Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 45.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzothiazole (76.0 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=4:1→2:1→1:1) and PTLC (DCM/EtOAc=95:5) to afford desired product (24.8 mg, 45.2%) as pale yellow solid. 1HNMR (CDCl3) 500 MHz δ: 8.23 (dd, J=7.7, 1.4 Hz, 1H), 8.06-8.01 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.53-7.38 (m, 5H), 7.36-7.29 (m, 2H), 7.17 (td, J=7.4, 1.1 Hz, 1H), 6.99-6.96 (m, 1H), 6.93-6.85 (m, 1H), 6.62 (dd, J=8.0, 4.6 Hz, 1H), 6.49-6.45 (m, 1H), 5.20 (br s, 1H), 2.69-2.26 (m, 4H), 2.21-2.09 (m, 1H), 1.97-1.85 (m, 1H), 1.41 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]#[CH:25])[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N+:27]=[N-:28].CN(C=O)C.O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+]>ClCCl.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]5[N:28]=[N:27][N:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH:25]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2cn(-c3ccccc3)nn2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reaction time: 2 h
Yield: 48.2 %

Procedure:
A solution of 2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Example 9A, 20 mgs, 0.056 mmol) and azidobenzene (Example 9B, 19 mgs, 0.159 mmol) in DMF (4 mL, 51.7 mmol) was treated at r.t. and under a nitrogen atmosphere with sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (8 mgs, 0.040 mmol) and copper(II) sulfate pentahydrate (5 mgs, 0.020 mmol). The mixture was stirred for 2 hours (reaction followed by HPLC) and was then diluted with dichloromethane (60 mL) and washed with sat. NaHCO3, brine and dried (MgSO4). The solvent was evaporated and the solid residue was triturated with acetonitrile (2×1 mL) and lyophilized to give the title material (13 mgs, 0.027 mmol, 49% yield). LC (Method A): 2.213 min. HRMS (ESI) calcd for C23H19N6O4S [M+H]+ m/z 475.1183, found 475.1204. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.04 (s, 1H), 8.37 (s, 1H), 7.90-7.99 (m, 2H), 7.58-7.67 (m, 2H), 7.51 (tt, J=7.4, 1.2 Hz, 1H), 6.97-7.03 (m, 1H), 6.83-6.88 (m, 1H), 6.71 (d, J=1.6 Hz, 1H), 5.38 (s, 3H), 4.20 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)O.[S-:17][C:18]#[N:19].[Na+].C1OCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:18]([NH2:19])=[S:17]
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(N)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
11.3 g of methyl 3-aminobenzoate are initially introduced into the reaction vessel as a solution in 75 ml of chlorobenzene, 2.07 ml of concentrated sulfuric acid (96%) are added dropwise at -5 to 0° C. in the course of 15 minutes, stirring is continued for 5 minutes, 6.8 g of sodium thiocyanate are then introduced in portions at a maximum of 0° C. and the mixture is stirred for a further 15 minutes. 0.2 ml of 15-crown-5 is then added, the mixture is stirred at a bath temperature of 10° C. for 10 hours and cooled and the precipitate formed is filtered off and washed 3 times with water. 13.5 g (85.9%) of the title compound of melting point 171°-172° C. result
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)nc1
Yield: 86.3 %

Procedure:
The solution of 4-(5-nitro-pyridin-2-yl)-morpholine (1.5 g, 7.18 mmol) in ethyl acetate (20 mL) in the presence of 10% palladium on carbon (0.75 g) was shaken under the hydrogen with a pressure of 50 psi at room temperature for 3 hr. After the reaction, the reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layer was collected, concentrated, and dried to give 6-morpholin-4-yl-pyridin-3-ylamine (1.11 g, crude) as a light red solid, which was directly used in the next step reaction without further purification. LCMS calcd for C9H14N3O (m/e) 179, obsd 180 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.C(O)(C)C.[OH-].[OH-].[Pd+2]>[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ncnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1csc2cncnc12
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A mixture of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine (2 g), palladium hydroxide on carbon (20%, 1 g) and sodium acetate (2 g) in a mixture of ethyl acetate and isopropanol (5/1, 30 mL) was shaken in a Parr apparatus under hydrogen atmosphere (50 PSI) overnight. The resulting mixture was filtered on a CELITE™ pad, the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone/DCM, 3/97) to afford 1 g of 7-methyl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[F:34][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][NH:9]4)=[CH:4][CH:3]=3)=[O:22])=[C:19]([CH3:18])[N:27]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1nc(-c2cccc(F)c2)ccc1C(=O)O
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Product: Cc1nc(-c2cccc(F)c2)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (48 mg, 0.20 mmol) and 2-methyl-6-(3-fluorophenyl)-nicotinic acid (D25) (50 mg, 0.22 mmol) as an off-white solid. MS(ES): MH+ 362, M-H+ 360.
Reaction SMILES: C[Mg]Br.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)#[CH:5].CON(C)[C:19]([C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1)=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:26][N:25]1[C:21]([C:19](=[O:20])[C:5]#[C:4][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=2)=[CH:22][CH:23]=[N:24]1
Reactant: CON(C)C(=O)c1ccnn1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)C#Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methyl magnesium bromide (9.70 mL, 1.0 M tetrahydrofuran solution) was added dropwise to a tetrahydrofuran (4.0 mL) solution of 1-ethynyl-4-(trifluoromethyl)benzene (1.80 mL) under cooling in an ice bath, and the obtained solution was then stirred for 2 hours. Thereafter, the reaction solution was cooled to −78° C., and a tetrahydrofuran (6.2 mL) solution of N-methoxy-N,1-dimethyl-1H-pyrazol-5-carboxamide (867 mg) was then added thereto. The obtained mixture was stirred for 1 hour, and was then stirred for 2.5 hours under cooling in an ice bath. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=9:1), so as to obtain the title compound (1.09 g) in the form of a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:16]C)[C:8](=O)[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[S:4]1.Cl.[Na]>>[CH3:10][C:6]1[N:7]=[C:8]([C:3]([O:2][CH3:1])=[O:16])[S:4][C:5]=1[C:11]1[S:12][CH:13]=[CH:14][N:15]=1
Reactant: COC1(OC)SC(c2nccs2)=C(C)NC1=O
Agent: Cl
Agent: [Na]
Product: COC(=O)c1nc(C)c(-c2nccs2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
A mixture of 2,2-dimethoxy-5-methyl-6-(2-thiazolyl)-2H-1,4-thiazin-3-(4H)-one (80 mg) and 2N hydrochloric acid solution (2 ml) was stirred at room temperature for 6 hours. Then the mixture was neutralized with saturated sodium bicarbonated aqueous solution and the resulting precipitates were collected to give methyl 4-methyl-5-(2-thiazolyl)-thiazole-2-carboxylate (58 mg, yield 82.2%) as colorless powder.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:33]=[CH:32][S:31][C:17]=5[N:18]=[C:19]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([O:26]C)=[O:25])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1.[OH-].[Na+]>C1COCC1.CO>[CH2:3]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:33]=[CH:32][S:31][C:17]=5[N:18]=[C:19]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Reaction time: 15 h
Yield: 15 %

Procedure:
To a stirred solution of methyl 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (70 mg, 0.15 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (2 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 15 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The precipitate was filtered, the cake was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (10 mg, 15%). 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.41 (s, 1H), 9.00 (s, 1H), 8.66 (d, 1H, J=8.1 Hz), 8.12-8.10 (m, 1H), 7.70 (t, 1H, J=7.9 Hz), 7.45 (s, 1H), 7.24-7.18 (m, 2H), 6.23 (d, 1H, J=7.5 Hz), 4.75 (s, 4H), 4.03 (s, 4H). LC-MS: 446 [M+H]+, tR=1.59 min. HPLC: 97.95% at 214 nm, 100% at 254 nm, tR=7.31 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl.O.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:27]([C:26]([F:31])([F:30])[C:25]([F:33])([F:32])[F:24])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (100 mg, 0.40 mmol) in pentafluoropropanoic acid (5 ml) was added hydrogen chloride (conc) (1 ml). The resulting solution was stirred overnight at 100° C. and then poured into water (50 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat). The resulting solution was extracted with ethyl acetate (3×30 ml), combined and dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 8% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-chlorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (60.8 mg, 40%).
Reaction SMILES: [C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:26]C(=O)C)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)CC.[ClH:34]>O>[ClH:34].[NH2:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:16]2[S:13]([NH:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:15])=[O:14]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Temperature: 25 °C

Procedure:
N-[5-[[[(1-naphthalenyl)methyl]amino]sulfonyl]-1-naphthalenyl]acetamide (226 mg, 0.56 mmol) was suspended in a mixed solution of 1-propanol (8 ml), concentrated hydrochloric acid (1 ml) and water (1 ml), and the mixture was refluxed for 1 hour. The crystal precipitated by cooling of the reaction mixture to room temperature was filtered and washed with the mixed solvent of 1-propanol/diisopropyl ether under reflux to give the title compound an a white crystal (201 mg, 90.8%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][CH2:15][C:16]1[S:24][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C.O>[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:14]([CH3:13])[CH2:15][C:16]2[S:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cc2cnccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2cnccc2s1)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
EDC hydrochloride (118 mg, 0.62 mmol) was added to a solution of methyl-thieno[3,2-c]pyridine-2-ylmethyl-amine (100 mg, 0.56 mmol), (E)-3-(6-amino-pyridin-3-yl)acrylic acid (101 mg, 0.62 mmol), HOBt H2O (83 mg, 0.62 mmol) and triethylamine (235 μL, 1.68 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature overnight then diluted with H2O (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow residue which was subjected to flash chromatography on silica gel (10% MeOH: CH2Cl2) to yield the title compound (61.0%). 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 7.76-7.67 (m, 3H), 7.32 (d, J=15.0 Hz, 1H), 6.76 (d, J=15.2 Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 4.95 (s, 2H), 4.76 (br s, 2H), 3.22 (s, 3H); MS (ES) m/e 325.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([N:6]([CH3:8])[CH3:7])=[C:4]([Cl:12])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[Si]([CH2:59][C:60]#[N:61])(C)C.O>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[F-].[Zn+2].[F-].C(OCC)(=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH2:59][C:60]#[N:61])[CH:10]=[C:9]([Cl:11])[C:5]=1[N:6]([CH3:8])[CH3:7]
Reactant: CN(C)c1c(Cl)cc(Br)cc1Cl
Reactant: C[Si](C)(C)CC#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1c(Cl)cc(CC#N)cc1Cl
Temperature: 90 °C

Procedure:
In a glass tube with screw-on lid, 2 g (7.43 mmol) of 4-bromo-2,6-dichloro-N,N-dimethylaniline (known from European Journal of Organic Chemistry (2006), (19), 4398-4404) are initially charged with 86 mg (0.14 mmol) of xantphos and 136 mg (0.14 mmol) of tris(dibenzylideneacetone)-dipalladium in 10 ml of DMF. 1.01 g (8.92 mmol) of trimethylsilylacetonitrile and 0.46 g (4.46 mmol) of zinc fluoride are then added, and in the closed vessel the reaction is heated at 90° C. for 16 hours. The reaction mixture is cooled, water and ethyl acetate are added and the mixture is filtered through silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:14][OH:15]>N1C=CC=CC=1.CCO.C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[N:14][OH:15]
Reactant: NO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O)c(C=NO)c1
Temperature: 20 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
To a solution of 2-hydroxy-5-nitrobenzaldehyde (2.10 g, 12.6 mmol) in pyridine (31.0 mL) and EtOH (5.0 mL) was added hydroxylamine hydrochloride (1.75 g, 25.2 mmol). After stirring at 20° C. for 10 h, the mixture was diluted with CH2Cl2 (125 mL) and washed with water (4×70 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and evaporated. The residue was triturated with EtOH and filtered. The resulting solid was rinsed with ether and dried under vacuum to obtain the title compound (1.86 g, 81% yield) as a yellowish solid: MS (electrospray, +ions) m/z 183 (M+H).
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[NH2:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][CH:37]=1)[O:10][CH2:11][C@@H:12]([O:31][C:32](=[O:34])[CH3:33])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1>C(Cl)Cl.N1C=CC=CC=1>[C:32]([O:31][C@@H:12]([CH2:13][N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:18][CH2:19]1)[CH2:11][O:10][C:9]1[CH:35]=[CH:36][CH:37]=[C:7]([N:6]=[S:1](=[O:3])=[O:2])[CH:8]=1)(=[O:34])[CH3:33]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc(N)c3)OC(C)=O)CC2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@@H](COc3cccc(N=S(=O)=O)c3)OC(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
A suitable sulfonyl chloride is added (1.2 mM) to a solution of (S)-1-(3-aminophenoxy)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)propane (1 mM) in CH2Cl2 (1.2 ml) and pyridine (0.5 ml). The mixture is shaken at room temperature up to the completion of the reaction. It is then diluted with CH2Cl2, and washed with saturated aqueous solution of Na2CO3 and then with water. The organic phase is dried with anhydrous Na2SO4, filtered and the solvent is distilled under vacuum. (S)-2-acetoxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]-1-(3-sulfonylaminophenoxy)propane is obtained.
Reaction SMILES: C(Cl)Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:25][OH:26])[CH:16]=1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH:25]=[O:26])[CH:16]=1
Reactant: OCc1cc(Br)c2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cc(Br)c2ccccc2c1
Temperature: -45 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Under a nitrogen atmosphere, an oxalyl chloride methylene chloride solution (2.0 M, 4.88 ml) was diluted with methylene chloride (40 ml), and dimethyl sulfoxide (0.9 ml, 12.7 mmol) was added dropwise thereto at −78° C. To this solution, a solution of (4-bromonaphthalene-2-yl)-methanol (1.15 g, 4.88 mmol) as synthesized according to a document [J. Med. Chem., 37, 2485 (1993)] in methylene chloride (10 ml) was added dropwise over 10 minutes. This reaction mixture was stirred at −78° C. for 15 minutes and −45° C. for one hour, and then triethylamine (4.0 ml, 29.3 mmol) was added dropwise thereto and stirred at 0° C. for 30 minutes. To the reaction solution, a saturated ammonium chloride aqueous solution was added and the resulting solution was extracted with methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (890 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20]CC)=O)[CH:3]=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C:18]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=1)=[O:20]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1
Reactant: CN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(O)cc(C(=O)NC)n1
Reaction time: 72 h

Procedure:
A solution of ethyl 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxylate (0.40 g) and methylamine in industrial methylated spirit (33%, 15 ml) in ethanol (15 ml) was stirred at ambient temperature for 6 hours and then allowed to stand for 3 days. The reaction mixture was evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol to yield the title compound, 0.26 g, m.p. 165°-6° C.