure:
1 M HCl in Et2O (5 ml, 5 mmol) was added dropwise to a solution of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (260 mg, 0.55 mmol) in DCM (3 ml). After 1 h a white solid precipitated, which was filtered, washed with DCM, dried under vacuum and purified by preparative HPLC to give 180 mg of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide as its trifluoroacetic salt.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4]([CH:14]=O)[CH:3]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4](/[CH:14]=[N:16]/[OH:17])[CH:3]=1
Reactant: NO
Reactant: CC1(C)OB(O)c2cc(C=O)cc(F)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2cc(/C=N/O)cc(F)c21
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (1.86 g, 8.94 mmol) and NH2OH.HCl (0.69 g, 9.84 mmol) in THF (16 mL) and H2O (4 mL) at rt was added NaOAc (0.92 g, 11.18 mmol). The reaction mixture was stirred for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (5:1 to 2:1) to give (E)-4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime (1.8 g, 95.8% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.34 (s, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.46 (dd, J=1.2 Hz, J=11.2 Hz, 1H), 1.524 (s, 6H) ppm.
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.C(OCC)(=O)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:27][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:28])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)CCC(=O)OCc2ccccc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
810 mg (5.0 mmol) of N,N'-carbonyldiimidazole were added to a solution of 1.04 g (5.0 mmol) of benzyl hydrogen succinate in 10 ml of acetonitrile, and the resulting mixture was stirred for 15 minutes, after which 565 mg (1.22 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Example 2) and 610 mg (5.0 mmol) of 4-N,N-dimethylaminopyridine were added. The mixture was then heated under reflux for 4 days, after which the reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed with 2 N aqueous hydrochloric acid and with 2 a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 15 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:1 to 1:1 by volume as the eluent, to give a crude product containing the title compound. The product was further purified by column chromatography through silica gel under the same conditions as above, to give the title compound as a viscous substance in a 15% yield.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[N:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.O>CC(C)=O.Cl>[OH:21][C:18]([C:16]1[CH:15]=[C:14]([C:22]([F:24])([F:25])[F:23])[N:13]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:17]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)c1cc(OC2CCC(=O)CC2)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[2-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.049 g, 0.14 mmol) was dissolved in acetone (3.7 mL) A solution of 12.0 M hydrogen chloride in water (0.43 mL, 5.2 mmol) was added and was stirred at 25° C. for 16 hours at which time LCMS showed about 70% reaction was complete. An additional 12.0 M hydrogen chloride in water (0.43 mL, 5.2 mmol) was added and was stirred for 3 hours; LCMS showed ˜90% reaction was complete and was quenched into excess NaHCO3, extracted with EtOAc and the organic extract was evaporated to give the product. This was used in the next reaction without purification. MS (ES): 318 (M+1).
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[C:7]([C:8]2[S:16][C:15]3[C:14](SC)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1>[Cl-].[NH4+].CN1C(=O)CCC1>[CH3:2][N:3]1[C:7]([C:8]2[S:16][C:15]3[C:14]([NH2:1])=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1
Reactant: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)sc12
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2s1
Temperature: 205 °C

Procedure:
Concentrated aqueous NH3 (0.5 mL) and saturated ammonium chloride solution (one drop) were added to a solution of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[3,2-d]pyrimidine (example 11) (40 mg) in NMP (2 mL). The vessel was sealed and heated in a microwave (CEM explorer, 200-210° C., 110 W) for 35 minutes. Dilution with water (1.5 mL) and purification by RPHPLC eluting with MeCN:H2O (2:98 to 40:60) gave the title compound as a pale brown solid (24 mg, 67.%);
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]([C:6]([N:8]([CH2:10][CH2:11]O)[CH3:9])=[O:7])=[C:4]([OH:16])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[NH2:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[C:6](=[O:7])[N:8]([CH3:9])[CH2:10][CH2:11][O:16][C:4]=2[CH:3]=1
Reactant: CN(CCO)C(=O)c1cc(Cl)c(N)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCOc2cc(N)c(Cl)cc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
4-Amino-5-chloro-2-hydroxy-N-(2-hydroxyethyl)-N-methylbenzamide (300 mg, 1.22 mmol) was stirred in dichloromethane at 0° C. under an atmosphere of nitrogen then TEA (247 mg, 2.4 mmol), triphenylphosphine (320 mg, 1.2 mmol) and DEAD (212 mg, 1.2 mmol) were added. The reaction was allowed to stir for 1 h at 0° C., after which time LCMS indicated the formation of a peak consistent with the target material. The volatiles were removed under reduced pressure and the resulting gum was dissolved in dichloromethane then passed through a SCX-2 20 g cartridge. The cartridge was washed with dichloromethane-methanol 10% and the fractions were collected in 100 mL flasks. TLC indicated that the fractions were not identical in composition which was verified by LCMS. The purest fraction was concentrated to afford the target material (18 mg, 5%).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(O)C>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:27]([OH:26])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 64 %

Procedure:
An ethanol solution of 25.2 g of sodium hydroxide was added with 160 g (0.60 mol) of 1-amidino-4-benzylpiperazine sulfate, followed by a dropwise addition of 129.4 g (0.60 mol) of diethyl ethoxymethylenemalonate over 20 minutes. After being refluxed for 5.5 hours, the reaction mixture was cooled and the precipitated crystals were collected by filtration. The thus-obtained crystals were washed with water and then dried, thereby obtaining 131.4 g of the above-identified compound (yield: 64%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1.N1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([O:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1)=[O:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(Cl)(Cl)Cl)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of trichloroacetyl chloride (0.5 ml.) in dry tetrahydrofuran (8 ml.) was added dropwise to a cooled (-80°) and stirred solution of 3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) and pyridine (0.35 ml.) in dry tetrahydrofuran (15 ml.). After 30 min. the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N-hydrochloric acid, aqueous sodium hydrogen carbonate, then water. The solution was dried and concentrated to leave a residue which was crystallised from benzene then benzene-petrol to afford the title compound (0.21 g.), m.p. 126°-127°, [α]D + 86°.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22]>>[Br:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Solvent: O
Product: Brc1ccc2c(C3CCNCC3)n[nH]c2c1
Reaction time: 20 h
Yield: 32 %

Procedure:
A mixture of 9.6 g of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine and 50 ml of hydrazine hydrate was stirred in an autoclave at 135°-140° C. for 20 hr. The reaction mixture was quenched with water and the solid was collected. The solid was recrystallized from acetonitrile (charcoal) to yield 2.6 g (32%) of product, mp 163°-165° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][OH:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCN(Cc1ccccc1)c1nc2ccccc2s1
Product: O=Cc1ccc(OCCN(Cc2ccccc2)c2nc3ccccc3s2)cc1

Procedure:
The title compound was prepared from 2-(N-(2-benzothiazolyl)-N-benzylamino)ethanol (8.25 g) and 4-fluorobenzaldehyde (3.6 g) by an analogous procedure to that described in Preparation 22.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[NH2:32][OH:33]>C1COCC1>[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=[N:32][OH:33])=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: NO
Reactant: Cc1ccc(NC(=O)Nc2ncc(C=O)s2)c(C(=O)C2CCCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ncc(C=NO)s2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
To a mixture of 2M aq NaHCO3 (5 mL) and 1-(2-cyclo-pentanecarbonyl-4-methylphenyl)-3-(5-formyl-thiazol-2-yl)-urea (72 mg, 0.2 mmol) in THF (5 mL) was added hydroxylamine hydrochloride (200 mg) at room temperature with stirring. The resulting mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate. The organic layer was washed (brine), dried (Na2SO4) and concentrated to obtain 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(hydroxyimino-methyl)-thiazol-2-yl]-urea (56 mg, 76%) as a mixture of syn and anti-isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and morpholine in NMP. ES-MS m/e (%): 455 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O>O>[O:13]=[C:11]1[C:10]2[C:9](=[N:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:7]2[CH:18]=[CH:19][C:4]([C:1]([OH:3])=[O:2])=[CH:5][C:6]1=2
Reactant: O=C(O)c1ccc(Oc2ncccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 80.6 %

Procedure:
A mixture of 2 g of 2-(p-carboxyphenoxy)nicotinic acid and 30 g of concentrated sulfuric acid is stirred at 180°-190°C for 40 minutes on an oil bath. After cooling with water, the reaction mixture is poured into ice water. A jelly-like substance produced crystallizes on heating. The crystals are filtered off, washed thoroughly with water, and recrystallized from aqueous dioxane to give 1.5 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7 -carboxylic acid melting at 293°-294°C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2]CC.[CH3:7][N:8]([CH2:12][C:13]([O-:15])=[O:14])[C:9]([NH2:11])=[NH:10].[Na+]>>[CH3:7][N:8]([CH2:12][C:13]([O:15][C:1](=[O:5])[CH2:2][N:8]([CH3:7])[C:9]([NH2:11])=[NH:10])=[O:14])[C:9]([NH2:11])=[NH:10]
Reactant: CCCC(=O)Cl
Reactant: CN(CC(=O)[O-])C(=N)N
Agent: [Na+]
Product: CN(CC(=O)OC(=O)CN(C)C(=N)N)C(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39 g (60 mmol) of the prepared butyryl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 12.08 g (66 mmol) of sodium 2-(1-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the butyryl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield butyric 2-(1-methylguanidino)acetic anhydride.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](OCC)(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[O-]CC.[Na+]>C(O)C>[OH:10][C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC(=O)c1ccccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of methyl anthranilate (121 g, 0.8 mol) and diethyl malonate (128 g, 0.8 mol) in ethanol (900 mL) was added a 20% solution (274 g) of sodium ethoxide in ethanol, and the mixture was stirred at room temperature for 30 min. Ethanol was evaporated, and the mixture was stirred at 140° C. for 12 hr. After cooling, the obtained solid was washed with diethyl ether, and dissolved in water. Insoluble materials were filtered off, the filtrate was acidified with 5N hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried under reduced pressure to give the title compound (161 g, 86%) as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH2:23]>>[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: NCC(O)CN
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: NCC(O)CNc1cc(-c2ccc(Cl)cc2)nc2ccccc12

Procedure:
The title compound, m.p. 283-287° C. and MS: m/e=328.2 (M+H+), was prepared from 4-chloro-2-(4-chloro-phenyl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][C:28]1([C:38]#[C:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=O)[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][CH2:27][C:28]1([C:38]2[CH:39]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=2)[CH2:29][CH2:30][C:31]2([O:32][CH2:33][CH2:34][O:35]2)[CH2:36][CH2:37]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (280 mg, 1.60 mmol) in ethanol (2.7 mL), triethylamine (0.447 mL, 3.20 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one (Reference Example 89) (540 mg, 1.33 mmol) in ethanol (2.7 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (458 mg, 0.872 mmol, 65%) as a white amorphous product.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)=[O:14])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2cn(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H20F3N5O2 (m/e) 419, obsd 420 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[Cl:8][C:9]1[C:14]([S:15][CH3:16])=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:10]=1>C1COCC1>[Cl:8][C:9]1[C:14]([S:15][CH3:16])=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:6]([NH2:5])=[O:7])=[CH:25][CH:24]=2)[N:10]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(-c2ccc(NC(N)=O)cc2)nc1N1CCOCC1
Yield: 31.2 %

Procedure:
Trimethylsilyl isocyanate (136 mg, 5 eq.) was added to a stirred solution of 4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (80 mg, 0.237 mmol.) in THF (2.0 ml) and the mixture was reacted to reflux for 16 hrs. The reaction mixture was extracted with EA and washed with brine. The crude was purified by Chromatography (Hexane/EtOAc 1:1) to give a product 28.1 mg (31.2%).