Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[NH+](C)[CH2:4][CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:4][CH:5]=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[NH:28]2)=[CH:23][CH:22]=1
Reactant: C[NH+](C)CCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CC=C(c3ccc([N+](=O)[O-])cc3)N2)cc1
Temperature: 25 °C

Procedure:
A mixture of N,N-dimethyl-N-4-nitrobenzoylethylammonium chloride (18.1 g; 0.07 m), 4-methoxyphenylhydrazine hydrochloride (12.2 g; 0.07 m) and sodium carbonate (21.2 g; 0.2 m) in ethanol (200 ml.) and water (10 ml.) was boiled for a few minutes to give a deep orange solution from which a dark orange solid precipitated. The mixture was cooled to room temperature and the product was filtered, washed well with water and was dried at 50° C. (14.38 g; 69% theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.COCCOC>CN(C=O)C.[Cl-].[Na+].O>[CH:16]1([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C1CCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Ethyl 4-nitro-1H-pyrrole-2-carboxylate (1.006 g, 5.432 mmol; see Example 1, step (i) above) was dissolved in DMF (20 mL, dry) to which was added potassium metal (0.492 g, 12.582 mmol) then it was heated to 80° C. and then it was left at that temperature for 1 h with stirring. The reaction mixture was cooled to 50-60° C. after which bromocyclopentane (1 mL, 1.390 g, 9.326 mmol) was added followed by KI (1.548 g, 9.326 mmol). The reaction mixture was heated again for 5 h with stirring at 80° C., after which time it was left stirring at room temperature under N2, overnight. The reaction mixture was diluted with brine under N2, at room temperature, and then it was extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude product (containing some DME). The product was purified using column chromatography [silica gel, 1/10 ethyl acetate/n-hexane (RF=0.24)]. Fractions containing the pure material were collected and the solvent removed to give pale yellow oil (440 mg, 32% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)C(=O)C(F)(F)F.[BH4-].[Na+].O.C(Cl)Cl>C(O)C>[CH3:1][NH:2][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 107.6 %

Procedure:
To a solution of 1.32 g (4.07 mM) of N-methyl-N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetamide in ethanol was added 0.23 g (6.08 mM) of sodium borohydride at room temperature and the mixture was stirred at room temperature for 2.5 hours. To this reaction mixture was further added 0.27 g (7.1 mM) of sodium borohydride and the mixture was stirred at room temperature for 20 hours. The mixture was then stirred at 60° C. for 1.5 hours. To this reaction mixture was added water to stop the reaction and methylene chloride was added for extraction. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off to provide the title compound as colorless oil (1.00 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[F:23][C:24]([F:34])([F:33])[CH:25]1[CH2:31][C:30](=[O:32])[O:29][C:27](=[O:28])[CH2:26]1>C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:7][C:2]=1[NH:1][C:30]([CH2:31][CH:25]([C:24]([F:23])([F:34])[F:33])[CH2:26][C:27]([OH:29])=[O:28])=[O:32]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 0.50 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.27 g of 3-trifluoromethylglutaric anhydride and 6 ml of toluene was stirred at 100° C. for one hour. After cooling to room temperature, the solvent was removed by distillation under reduced pressure to obtain 0.7 g of the desired compound as crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: CCCCBr
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Product: CCCCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and 1-butylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 319 (M+, 6), 278 (31), 277 (19), 276 (bp), 70 (30).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH-].[Na+].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][CH2:25][OH:26])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1.C(Cl)(Cl)Cl.CO>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:24][CH2:25][O:26][CH2:3][C:2]#[CH:1])[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCO
Reactant: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Reaction time: 18 h
Yield: 99.6 %

Procedure:
Propargyl bromide (10.0 ml, 89.8 mmol, 80% in toluene) and benzyltrimethylammonium chloride (0.60 g, 3.2 mmol) were dissolved in dichloromethane (130 ml). The solution was treated with sodium hydroxide (130 ml, 50% w/w in water). 2-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (20.0 g, 73.7 mmol) was added and the mixture was vigorously stirred for 18 hours. Thin layer chromatography (9/1 chloroform/methanol) indicated complete conversion. The mixture was diluted with water (200 ml) and the phases were separated. The aqueous fraction was extracted with additional dichloromethane (3×150 ml). The combined organic fractions were washed with brine (100 ml), dried (Na2SO4), filtered and concentrated to yield 22.7 g of 2-(2-methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[CH:29]1([CH2:32][N:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39](O)=[O:40])[C:34]2=[O:42])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:1][C:2]3[CH:27]=[CH:26][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:13]=[C:14]([C:16]6[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=6)[S:15][C:8]=45)=[C:4]([F:28])[CH:3]=3)=[O:40])[C:34]2=[O:42])[CH2:30][CH2:31]1
Reactant: O=C(O)c1nccn(CC2CC2)c1=O
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5nccn(CC6CC6)c5=O)cc4F)c3s2)cc1
Yield: 22 %

Procedure:
Prepared from 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A) and 4-(cyclopropylmethyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 8 mg (22%) of the desired product. LRMS (ESI pos) m/e 570.2 (M+1). 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.08 (dd, 1H), 8.03 (d, 1H), 7.93 (q, 4H), 7.79 (d, 1H), 7.76 (s, 1H), 7.55 (m, 1H), 7.40 (t, 1H), 6.67 (d, 1H), 4.02 (d, 2H), 2.97 (s, 3H), 1.41 (m, 1H), 0.69 (m, 2H), 0.52 (m, 2H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −128.6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])[CH2:17]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl>O1CCCC1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:38])[CH3:2])[CH:5]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:31])([F:32])[F:33])[OH:29])=[N:19]1
Reactant: CC(=O)c1cccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
To a mixture of 5-(3′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (39.0 mg, 0.07 mmol) prepared in Example 224 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 120.0 uL, 0.36 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 20.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]Br.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:29][C:21]2[S:20][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2nc3ccccc3s2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (benzo[d]-thiazol-2-yl)methylbromide (251 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.118 g (29.6%);; MS m/z: 399.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.56 (q, 2H, 3J=7.6 Hz); 4.74 (s, 2H); 5.02 (s, 2H); 6.85-6.86 (m, 2H); 7.15-7.17 (m, 2H); 7.26-7.27 (m, 2H); 7.36-7.39 (m, 2H); 7.46-7.49 (m, 1H); 7.94-7.95 (m, 2H), 7.98-8.00 (m, 1H); 11.98 (br s, 1H); HPLC (METHOD [A]): rt 17.02 min (97.8%)
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=1)[NH2:27]>>[CH2:35]([O:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:33]=[CH:32][N:31]=1)[CH3:36]
Reactant: CCOc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: CCOc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-ethoxypyridine according to the method described for example 43. MS: M=444.2 (M+H)+
Reaction SMILES: [CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(CC(=O)O)cc2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 123, 0.1 g, 0.23 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a white solid (0.068 g, 72%). 1H NMR (300 MHz, CDCl3): δ 9.05 (br s, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.66 (s, 1H), 7.44-7.37 (m, 3H), 7.23-7.21 (m, 2H), 5.20 (heptet, 1H, J=6.0 Hz), 4.21 (s, 2H), 3.52 (s, 2H), 2.36 (s, 3H), 1.94 (m, 1H), 1.36 (d, 6H, J=6.0 Hz), 0.55-0.43 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=2[N:16]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][O:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([NH2:11])[S:13][C:14]=2[CH:20]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
add 289 mg of 2-(bromomethyl)-1,3-dichlorobenzene to a solution of 200 mg of 2-amino-1,3-benzothiazol-6-ol in 12.1 cm3 of a 0.1N aqueous solution of sodium hydroxide. The suspension obtained is stirred for 24 hours at about 20° C. The pH is then adjusted to the range 4-5 by adding glacial acetic acid then to 6-7 by adding solid sodium hydrogen carbonate. The mixture obtained is extracted 3 times with 40 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, treated with vegetable black, then filtered and concentrated under reduced pressure (0.2 kPa). After purification of the residue by filtration on silica [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 70 mg of 6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a grey meringue, which has the following characteristics:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1ccc(Br)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
As illustrated in Scheme 1, to a mixture of 5-bromo-2-furaldehyde (2.0 g, 11.4 mmol), tetrabutylammonium bromide (3.7 g, 11.4 mmol), potassium carbonate (3.93 g, 28.5 mmol), 2-methylphenyl boronic acid (1.7 g, 12.5 mmol) and palladium (II) acetate (55.2 mg, 0.23 mmol) is added water (20 mL). The reaction mixture is then stirred vigorously for 16 hour at 25° C. Once complete, the reaction mixture is poured into a separatory funnel and diluted with water (50 mL) and ethyl acetate (150 mL). The organic layer is separated and treated with 5.0 g of activated charcoal for 30 min after which time the suspension is filtered through a pad of celite and the filtrate concentrated to afford the crude coupling product as a yellow oil. The crude product is purified by column chromatography (5→10% ethyl acetate in hexanes) to afford 1.8 g of 5-(2′-methylphenyl)-2-furaldehyde.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13](O)=O)=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N:22]1C=CC=CC=1>>[CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]#[N:22])=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(C)OC(=O)c1ncc(Br)cc1C(=O)O
Agent: CS(=O)(=O)Cl
Product: CC(C)OC(=O)c1ncc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (630 mg, 2.187 mmol) in pyridine (8 ml) at 0° C. was added methane sulfonyl chloride (0.34 ml, 4.37 mmol, 2 equiv.) and the reaction mixture was stirred for 1 hour at 25° C. Then NH3 gas was purged in to reaction mixture at 0° C. and stirred at 25° C. for 30 minutes. The excess NH3 was evaporated off in vacuo. The reaction mixture was cooled to 0° C., a fresh lot of methane sulfonyl chloride (1.35 ml, 17.49 mmol, 8 equiv.) was added drop wise to the mixture and stirring was continued at 25° C. for another 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc (2×40 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The resulting crude material was purified by column chromatography over normal silica gel (10% EtOAc in hexane) to give 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (320 mg, 54%) as yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1nc(COc2ccc(CO)cc2OC)c(C)o1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl (2E)-3-{4[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (11.94 g) in tetrahydrofuran (200 mL)-ethanol (20 mL) was gradually added sodium borohydride (650 mg) at 0° C. After stirring the reaction mixture for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals of ethyl (2E)-3-{4[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (11.0 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-97° C.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([SH:24])=[N:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II>>[CH2:1]([N:9]1[C:10](=[O:11])[C:12]2[C:13](=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)[S:24]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(NCCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1CCc1ccccc1
Yield: 71.5 %

Procedure:
Using the procedure of Example 20, 2.0 g (5.96 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid phenethyl-amide were treated with 1.66 g (6.56 mmol) of iodine to give 1.42 g of the title compound after recrystallization from isopropanol, mp 144°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:23])=[C:11]3[N:21]=[CH:20][N:19]([CH3:22])[C:12]3=[N:13][C:14]=2[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([F:24])[CH:3]=1.Br[C:26]#[N:27].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:27][C:26]1[O:16][C:15]([C:14]2[N:13]=[C:12]3[N:19]([CH3:22])[CH:20]=[N:21][C:11]3=[C:10]([F:23])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:24])=[N:17][N:18]=1
Reactant: N#CBr
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NN)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(-c3nnc(N)o3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3 -methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid hydrazide (1.00 equivalent) in 1,4-dioxane at room temperature is added BrCN (2.0 equivalents) followed by a solution of NaHCO3 (1.0 equivalents) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford [5-(5-amino-[1,3,4]oxadiazol-2-yl)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-(4-bromo-2-fluorophenyl)-amine.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][OH:30])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[N:27]=[CH:26][N:25]([CH2:28][CH2:29][O:30][S:39]([C:42]4[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=4)(=[O:41])=[O:40])[N:24]=3)[C@H:17]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O[C@H]1OCCN(Cc2ncn(CCO)n2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cnc(CN3CCO[C@H](O[C@H](C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The alcohol from step (a), above, (1.81 g, 3.22 mM) was dissolved in dichloromethane (20 ml), tosyl chloride (1.84 g, 9.66 mM) and triethylamine (1.34 ml, 9.66 mM) were added and the reaction stirred at room temperature for 18 hrs. The solvent was removed and the residue redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The product was purified on silica eluting with methanol-clichloromethane mixtures (1.87 g).