Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].[Na].C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH:15][CH2:23][CH3:24])=[N:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2N)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCNc1ncc(Nc2ccc(Cl)cc2)nc1-n1nc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
5-(4-Chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl) -pyrazine-2-amine (84 mg, 1.5 mmol) was dissolved in dichloroethane (4 mL). Acetaldehyde (83 μL, 1.5 mmol) was added and the reaction mixture was stirred for one hour at room temperature. Sodium triaceoxyborohydride (70 mg, 0.3 mmol) was added and the reaction mixture was stirred overnight at room temperature. Aqueous sodium hydrogen carbonate and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give 5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-2-ethylamino-pyrazine (49 mg, 80%) as a green solid. Mp. 122-124° C. LC-ESI-HRMS of [M+H]+ shows 343.1444 Da. Calc. 343.143797 Da, dev. 1.8 ppm
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[N:13]1([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([NH2:12])=[N:10][N:11]=3)[N:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Solvent: O
Product: Nc1nnc2ccc(N3CCCCC3)nn12

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 100 mg) were initially charged in water (1 ml) and admixed with piperidine (260 μl) with stirring. Thereafter, the mixture was heated to reflux for 1 h and, after cooling, freed of the solvent. Subsequently, the mixture was admixed with water and the solid formed was filtered off with suction and dried. The mother liquor was dried and admixed with a little water. The solid obtained was filtered off with suction and dried. The filtrate was then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The three resulting solid fractions were combined and gave rise to 56 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 34 %

Procedure:
After suspending a crude product of 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (88.4 mg) in ethanol (3 ml), D-10-camphorsulfonic acid (51.3 mg) was added and the mixture was stirred for 5 minutes. A 0.2 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.3 ml) was added thereto and the mixture was stirred for 62 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and then the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:9). Fractions containing the target compound were concentrated, and then diethyl ether (1 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (44.7 mg, 34%) as pale pink powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH2:18][CH3:19])[C:22]([NH:21][CH3:20])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)NC)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of 1-benzyloxycarbonyl-4-(N-ethylamino)-piperidine (4.0 g) and methyl isocyanate (11 mL) was stirred for 30 hours at ambient temperature. The reaction mixture was diluted with chloroform and evaporated to give the urea as an oil; MS: m/z=320(M+1). The material was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.OO.C([O-])([O-])=[O:37].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:37])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(C(N)=O)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 47.1 %

Procedure:
6-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (50 mg, 0.11 mmol) and H2O2 (0.04 mL, 30%), K2CO3 (6.27 mg, 0.046 mmol) in DMSO (0.39 mL) was stirred overnight at room temperature. The reaction was added water and EtOAc. The layer was separated. The organic phase was washed with brine and dried, concentrated to give the product (9.95 mg, 19%) LC-MS Method 2 tR=1.083, m/z=460.1; 1H NMR (CD3OD) 1.21 (m, 1H), 1.51 (d, 3H), 1.53-1.64 (m, 1H), 1.85-1.94 (m, 2H), 2.10-2.21 (m, 1H), 2.29 (m, 1H), 2.42 (m, 1H), 3.03 (m, 1H), 3.39 (t, 2H), 5.52 (m, 1H), 6.99 (d, 2H), 7.21-7.34 (m, 5H), 7.22 (d, 2H), 7.31 (d, 1H), 8.22 (d, 1H), 8.98 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[K+]>C(Cl)(Cl)Cl>[Br:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=12
Reactant: Cc1cc(C)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
To a solution of 2.0g (13.6 mmloes) 5,7-dimethyl pyrazolo[1,5-a]-pyrimidine [Y. Makisumi, Chem. Pharm. Bull. (Tokyo) 10, 612 (1962)] in CHCl3 (25 ml) was added N-bromosuccinimide (NBS) [2.42 g (13.6 mmloes)]. This mixture was heated on the steam bath for 10 minutes, and then allowed to cool to room temperature. The clear yellow solution was then added to an ice cold solution of potassium hydroxide (50 ml, 2N) with good stirring. The CHCl3 layer was dried over Na2SO4, then chromatographed on basic alumina. Evaporation on the CHCl3 eluant afforded a white solid which was further purified by recrystallization from petroleum ether (30°-60°) to give 1.7g (56%) of analytically pure product; mp 115°-6°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixed solution of methyl 2,5-dihydroxybenzoate (10.0 g), potassium carbonate (12.3 g) and acetone (100 ml) was added benzyl bromide (7.43 ml), and the mixture was stirred overnight at room temperature. After the insoluble material was removed by filtration, the mother solution was concentrated. The obtained residue was purified by column chromatography (LL, Biotage cartridge, ethyl acetate:n-hexane=1:9→1:5) to give methyl 5-benzyloxy-2-hydroxybenzoate (9.63 g, 63%) as colorless crystals.
Reaction SMILES: O1CCCC1.[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Li+:26]>O>[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)[CH2:8][C:9]([O-:11])=[O:10].[Li+:26]
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a tetrahydrofuran (350 ml) solution of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (5 g, 18.17 mmol) (Example 1A) is added lithium hydroxide (435 mg, 18.17 mmol) in water (150 ml). The solution is stirred at room temperature for 4 hours, and then concentrated to afford a white solid. The crude product is used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:8]=[C:7]([C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[O:26])[N:25]=2)[N:6]=1)(=[O:4])=[O:3].C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[C:7]([C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[O:26])[N:25]=2)[N:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)CCc1cc(-c2nc(=O)c3ccccc3s2)nc(S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)c1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
tert-Butyl 3-[2-(methylsulfonyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.20 g, 0.45 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.11 g, 63%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.145 g; 1.047 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.0013 mmol) and 3-pyridinylboronic acid (0.064 g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH2:36][CH3:37])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([CH2:36][CH3:37])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: CCc1cc(P(C)(C)=O)ccc1N
Product: CCc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(Dimethylphosphoryl)-2-ethylaniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: Cn1cc(C=O)c2cc(F)ccc21
Yield: 50 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 5-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethyl indole-2-carboxylate, the title compound (0.16 g, 50%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28](C)[CH:27]=[C:26](C)[N:25]=1.C[CH2:33][N:34](C(C)C)[CH:35](C)C>C(#N)C>[CH3:33][N:34]([CH3:35])[C:26]1[CH:27]=[C:28]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[O:21][N:20]=[C:19]([CH3:22])[N:18]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:29]=[CH:24][N:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CC#N
Product: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCN(c4cc(N(C)C)ncn4)C[C@H]32)n1
Temperature: 200 °C
Yield: 54.7 %

Procedure:
A mixture of Intermediate 12 (50 mg, 0.17 mmol), 2-chloro-4,6-dimethylpyrimidine (24 mg, 0.17 mmol) and DIPEA (0.87 mL, 0.5 mmol) in ACN (1 mL) was heated in the microwave at 200° C. for 2 h. The mixture was concentrated in vacuo and chromatography (Hex to 100% EtOAc/Hex) to afford the desired product as a pale yellow foam (39 mg, 55%). MS (ESI) mass calculated for C22H25N7O2, 419.2; m/z found, 420.2. 1H NMR (500 MHz, CDCl3): 8.15 (s, 1H), 8.12-8.04 (m, 1H), 7.59-7.50 (m, 2H), 7.25-7.17 (m, 1H), 5.22 (s, 1H), 4.44-4.33 (m, 2H), 4.11-3.99 (m, 1H), 3.94-3.73 (m, 2H), 3.68-3.60 (m, 1H), 3.11-3.05 (m, 6H), 3.02-2.86 (m, 2H), 2.45-2.42 (m, 3H), 2.22-1.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[CH:36]=2)=[C:28]([F:48])[CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:26]([NH:25][C:16]([C:5]5[C:6](=[O:15])[N:7]([C:8]6[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=6)[C:2]([CH3:1])=[CH:3][CH:4]=5)=[O:18])=[CH:27][C:28]=4[F:48])=[CH:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Cc1cccc(-n2c(C)ccc(C(=O)O)c2=O)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(-n2c(C)ccc(C(=O)Nc3ccc(Oc4ccc5nc(NC(=O)C6CC6)cn5c4)c(F)c3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution (3 mL) of 6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.50 mmol) in tetrahydrofuran were added oxalyl dichloride (130 mg, 1.0 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the solvent was evaporated. N,N-Dimethylformamide (3.0 mL) and a solution (2.0 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) in N,N-dimethylformamide were successively added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (150 mg, 69%) as a brown solid.
Reaction SMILES: [CH3:1][O-].[Na+:3].Cl.[N:5]1[CH:10]=[CH:9][C:8](CCl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:1][S:13][CH:14]([CH3:18])[C:15]([O-:17])=[O:16].[Na+:3]
Reactant: ClCc1ccncc1
Reactant: CC(S)C(=O)O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(SCc1ccccn1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium methoxide (5.1 g., 94 mmoles) was dissolved in 50 ml. of absolute ethanol and cooled in an ice bath. A slurry of 4-picolyl chloride hydrochloride (5.0 g., 30.4 mmoles) in 45 ml. of ethanol was added and the chilled reaction mixture stirred for approximately 10 minutes. Finally, 2-mercaptopropionic acid (3.23 g., 30.4 mmoles) dissolved in 5 ml. of ethanol was added over a 10 minute period. The mixture was allowed to warm to room temperature and stirred overnight (approximately 16 hours). The reaction was filtered through filter aid to remove salts, carbon treated and concentrated to crude sodium 2(4-picolylthio)propionate (approximately 7 g. of oil used directly in the next step).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[O:13])(=[O:10])=[O:9]>[Pd].O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)=[O:13])(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cccc(N)c1

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(2-methylphenylsulphonylaminocarbonyl)-3-nitrobenzene (3 g, 9.4 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (2 ml) and ethanol (60 ml), the title compound was afforded as a yellow solid. This was recrystallised from ethanol to give a pale yellow crystalline solid (2.21 g, 8.1%). mp 150°-152° C. 1H NMR (360 MHz, D6-DMSO) δ 2.61(3H, s), 6.78 (1H, d, J=7.8 Hz), 6.97-7.03 (2H, m), 7.12 (1H, t, J=7.8 Hz), 7.39-7.47 (2H, m), 7.58 (1H, t, J=7.5 Hz), 8.02 (1H, d, J =7.9 Hz).
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:6][CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].[CH:36]1([C:42](Cl)=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:42]2[O:4][N:3]=[C:2]([N:5]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:6][CH2:7][C:8]3[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:21])([CH3:22])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)[N:1]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(C3CCCCC3)n2)cc1)C(=O)O

Procedure:
Similarly prepared from tert-butyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and cyclohexanecarbonyl chloride.
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9][N+:10]1C=CC=C[CH:11]=1)([CH3:5])([CH3:4])[CH3:3].C([OH:26])C.N([C:29]1[CH:34]=[CH:33]C=[CH:31][CH:30]=1)=O.[OH-].[Na+]>O>[C:2]([C:6]1[CH:7]=[C:8]([C:9]2([N+:10]([O-:26])=[CH2:11])[CH:31]=[CH:30][CH:29]=[CH:34][CH2:33]2)[CH:16]=[C:17]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:18]=1[OH:19])([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCO
Reactant: O=Nc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=[N+]([O-])C1(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C=CC=CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a clean dry 250 ml. round bottom 3-neck flask equipped with a magnetic stirrer, thermometer and addition funnel was added 6.69 g. (0.02 mole) of 3,5-di-t-butyl-4-hydroxy -benzylpyridinium chloride in 100 ml. of ethanol and 2.36 g. (0.022 mole) of nitrosobenzene. The clear solution was cooled to 0° to 5° C. and sodium hydroxide (2.45 g.; 0.06 mole) in 60 ml. of water was added dropwise in 40 minutes. The reaction mixture was stirred an additional 3 hours at ambient temperature and then diluted with 50 ml. water, filtered, and the collected product dried to yield 5.07 g. (79.2% yield) of 1-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenyl-nitrone, MP-137°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[F:19]C1C=CC(CC2N=CC=CC=2C=O)=CC=1.CO[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]2[C:49]([CH:50]=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:39][CH:38]=1.Cl>CO>[F:19][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]2[C:49]([CH:50]=[CH:17][C:16]([C:15]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:11][CH:12]=[CH:13][CH:14]=3)=[O:18])=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reactant: COc1ccc(Nc2ncccc2C(C)=O)cc1
Reactant: O=Cc1cccnc1Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ncccc2C(=O)C=Cc2cccnc2Nc2ccc(F)cc2)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 1-(2-(4-methoxyphenylamino)pyridin-3-yl)ethanone (100 mg, 0.462 mmol) in methanol (5 mL) was added 2N Ba(OH)2solution (2 ml) and stirred for 5 minutes. Then added 2-(4-fluorobenzyl)nicotinaldehyde (112.03 mg, 0.462 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (8l) (164 mg, 90% yield).