Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH:20]1([CH2:23][O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]2[N:29]=[CH:30][C:31]([NH:34][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:32][CH:33]=2)[CH2:22][CH2:21]1
Reactant: CN(CCOCC1CC1)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Product: CN(CCOCC1CC1)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-cyclopropylmethoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C23H22BrF3N4O3 (m/e) 539, obsd 540 (M+H).
Reaction SMILES: [I-].[Na+].Cl[Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:8][C:9]1[N:17]=[C:16]2[N:11]([C:12]([O:19][CH3:20])=[N:13][CH:14]=[C:15]2[Cl:18])[N:10]=1.C(N(CC)CC)C>C(#N)C.C(OCC)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:8][C:9]1[N:17]=[C:16]2[N:11]([C:12]([O:19][CH3:20])=[N:13][CH:14]=[C:15]2[Cl:18])[N:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ncc(Cl)c2nc(N)nn12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ncc(Cl)c2nc(N[Si](C)(C)C)nn12
Reaction time: 0.17 h

Procedure:
A mixture of 12.7 g (85 mmol) of sodium iodide in 425 mL of dry acetonitrile was prepared under nitrogen in a predried 2 L flask and to this mixture 9.25 g (10.8 mL, 85 mmol) of chlorotrimethylsilane was added by means of a syringe at ambient temperature with stirring. After 10 min, 17.0 g (85 mmol) of 2-amino-8-chloro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine and 8.62 g (11.9 mL, 85 mmol) of triethylamine were added with stirring. The mixture was allowed to react for 12 hours at ambient temperature with stirring and was then diluted with 500 mL of dry diethyl ether. The salts that precipitated were removed by filtration on a dry scintered glass filter and the filtrate was concentrated by evaporation under reduced pressure. The residue was diluted with another 500 mL of dry diethyl ether the salt removal procedure was repeated. The title compound was obtained as the solid residue and amounted to 19.5 g (84 percent of theory).
Reaction SMILES: [Na].[S:2]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])(O)(=[O:4])=[O:3].S(Cl)([Cl:16])=O>CN(C)C=O.C(OCC)C.O>[CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:2]([Cl:16])(=[O:4])=[O:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccccc1S(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 38.2 %

Procedure:
To a solution of 2-sulfobenzaldehyde sodium salt (2.0 g, 9.6 mmol) in 0.8 mL of dry N,N-dimethylformamide was added thionyl chloride (7.0 mL, 96 mmol) under nitrogen at 0° C. After being stirred at 100° C. for 3 min, the reaction mixture was diluted with diethyl ether and water at 0° C., successively. The separated organic layer was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 2-formylbenzenesulfonyl chloride (0.75 g). To a solution of the above product, pyridine (0.57 mL, 7.0 mmol), and N,N-dimethylaminopyridine (21 mg, 0.17 mmol) in 3.5 mL of dry dichloromethane was added dimethylamine/ethanol solution (0.62 mL, 5.6 M, 3.5 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to obtain the title compound as a colorless oil (280 mg, 2 steps 14%).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([Cl:30])[CH:8]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:30][C:9]1[CH:8]=[C:7]([C:37]2[C:32]([CH3:31])=[CH:33][C:34]([O:47][CH2:48][C:49]3([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]3)=[N:35][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1Cl
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
N,N-dimethylformamide (3.3 mL) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (200 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-methyl)cyclobutanecarboxylate (164 mg) and palladium chloride (dppf) methylene chloride complex (18 mg), and after adding 2N aqueous sodium carbonate solution (0.66 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 3 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain ethyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}-cyclobutanecarboxylate (214 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[C:27]2[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=2)[C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)cc1Br
Reactant: CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(C(=O)OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1.21 g, 4.15 mmol) in dry dichloromethane (22.5 mL) was added dropwise oxalyl chloride (0.43 mL, 4.96 mmol) followed by N,N-dimethylformamide (1 mL). After being stirred for 2 h at room temperature, the reaction mixture was evaporated and the residue was dissolved in dry dichloromethane (20 mL) at room temperature under agron. After cooling to −5° C., ethylbenzene (0.46 g, 4.35 mmol) was added. Then AlCl3 (1.72 g, 12.8 mmol) was added portionwise and the reaction temperature was kept between −5° C. and 0° C. After being stirred at the same temperature for two hours, the reaction mixture was poured onto ice water and extracted with dichloromethane (100 mL). The combined organic layers were washed with 1 M HCl (60 mL), water (30 mL) and brine (60 mL), dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as a yellow solid. Yield: 1.37 g (87%). 1H NMR (CDCl3, 300 MHz): δ 7.89 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 3.98 (s, 3H), 2.70 (q, J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH:13]3[CH2:15][CH2:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccn(C3CC3)n2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-(4-bromophenyl)-1H-pyrazole (302 g, 1.35 mol), cyclopropylboronic acid (233 g, 2.71 mol), copper(II) acetate (246 g, 1.35 mol), 4-(dimethylamino)pyridine (662 g, 5.42 mol), cesium carbonate (1103 g, 3.39 mol), and 1,4-dioxane (8 L) was stirred at 90° C. for 36 h. The reaction mixture was cooled to room temperature before being filtered through Celite™, which was washed with EtOAc (4 L). The filtrate was acidified to pH 5 with 2 N HCl. The aqueous layer was extracted with EtOAc (12 L). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was purified on an ISCO 1500 g column eluting with a 0-20% EtOAc/Heptane gradient to afford the title compound. LC-MS: calculated for C12H11BrN2 262.01, 264.01, observed m/e: 263.04, 265.06 (M+H)+ (Rt 1.19/2 min).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[CH3:13])=[O:4].O[CH:15](C1C=CC(C(=O)C)=C(C)C=1)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:15])=[CH:7][C:6]=1[CH3:13])=[O:4]
Reactant: Cc1cc(CO)ccc1C(=O)CBr
Reactant: CC(=O)c1ccc(C(C)O)cc1C
Product: Cc1cc(C(C)O)ccc1C(=O)CBr
Yield: 82 %

Procedure:
2-Bromo-1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]ethanone is prepared following preparation 1b employing 1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]-ethanone instead of 1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=O)=O.[CH3:30][CH:31]([CH3:48])[CH2:32][C:33]#[C:34][Sn](CCCC)(CCCC)CCCC>>[CH2:21]([O:20][C:18]([NH:17][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[C:34]#[C:33][CH2:32][CH:31]([CH3:48])[CH3:30])[C:13]([O:15][CH3:16])=[O:14])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Reactant: CCCC[Sn](C#CCC(C)C)(CCCC)CCCC
Product: COC(=O)c1ccc(C#CCC(C)C)c(NC(=O)OCc2ccccc2)c1
Yield: 88.9 %

Procedure:
Methyl 3-benzyloxycarbonylamino-4-(4-methyl-1-pentynyl)benzoate (2.25 g) was prepared from 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (3.0 g) and (4-methyl-1-pentynyl)(tributyl)stannane (2.7 g) in a similar manner to that of Preparation 1 (2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>O1CCCC1>[CH2:43]([NH:45][C:46](=[O:47])[O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[C:5]([C:16]#[N:17])[CH:4]=[C:3]([NH:18][C:19]3[N:24]=[C:23]([NH:25][CH:35]4[CH2:37][CH2:36]4)[C:22]4=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]4[N:20]=3)[C:2]=2[Cl:1])[CH2:9]1)[CH3:44]
Reactant: CCN=C=O
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)OCC1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCO1
Temperature: 50 °C

Procedure:
To a vial was charged with 2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 1) (30 mg, 0.051 mmol) in tetrahydrofuran (256 μl) was added ethyl isocyanate (4.86 μl, 0.061 mmol). The vial was capped and heated at 50° C. over the weekend. Reaction temperature was raised to 70° C. for 6 h to get full conversion. Solvent was removed in vacuo and the crude residue was taken forward as is.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2OCC[O:14]2)=[O:9])[NH:5][C:6]=1[Br:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]=[O:14])=[O:9])[NH:5][C:6]=1[Br:7]
Reactant: O=C(NCCC1OCCO1)c1cc(Br)c(Br)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=CCCNC(=O)c1cc(Br)c(Br)[nH]1
Yield: 90.8 %

Procedure:
A mixture of 11 (5.0 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.84 mmol) in 80 mL of acetone/water (1:1) was refluxed for 12 h. After cooling, the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was recrystallized from acetone/CH2Cl2 to afford 12 (4.0 g, 91%) as a colorless solid: mp 160-163° C.; 1H NMR (CD3COCD3) d 2.73 (td, 2H, J=6.5, 1.5), 3.63 (q, 2H, J=6.5 ), 6.85 (d, 1H, J=2.9), 7.63 (br, 1H), 9.75 (t, 1H, J=1.5), 11.73 (br, 1H); 13C NMR (CD3COCD3) d 33.9 (e), 44.3 (e), 99.5 (e), 105.6 (e), 113.3 (o), 128.8 (e), 160.3 (e), 201.6 (o); IR (nujol) 3212, 1715, 1610, 1561 cm−1; MS, m/z (relative intensity) 327 (M++5, 50), 325 (M++3, 100), 323 (M++1, 50), 247 (25), 226 (22), 171 (20), 127 (19); Anal. Calcd for C8H8N2O2Br2: C, 29.66; H, 2.49; N, 8.65; Found: C, 29.49; H, 2.57; N, 8.53.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=2)[C:18](=[O:30])[NH:17][C:16]1=[O:31]>CN(C)C=O>[CH3:11][O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][CH:14]=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[CH:26]4)[CH:23]=3)[C:18](=[O:30])[NH:17][C:16]2=[O:31])[O:4][CH:5]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: COc1coc(CN)cc1=O
Solvent: CN(C)C=O
Product: COc1coc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyran-4-one (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.80 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a beige solid, 106 mg, (36%), mp 251-4° C. dec; MS (ES−): m/z 390.1 (M−H).
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([N:17]1[C@H:25]([C:26]([O:28]C)=[O:27])[CH2:24][C:19]2([S:23][CH2:22][CH2:21][S:20]2)[CH2:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].[OH-].[Na+]>>[OH:3][P:2]([CH2:14][C:15]([N:17]1[C@H:25]([C:26]([OH:28])=[O:27])[CH2:24][C:19]2([S:20][CH2:21][CH2:22][S:23]2)[CH2:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:1]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Yield: 94.5 %

Procedure:
(S)-7-[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, methyl ester (2.99 g) and 1 N sodium hydroxide (15 ml) is stirred for 30 minutes at room temperature. The reaction mixture is extracted with ether (50 ml) and the aqueous phase is acidified with concentrated hydrochloric acid to pH 1.0. A solid precipitates out of solution along with an oil. This is extracted into ethyl acetate, passed through sodium sulfate, and the solvent is stripped yielding 2.74 g of the title compound, melting point 105.5°-107° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1.CCN=C=NCCCN(C)C.Cl.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([N:50]([CH3:52])[CH3:51])[CH:48]=3)[N:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.CO.CCOC(C)=O>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.O>[ClH:1].[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[C:47]([N:50]([CH3:52])[CH3:51])[CH:48]=5)[N:43]=[CH:42][CH:41]=4)=[CH:37][CH:38]=3)=[O:16])=[CH:17][CH:18]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1
Reactant: Cc1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Reactant: CN(C)c1ccc2nccc(Nc3ccc(N)cc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Compound D2 (111 mg, 0.4 mmol), EDCl (155 mg, 0.72 mmol) and DMAP (174 mg, 1.44 mmol) in N-methyl pyrrolidinone (5 mL) was stirred 5 min at 20° C. N4-(4-Aminophenyl)-N6,N6-dimethyl-4,6-quinolinediamine (100 mg, 0.36 mmol) was then added and the reaction mixture was stirred at 20° C. for 20 h. The reaction mixture was diluted with water and stirred. The resulting precipitate was filtered washed with water and air dried. This solid was dissolved in hot MeOH, boiled with charcoal and filtered through a pad of celite. The filtrate was evaporated to dryness and the resulting residue was dissolved in MeOH (10 mL), 1.25 M HCl in MeOH (1 mL) was added and stirred 10 min. The solvent was evaporated and the residue was recrystallized from MeOH/EtOAc to give Cpd. HH (135 mg, 65%) as a yellow solid; m.p. (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 14.10 (br, 1H, N+H), 12.75 (br, 1H, N+H), 10.85 (br, 1H, NH), 10.45 (s, 1H, NH), 10.40 (s, 1H, NH), 8.27 (d, J=6.8 Hz, 1H, ArH), 8.08-7.99 (m, 6H, ArH), 7.88 (d, J=9.4 Hz, 1H, ArH), 7.65 (dd, J=9.4, 2.5 Hz, 1H, ArH), 7.54 (d, J=2.4 Hz, 1H, ArH), 7.45 (d, J=8.9 Hz, 2H, ArH), 6.67 (d, J=6.8 Hz, 1H, ArH), 6.27 (s, 1H, ArH), 3.12 [s, 6H, N(CH3)2], 2.32 (s, 3H, CH3); mass APCl+505.
Reaction SMILES: [CH2:1]([C:3]1[C:23]([N+:24]([O-])=O)=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2].C(O)(=O)C>C(O)C.O.[Zn]>[CH2:1]([C:3]1[C:23]([NH2:24])=[C:6]2[C:7]([O:21][CH3:22])=[CH:8][CH:9]=[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1N
Temperature: 60 °C

Procedure:
2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitropyrazolo[1,5-a]pyridine (185 mg) was dissolved in a mixture of ethanol (7 mL) and water (7.5 mL), and then acetic acid (0.3 mL) and zinc powder (185 mg) were added and the reaction mixture was heated at 60° C. for 20 minutes. The reaction mixture was filtered with celite, and the obtained filtrate was concentrated under reduced pressure. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine as a crude product.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9](Br)=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc(-c2ccc(-c3ccccc3)cc2)s1
Product: c1ccc(-c2ccc(-c3ncc(-c4ccccc4)s3)cc2)cc1
Yield: 97.7 %

Procedure:
The compound of the title was prepared in a similar way to example 3 from 2-(biphenyl-4-yl)-5-bromothiazole (311 mg, 0.98 mmol) and phenylboronic acid (955 mg, 1.27 mmol) for 4 h at 100° C. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 8:2) afforded 300 mg of 2-(biphenyl-4-yl)-5-phenylthiazole as a white solid (98% yield). EM (IE): m/z (%): 313; (M+, 100). HRMS (ESI): (M+H)+: calculated for C21H15NS: 314.0925. found: 314.0995.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]([CH2:26]O)[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29]C(Br)(Br)Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH:11]([CH2:26][Br:29])[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(NC(CO)CCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(CBr)CCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At −20° C. under N2 to the suspension of 3-2 (253 mg, 0.66 mmol) and TPP (260 mg, 1.5 equiv) in toluene is added tetrabromocarbon (242 mg, 1.1 equiv) and the reaction mixture stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the crude product purified by column chromatography eluted with hexane and EtOAc (2:1). The purified product, [1-Bromomethyl-4-phthalimido-butyl]-carbamic acid benzyl ester (3-3), is obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])[CH:38]=[CH2:39])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C=O)C>[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])/[CH:38]=[CH:39]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC(C)(C)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.4 g, 3 mmol) in DMF (20 mL) is added (1,1-dimethylallyl)-carbamic acid tert-butyl ester (560 mg, 3 mmol), triethylamine (0.7 mL, 5 mmol) and tert-di(mu-acetato) bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (25 mg). The mixture is stirred at 80° C. for 18 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound