Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:41])=[CH:28][C:29]=2[O:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:24]=[CH:23][N:22]=1.O[CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:41][CH2:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:28][C:29]=2[O:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:24]=[CH:23][N:22]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OCCCN4CCOCC4)c23)c1
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)cc(OCCCN4CCOCC4)c23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
Di-tert-butyl azodicarboxylate (0.035 g) was added dropwise to a stirred mixture of 4-(2-chloro-5-methoxyanilino)-7-hydroxy-5-(3-morpholinopropoxy)quinazoline (0.045 g), 4-(3-hydroxypropyl)morpholine (0.016 g), triphenylphosphine (0.04 g) and methylene chloride (1 ml). The reaction mixture was stirred at ambient temperature for 10 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.018 g); NMR Spectrum: (DMSOd6 and CF3COOD) 2.2–2.4 (m, 4H), 3.15 (m, 4H), 3.35 (m, 4H), 3.5 (m, 4H), 3.7 (m, 4H), 3.8 (s, 3H), 4.02 (t, 4H), 4.35 (t, 2H), 4.6 (t, 2H), 6.95 (s, 1H), 7.03 (s, 1H), 7.05 (m, 1H), 7.5 (s, 1H), 7.6 (d, 1H), 8.88 (s, 1H); Mass Spectrum: M+H+ 572 and 574.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(N2CCCCC2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCC(N2CCCCC2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Subsequently, ammonium chloride (0.7 g) and iron powder (3.8 g) were added to a mixed solvent of water (30 ml) and ethanol (120 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-piperidinopiperidin-1-yl)benzonitrile (6.2 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (4.8 g), melting point: 110–112° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].O>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)[CH:19]=[CH2:18]
Reactant: Cc1nc2cc(O)ccc2o1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2oc(C)nc2c1

Procedure:
2.58 g of 5-hydroxy-2-methylbenzoxazole (publication: Synthesis, 1982, 68-69) was dissolved in 15 ml of N,N-dimethylformamide and 15 ml of acetonitrile. Thereafter, 2.39 g of potassium carbonate and 1.61 ml of allyl bromide were successively added to the reaction solution. Approximately 6 hours later, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.78 g of the subject compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[CH2:10][CH2:9]1)(C)(C)C.CO.Br.C(Br)(=O)C>C1(C)C=CC=CC=1>[Br:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCCCCBr)CC1
Agent: Br
Agent: CC(=O)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](CCCCCBr)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., a solution of 4.4 g (12.63 mmol) of trans-[4-(5-Bromo-pentyl)-cyclohexyl]-carbamic acid tert-butyl ester were received in 9 m MeOH was added to 40 ml of a HBr solution in MeOH (made by dropping at 0° C., 4.7 ml (63.07 mmol) of acetylbromide to 35 ml MeOH). The suspension was stirred for 16 h at RT, diluted with toluene and evaporated (2×). The residue was suspended in EtOAc (40 ml) cooled (−10 to −15° C.) and filtered to give 4.05 g (97%) of trans-4-(5-Bromo-pentyl)-cyclohexylamine as hydrobromide salt, MS: 248 (MH+, 1Br).
Reaction SMILES: CN.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][CH3:17])=O)=[C:9]([O:18]C)[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:16][CH3:17])=[C:9]([OH:18])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CNC(=O)Cc1ccc(C(C)(C)C)cc1OC
Agent: CN
Product: CNCCc1ccc(C(C)(C)C)cc1O

Procedure:
Reaction of the product of Step B in Example 75 with methylamine instead of dimethylamine as described in Step C of Example 75 afforded 2-(4-tert-butyl-2-methoxyphenyl)-N-methylacetamide. Treatment of this later product according to the procedures described in Steps D and E of example 75 affords the title compound.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:10].[OH2:11]>>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:10].[CH2:6]([OH:11])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: O
Agent: O=C([O-])c1ccccc1
Agent: [Na+]
Product: OCCCCCCO

Procedure:
The coolant composition of the present invention can be prepared by merely mixing the components (A), (B) and (C) each in a specified amount to give a uniform mixture. In an actual procedure, it is advantageous that sodium benzoate as the component (B) is first dissolved in water as the component (C) to give a uniform aqueous solution of sodium benzoate into which liquid 1,6-hexanediol prepared in advance by heating the solidified compound having a melting point of about 43° C. is added as the component (A) under agitation with a suitable stirrer. It is important in this case that entrainment of air into the mixture under agitation is minimized in order to avoid increase of the dissolved oxygen therein by adequately selecting the types of the stirrer blades and the velocity of stirrer revolution.
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH3:35])[CH:4]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:34]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:23]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:35]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl)carbonyl]amino}propanoate (85.0 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (75.4 mg, 94%) as a white solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][S:25][C:26]3[S:27][CH:28]=[N:29][N:30]=3)[C@H:8]2[S:7]1.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][S:25][C:26]3[S:27][CH:28]=[N:29][N:30]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Yield: 43.6 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate (4.65 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, ethyl acetate (150 ml) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was washed with 5% hydrochloric acid saturated with sodium chloride, and then extracted with a sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and benzene to give 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid (1.5 g), mp 197° to 199° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(OC(C)C)(C)C.CO>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:2][C:3]5[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: Cc1ccc(CBr)cc1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 68 %

Procedure:
Using α-bromo-p-xylene and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 68%. mp. 84–85° C. (diisopropyl ether-methanol). 1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.59 (3H, s), 2.07 (3H, s), 2.24 (3H, s), 2.25 (3H, s), 2.33 (3H, s), 3.05–3.35 (8H, m), 3.78 (3H, s), 4.49 (2H, s), 4.66 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.13 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]>O>[CH2:9]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)C1
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)C1

Procedure:
1.5 g of 1A was mixed with 25 ml of distilled water and a few boiling chips and boiled under a nitrogen blanket. After 40 minutes reflux, the initial oily two phase system became homogenous. The water was stripped on a rotary evaporator and the product readily crystallized. After drying in a vacuum oven at 60°, N-benzylazetidine-3-carboxylic acid (1), m.p.: 152°-154°, was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)([O-])=O>CCO>[N:14]1([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[NH2:1])[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cccn1
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1-n1cccn1
Yield: 47.8 %

Procedure:
Method C3 was used 1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-pyrazole (1.80 g, 7.00 mmol) in EtOH (40 mL) to give 760 mg (48%) of the title compound as white crystals after crystallization from hexane.
Reaction SMILES: C(OC(=O)N[C@H](C(=O)NC1N(C(C)(C)C)N=C(C2(C3C=CC=CC=3)CCN(C3CC3)CC2)C=1)C)C1C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH2:49][C:50]([NH:52][CH:53]([S:66][CH:67](C)C)[C:54]([NH:56][C:57]2[NH:61][N:60]=[C:59]([C:62]([CH3:65])([CH3:64])[CH3:63])[CH:58]=2)=[O:55])=[O:51])[CH:45]=[C:46]([F:48])[CH:47]=1>>[F:41][C:42]1[CH:43]=[C:44]([CH2:49][C:50]([NH:52][CH:53]([S:66][CH3:67])[C:54]([NH:56][C:57]2[NH:61][N:60]=[C:59]([C:62]([CH3:63])([CH3:65])[CH3:64])[CH:58]=2)=[O:55])=[O:51])[CH:45]=[C:46]([F:48])[CH:47]=1
Reactant: CC(C)SC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cc(C(C)(C)C)n[nH]1
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C3CC3)CC2)nn1C(C)(C)C
Product: CSC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cc(C(C)(C)C)n[nH]1

Procedure:
This compound was prepared from the acid 11 (Example 114) using a three step procedure analogous to that used for the preparation of 18 from 14 (Example 114). Compound 21 gave the following mass spectral data: m/z=419.2 (M+H)+.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([CH:31](OCC)[O:32]CC)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=4)[CH:12]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=4)[C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(OCC)OCC)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.22 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 3 hr. Then the mixture was neutralized (basified) with potassium carbonate to pH=8. The resulting suspension was filtered to give 4,4′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazine-8,9-diyl)dibenzaldehyde (80 mg, yield 97%) as a light yellow solid. LC-MS (ESI) m/z: 396 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH3:12][NH2:13]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:13][CH3:12])=[O:10])[CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cc(Cl)ccn1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate (29.9 g, 174.9 mmol) in MeOH (15 mL) at 0° C. was added 2M methylamine in THF (437 mL, 874 nunol) dropwise. The reaction was allowed to stir at 0° C. for 3 h. The mixture was then concentrated and extracted with EtOAc (2×). The organic solutions were combined, washed with brine, dried over Na2SO4 and concentrated to give 4-chloro-N-methylpyridine-2-carboxamide (25 g, 84%). 1H NMR (300 MHz, d6-DMSO) δ: 8.85 (br s, 1H), 8.61 (d, 1H), 8.00 (d, 1H), 7.74 (dd, 1H), 2.81 (d, 3H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na].Cl[C:7]1[N:12]=[C:11]([N:13]([CH2:16][C:17]2[S:21][C:20]([Cl:22])=[N:19][CH:18]=2)[CH2:14][CH3:15])[C:10]([N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1>ClCCl>[CH2:1]([O:4][C:7]1[N:12]=[C:11]([N:13]([CH2:16][C:17]2[S:21][C:20]([Cl:22])=[N:19][CH:18]=2)[CH2:14][CH3:15])[C:10]([N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1)[C:2]#[CH:3]
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#CCO
Agent: [Na]
Solvent: ClCCl
Product: C#CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Yield: 23.8 %

Procedure:
0.52 g of sodium propargyl alcohol and 10 mL of anhydrous dichloromethane were added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at room temperature, 1.15 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, prepared according to the example 1, in 5 mL of dichloromethane was added dropwise. After that, the reaction mixture was stirred at room temperature for 1 to 2 hours, and then stirred at reflux temperature for 2 to 5 hours. After cooling down to the room temperature, the reaction mixture was treated by the method according to example 1 to obtain 0.29 g of 6-propargyloxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a viscous yellow-green solid in a yield of 23.8%. GC-MS (M+) (EI, 70 eV, m/z) calc: 352. found: 352. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm): (CDCl3) 1.212 (t, J=7.2 Hz, 3H, CH3), 2.497 (t, J=2.4 Hz, 1H, CH), 3.265 (q, J=7.2 Hz, 2H, CH2), 4.850 (s, 2H, CH2), 4.969 (s, 2H, CH2), 6.263 (d, J=8.7 Hz, 1H, Py H), 7.489 (s, 1H, Thiazole-H), 8.182 (d, J=8.7 Hz, 1H, Py H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15])=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([CH3:20])[O:7]2.[NH2:22]/[C:23](/[CH3:30])=[CH:24]\[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(O)C>[C:14]([C:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:20])=[CH:5][C:4]3=[O:21])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:22][C:17]=1[CH3:18])(=[O:16])[CH3:15]
Reactant: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
150 mg (0.52 mmol) of 3-[(5-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 33.6 mg (0.26 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol and heated under reflux under argon for 3 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 2:1). 50.1 mg (48% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:6][C:7]=1[NH:8][CH:9]1[CH2:11][CH2:10]1.[CH3:18][S:19][CH2:20][CH2:21][C:22](Cl)=[O:23].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:6][C:7]=1[N:8]([CH:9]1[CH2:11][CH2:10]1)[C:22](=[O:23])[CH2:21][CH2:20][S:19][CH3:18]
Reactant: CSCCC(=O)Cl
Reactant: Clc1nc(-c2cccnc2)sc1NC1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: CSCCC(=O)N(c1sc(-c2cccnc2)nc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 4-chloro-N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine HCl salt (288 mg, 1 mmol) and DMAP (305 mg, 2.500 mmol) in CH2ClCH2Cl (1 mL) was added 3-(methylthio)propanoyl chloride (166 mg, 1.200 mmol), and the mixture stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate, mixed with aqueous NaHCO3 (10 mL). The organic phase was separated, rinsed with brine (2×), dried over MgSO4 and concentrated in vacuo to give a yellow gum. This gum was purified on reverse phase column chromatography (C-18, CH3CN/H2O) to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-cyclopropyl-3-(methylthio)propanamide (82 mg, 22%) as a brown gum: 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 0.6H), 9.02 (s, 0.4H), 8.71 (s, 6H), 8.61 (d, J=3.4 Hz, 0.4H), 8.21 (d, J=7.6 Hz, 1H), 8.19-8.10 (m, 1H), 7.41 (d, J=5.6, 0.6H), 7.35 (dd, J=8.3, 4.5 Hz, 0.4H), 3.16 (bs, 1H), 2.91 (s, 3H), 2.88-2.72 (m, 2H), 2.11 (m, 2H), 0.85 (m, 4H); ESIMS (m/z) 354.56 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]1[OH:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:10][CH:9]1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 1585 %

Procedure:
A solution of 2.92 g of 204 (6.41 mmol) in 10 ml of anhydrous MeOH was added with 100 mg of PPTS (0.40 mmol, 6.2 mole %) and stirred at RT overnight. After checking completion of the reaction by means of TLC (EE/CH 1:7), the solution was concentrated, the remaining residue taken up in 25 ml of ethyl acetate and filtered over a small amount of silica gel. The filtrate was concentrated and further purified using silica gel column chromatography (EE/CH 1:7), thereby obtaining 2.98 g of 59 (6.34 mmol, 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[N:21][NH:22][C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:37])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:37][C:15]1[C:16]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:17]=2[CH:18]=[N:19][C:14]=1[NH:13][C:11]([NH:10][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])=[O:12]
Reactant: Cc1cc(-c2n[nH]c3cc(NC(=O)N[C@H](C)c4ccc(Cl)cc4)ncc23)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2n[nH]c3c(Br)c(NC(=O)N[C@H](C)c4ccc(Cl)cc4)ncc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a stirred solution of 1-[(1R)-1-(4-chlorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea (Example 19; 82 mg, 0.202 mmol) in MeCN (2 mL) was added NBS (47 mg, 0.262 mmol). The mixture was left to stir for 1 h at room temperature and then treated with 1N Na2S2O3, and extracted with chloroform:iPrOH (3:1, x3). The combined organics were dried (Na2SO4), concentrated in vacuo and purified by column chromatography on silica gel to yield 1-[7-bromo-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-[(1R)-1-(4-chlorophenyl)ethyl]urea (42 mg, 0.086 mmol, 43%). MS ESI calc'd. for C21H19BrClN6O [M+1]+ 485, found 485.