Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][S:15]([C:13]2[S:14][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.23 g, 97%) as a white solid. MS (ISN) 331.0 [(M−H)−], mp 125° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:20][C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:41][CH2:42][CH2:43][CH2:44]O.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)(C)C.CCOC(C)=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:44][CH2:43][CH2:42][Br:41])[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Reactant: OCCCBr
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCBr
Yield: 21 %

Procedure:
A solution of 8-(6-Bromo-benzo[1,3]dioxol-5-ylsulfanyl)adenine (513 mg, 1.4 mmol), PPh3 (808 mg, 3.08 mmol), 3-bromo-1-propanol (253 mg, 165 L, 1.82 mmol), DBAD (1612 mg, 7 mmol) in toluene (43.8 mL) and CH2Cl2 (8.75, mL) was stirred at room temperature for 20 min. The reaction mixture was loaded to a silica gel column (CHCl3 then CHCl3:EtOAc:hexanes: i-Propanol at 4:4:2:1) to provide the 9N-alkylated compound, 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-bromo-propyl)adenine) (142.6 mg, 21% yield). A solution of this product (142.6 mg, 0.29 mmol) in 1,4-dioxane (12 mL) and i-propylamine (3 mL) was stirred at 100° C. for 2.5 h. The solvent was removed under vacuum and the crude purified by preparatory thin layer chromatography on silica gel (CHCl3:MeOH:NH4OH at 10:1:0.5 then EtOAc:CH2Cl2:MeOH at 2:2:1) to afford 12 (51 mg, 8% yield). 1H NMR (400 MHz, CDCl3) 8.30 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), 6.48 (bs, 2H), 5.94 (s, 2H), 4.29 (t, J=7.0 Hz, 2H), 2.74-2.68 (m, 1H), 2.57 (t, J=6.8 Hz, 2H), 2.02-1.95 (m, 2H), 1.02 (d, J=6.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) 154.8, 152.9, 151.5, 148.8, 148.0, 145.2, 123.8, 120.0, 116.7, 113.2, 112.2, 102.3, 48.6, 43.8, 41.7, 30.2, 22.8; MS m/z 465.0 (M+H)+. HPLC: (a) 99.1% (65% water-35% acetonitrile); (b) 98.0% (20% to 40% acetonitrile).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
A mixture of 0.044 g (0.0001 mole) of (rac)-4-(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-12), 0.045 g (0.00012 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 mL (0.0003 mole) of ethyldiisopropyl amine and 1 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.038 g of (rac)-4-(9-cyclopentyl-7-ethyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-13) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[S:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:16]=[N:15][CH:14]=[CH:13][C:18]=2[S:19][C:20]([CH3:26])([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)Sc1ccncc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Sc1ccncc1-c1ccc(C#N)cc1
Temperature: 150 °C
Yield: 70 %

Procedure:
To a mixture of 4-cyanophenylboronic acid (49 mg, 0.33 mmol) and Pd(dppf)Cl2 (9 mg, 5% mole) were added a solution of freshly purified ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate from (step B, 67 mg, 0.22 mmol) in THF (1 mL), acetonitrile (0.5 mL), and sodium carbonate (1M aqueous, 0.5 mL). The resulting mixture was degassed by nitrogen bubbling for 1 minute, and then heated to 150° C. for 30 minutes under microwave irradiation. The mixture was loaded on to a 5 g ISCO loading cartridge and eluded with a gradient of 0-100% ethyl acetate in hexane on a 12 g ISCO column to yield ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate (0.049 g, 70%).
Reaction SMILES: [C:1]([C:4](=[C:6]1[S:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[S:7]1)[Cl:5])(O)=[O:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O>C(OCC)C.C(OCC)(=O)C.Cl>[Cl:5][C:4](=[C:6]1[S:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[S:9]1)[CH:1]=[O:2]
Reactant: COC(=O)C1SC(=C(Cl)C(=O)O)S1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1SC(=C(Cl)C=O)S1

Procedure:
Methyl 2-(1-carboxy-1-chloromethylene)-1,3-dithietane-4-carboxylate (1.29 g) and oxalyl chloride (700 μl) are reacted together in ethyl ether in the presence of N,N-dimethylformamide (50 μl), and the reaction mixture is concentrated under reduced pressure. The resulting residue comprising methyl 2-(1-chlorocarbonyl-1-chloromethylene)-1,3-dithietane-4-carboxylate is dissolved in THF (70 ml) and reacted with lithium tri-t-butoxyalminum hydride (1.36 g) at -78° C. for 30 minutes. The reaction mixture is diluted with a mixture of ethyl acetate and dil. HCl, and the organic layer is separated after vigorous stirring. The separated organic layer is dried, vacuum concentrated, and purified by chromatography over silica gel to give methyl 2-(1-chloro-1-formylmethylene)-1,3-dithietane-4-carboxylate. Yield: 328 mg (27%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:14]1
Reactant: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCNC3)oc12
Yield: 25.1 %

Procedure:
A mixture of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (100 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (30 mL) was stirred at room temperature over 1 atm hydrogen for 2 hr. The mixture was evaporated under reduced pressure and purified by pre-HPLC to give 16 mg of 2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide as a solid. Yield 25%. 1H-NMR (400 MHz, DMSO-d6): δ 1.50-1.53 (m, 1H), 1.65-1.67 (m, 1H), 1.81-1.84 (m, 1H), 2.16-2.19 (m, 1H), 2.50-2.54 (m, 1H), 2.81-2.90 (m, 2H), 3.07-3.12 (m, 1H), 3.28-3.31 (m, 1H), 7.39-7.43 (t, J=8.0 Hz, 1H), 7.72-7.78 (m, 3H), 7.83-7.85 (m, 1H). LC-MS (ESI) m/z: 246 (M+1)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>C(O)(C)C>[C:22]1([C:9]2[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:4]3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(=O)CC3)nc2c1
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(Nc4ccccc4)CC3)nc2c1

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(4-oxopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (329.7 mg, 0.91 mmol, 1.00 equiv) in isopropanol (12 mL). Then aniline (255.2 mg, 2.74 mmol, 3.00 equiv) and acetic acid (221.8 mg, 3.70 mmol, 4.00 equiv) was added dropwise with stirring. The resulting solution was stirred for 1 h at 60° C. in an oil bath. To the above NaHB(OAc)3 (968.1 mg, 4.57 mmol, 4.57 equiv) was added at 0° C. The resulting solution was stirred for an additional 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers were combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (30:1). This resulted in 297.4 mg (74%) of methyl 2-phenyl-3-(4-(phenylamino)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2.[OH-].[Na+]>CO.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.26 mmol, 1.00 equiv, 95%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (55.7 mg, 1.39 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stirring. The resulting solution was stirred for overnight at 50° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was diluted with water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration and washed with methanol. This resulted in 68.1 mg (66%) of 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(N[C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17](OC)[C:16](OC)=[CH:15][C:14]=1[NH2:23])CC1C=CC=CC=1.NC1C=CC=CC=1C=C(C)C(O)=O.[CH:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[C:41]([OH:48])[CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:45]([C:44]1[CH:39]=[CH:40][C:41]([O:48][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:23])=[CH:42][CH:43]=1)([O-:47])=[O:46]
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(=Cc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=Cc1ccccc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 88.4 %

Procedure:
Into 20 ml of dichloromethane, 0.19 g (1.1 mmol) of (E) 3-(2-aminophenyl)-2-methyl-2-propenoic acid and 0.18 g of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 10 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. While the mixture was stirred under cooling with ice, 0.41 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The liquid was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Further, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 0.29 g of the aimed product was obtained as a crystal (yield: 91%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:16]#[N:17])[CH:8]([F:22])[CH2:7]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:16]#[N:17])[CH:8]([F:22])[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(Oc5cc(F)cc(C#N)c5)C(F)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 3-[(1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl)oxy]-5-fluorobenzonitrile (11 mg, 0.018 mmol) in DCM (0.5 mL) was added 0.5 ml TFA. The mixture was stirred for 1 hour and solvent was removed. The residue was dissolved in methanol (1 mL), and 0.2 ml EDA was added. After stirring for 2 hours, The reaction solution was diluted with methanol and purified by preparative-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) afforded product (5.4 mg, 62%). The product was synthesized from diastereomer 1 using same procedure in 61% yield LCMS (M+H)+: 489.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.[CH3:28][N:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([N:29]([CH3:30])[CH3:28])[CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cn[nH]c3)sc2n1
Reactant: CN(C)c1cccc(B(O)O)c1
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: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N(C)C)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 110 °C
Yield: 7.4 %

Procedure:
A mixture of N-[3-bromo-6-methyl-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Example 100) (100 mg, 0.207 mmol), 3-(N,N-dimethylamino)-phenylboronic acid (68.2 mg, 0.413 mmol) and tetrakis(triphenylphosphine)palladium(0) (11.9 mg, 10.34 μmol) and potassium carbonate (86 mg, 0.620 mmol) in 1,4-dioxane (1 mL), DMF (0.5 mL) and water (0.25 mL) was heated at 110° C. overnight (ca. 22 h). After cooling to RT, the reaction mixture was filtered through celite and the filtrate concentrated and purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM. The material was then passed through an SCX cartridge, eluting with MeOH (ca. 60 mL) and 2M NH3 in MeOH (60 mL), to give the title compound (8 mg). LCMS (A) m/z: 524 [M+1]+, Rt 1.28 min (acidic).
Reaction SMILES: [CH2:1]([C:3]([C:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>CO.CCOCC.O>[CH2:1]([C:3]([C:7]1[CH:11]=[CH:10][C:9](=[C:13]([CH3:15])[CH3:12])[CH:8]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCC(C)(CC)C1=CC=CC1
Solvent: CO
Solvent: C1CCNC1
Solvent: O
Product: CCC(C)(CC)C1=CC(=C(C)C)C=C1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 2.50 g (16.6 mmol) of (1-ethyl-1-methylpropyl)cyclopentadiene in 20 ml of methanol, 8.4 ml (114.4 mmol) of acetone and 2.8 ml (33.5 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.90 g (15.24 mmol) of a yellow liquid (yield: 92%). The analyzed values are given below.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:45]([Si:48]([CH:66]([CH3:68])[CH3:67])([CH:63]([CH3:65])[CH3:64])[O:49][C:50]1[CH:59]=[C:58]2[C:53]([CH:54]=[CH:55][CH:56]=[C:57]2[C:60](O)=[O:61])=[CH:52][CH:51]=1)([CH3:47])[CH3:46].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:60]([C:57]1[C:58]2[C:53](=[CH:52][CH:51]=[C:50]([O:49][Si:48]([CH:63]([CH3:65])[CH3:64])([CH:66]([CH3:68])[CH3:67])[CH:45]([CH3:46])[CH3:47])[CH:59]=2)[CH:54]=[CH:55][CH:56]=1)=[O:61])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)NCCNC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Reaction time: 4 h

Procedure:
To 2-(tert-butoxycarbonylamino)ethylamine (70 mg, 0.44 mmol) in dry THF (1 mL) under argon were added PYBOP (226 g, 0.43 mmol), 7-(triisopropylsilyloxy)-1-naphthoic acid, as described above in Step D, (148 mg, 0.43 mmol), and N,N-diisopropylethylamine (0.115 mL, 0.66 mmol). The reaction mixture was stirred for 4 hrs, then partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2 −10% to 15% EtOAc to yield the desired product as a white solid.
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[N:30][CH:29]=[C:28]2Cl.CN(C=O)C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[N:30][CH:29]=[CH:28]2
Reactant: Clc1cnnc2ccc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1ccc2nnccc2c1
Temperature: 80 °C
Yield: 31 %

Procedure:
To a stirred mixture of bis(pinacolato)diboron (6.4 g, 25 mmol), potassium acetate (6.8 g, 69 mmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(II)dichloromethane adduct (0.50 g, 0.69 mmol), and 6-bromo-4-chlorocinnoline (5.60 g, 23 mmol), was added DMF (50.00 mL, 646 mmol) and the overall mixture was heated at 80° C. overnight. After cooling and checking by LC-MS, the overall mixture was concentrated with silica and purified with ISCO (40 g, hexanes/EA, 1:0 to 1:1) to provide the title compound 6-bromocinnoline (1.48, 31%) as a yellow solid. LCMS (API-ES) m/z (%): 210.0 (100%, M++H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+].[P:29]([O-:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>CN(C=O)C>[CH2:31]([O:30][P:29]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)([O:33][CH2:34][CH3:35])=[O:36])[CH3:32]
Reactant: Brc1ccsc1
Reactant: CCOP([O-])OCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccsc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Under nitrogen, 0.0815 g (0.5 mmols) of 3-bromothiophene and 0.0231 g (0.02 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in DMF, to which 0.0829 g (0.6 mmols) of commercially available diethyl phosphite and 0.0776 g (0.6 mmols) of diisopropylethylamine were added at room temperature. Thereafter, the reaction mixture was heated to 110° C. and stirred for 4 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a yellow oil at a yield of 0.0782 g (yield: 71%).