Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)=[C:4]([C@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:25][C:26](=[CH2:28])[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]2)=[C:4]([C@H:10]([O:16][C:26]([CH3:28])([CH3:27])[CH3:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)[C@@H](O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: C=C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A stirred ice-cold yellow mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.45 g, 6.14 mmol) and 70% HClO4 (1.054 ml, 12.27 mmol) in CH2Cl2 (100 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). After 2 h, cold bath was removed and the turbid reaction mixture stirred for 22 h at rt. LCMS at this point showed 4:1 product to sm. So, saturated with isobutylene (5 min) at rt and stirred for additional 24 h. Then, neutralized with sat. Na2CO3 (30 mL), organic layer separated and aqueous layer extracted with CH2Cl2 (25 mL). The combined organic layers dried (MgSO4), filtered, concentrated and purified by flash chromatography using 5, 10, 15, 20 and 40% EtOAc/hex to afford (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (2.3074 g, 5.07 mmol, 83% yield) as yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.19 (br. s., 1H), 4.17-4.24 (m, 1H), 4.08-4.14 (m, 1H), 4.04 (dt, J=2.5, 12.1 Hz, 1H), 3.51 (dt, J=2.5, 12.1 Hz, 1H), 2.85-2.91 (m, 1H), 2.64 (s, 3H), 2.57-2.62 (m, 1H), 2.55 (s, 3H), 1.55-1.66 (m, 2H), 1.41-1.46 (m, 1H), 1.32-1.37 (m, 1H), 1.21 (s, 9H), 1.20 (t, J=7.2 Hz, 2H), 1.08 (s, 3H), 1.03 (s, 3H). LCMS (M+H)=457.4. And (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (0.3 g, 0.751 mmol, 12.24% yield) as pale yellow paste: LCMS (M+H)=401.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1.NC1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1N.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(I)cc23)cc1Cl
Reactant: OCCN1CCOCC1
Agent: [Cu]I
Agent: Nc1ccc2ccccc2c1-c1c(N)ccc2ccccc12
Agent: O=C([O-])[O-]
Solvent: O
Product: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(OCCN4CCOCC4)cc23)cc1Cl
Temperature: 110 °C

Procedure:
A 2.5 dram reaction vial was charged with N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (0.250 g, 0.524 mmol), 2-morpholinoethanol (1 ml, 8.17 mmol) as solvent, copper(I) iodide (0.020 g, 0.105 mmol), racemic-2,2′-diamino-1,1′-binaphthyl (0.030 g, 0.105 mmol), and cesium carbonate (0.513 g, 1.573 mmol). The reaction mixture was heated at 110° C. overnight. After cooling, water was added to the reaction mixture, and the resultant precipitate was collected by filtration. The solid residue was purified via ISCO (silica, 12 g column, 95% dichloromethane-5% methanol-0.1% NH4OH) to yield the desired compound as a brown solid. The solid was further washed with a mixture of water and saturated NaHCO3 solution and dried. The product off the column was further purified by prep TLC (silica gel, 1000 micron, 95% dichloromethane-5% methanol-0.1% NH4OH) to afford the desired product as a light brown solid (21.2 mg, 8%), LCMS m/z=480.0 (M+1) (Method C) (retention time=2.09 min). 1H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.47 (d, J=1.8 Hz, 1H), 8.66-8.57 (m, 2H), 8.21 (dd, J=6.8, 2.6 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.87 (ddd, J=8.9, 4.3, 2.7 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.57-7.47 (m, 3H), 4.25 (t, J=5.8 Hz, 2H), 3.64-3.55 (m, 4H), 2.78 (t, J=5.7 Hz, 2H), 2.55-2.49 (m, 4H).
Reaction SMILES: [C:1]1([C:13]([OH:15])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.S(Cl)(Cl)=O.[CH3:20][C:21]1[N:25]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:23][C:22]=1[CH2:45][NH:46]C.C(N(CC)CC)C>C(#N)C>[CH3:20][C:21]1[N:25]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=[N:23][C:22]=1[CH2:45][NH:46][C:13]([C:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1)=[O:15]
Reactant: CNCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(CNC(=O)c2cn3c4c(cccc24)CCC3)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h

Procedure:
1.2 g (6.0 mmol) of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid were mixed with 15 ml of thionyl chloride and boiled for 2.5 hours. The excess of thionyl chloride was distilled off in vacuo, and toluene was added. The mixture was evaporated in vacuo again, and the residue was dissolved in 20 ml of acetonitrile. A solution of 2.2 g (6.0 mmol) of 5-methyl-4-(methylamino)methyl-1-triphenylmethyl-1H-imidazole and 1.7 ml (12 mmol) of triethyl amine in 25 ml of acetonitrile was added, the mixture was boiled for 1 hour, and evaporated in vacuo. The residue was shaken with methylene chloride and 2 N NaOH. The organic layer was washed with water and evaporated in vacuo. The residue was chromatographed on silicagel using methylene chloride/methanol (95/5) as an eluent. After evaporating the desired fractions 2.0 g of N-methyl, N-[(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl]-5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline-1-carboxamide were obtained. This product was treated as described in Example I to remove the triphenylmethyl group, and purified. 0.46 g of the desired title compound were obtained.
Reaction SMILES: [CH2:1](B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:19]=[C:20]([C:33]2[N:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[N:34]=2)[C:21]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:22][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O.O1CCOCC1>[CH2:1]([C:18]1[CH:19]=[C:20]([C:33]2[N:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[N:34]=2)[C:21]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[N:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccccc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 62.8 %

Procedure:
A mixture of 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific Inc., 90 mg, 0.411 mmol), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 mg, 0.274 mmol), Pd2dba3 (12.54 mg, 0.014 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (X-Phos, 13.06 mg, 0.027 mmol) (Strem Co.) was purged with argon and then treated with dioxane (2.50 mL), water (0.25 mL) and sodium carbonate (72.6 mg, 0.685 mmol) and heated under a microwave irradiation at 140° C. for 30 min. The mixture was filtered through a short plug of Celite® (diatomaceous earth), washed with EtOAc (×3), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure hexanes to 30% EtOAc in hexanes) to give 4-(5-benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 62.8%) as a yellow syrup. m/z (ESI, +ve ion) 640.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCNc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCNc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, N-phenylethylenediamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[C:4]([O:27]CC2C=CC=CC=2)[N:3]=1>[Pd].C(O)C>[OH:27][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[C:6]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(OCc2ccccc2)nc(C)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(O)nc(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ethanol solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-{2,3-dimethyl-6-[(phenylmethyl)oxy]-4-pyridinyl}-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added palladium (10% w/w over carbon, 0.1 eq.). The resulting suspension was evacuated and purged with hydrogen. Under a balloon-filled hydrogen atmosphere, the reaction mixture was stirred at RT for 2 h. The reaction was then quenched with CH2Cl2, filtered through a bed of celite and the insolubles rinsed with EtOAc. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:14])[CH3:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][CH2:28][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:14])[CH3:13])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: NCCCN
Reactant: CC(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: CC(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
A mixture of 1-[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]ethanol (150 mg, 0.387 mmol) and propane-1,3-diamine (55 mg, 0.74 mmol) was heated with stirring in a sealed 0.5 mL of microwave process vial for 1.5 hours at 150° C. under microwave irradiation. The reaction mixture was purified by preparative HPLC and SPE to afford 70.2 mg of the desired product (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.05 (m, 2 H), 7.86-7.80 (d, J=7.6 Hz, 1 H), 7.78-7.75 (m, 2 H), 7.72-7.62 (t, J=1.2 Hz, 1 H), 7.60-7.50 (t, J=1.2 Hz, 1 H), 5.94 (s, 1 H), 5.30 (s, 2 H), 4.98-4.92 (m, 1 H), 4.58-4.45 (m, 2 H), 3.78-3.70 (t, J=2.8 Hz, 2 H), 3.62-3.53 (t, J=4.4 Hz, 2 H), 3.10-3.02 (t, J=6.8 Hz, 2 H), 2.12-2.02 (m, 2 H), 1.50-1.40 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][O:12]C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH:11]=[O:12])[C:6]=2[CH:10]=1
Reactant: COC(Cl)Cl
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=Cc1csc2ccc(Br)cc12
Reaction time: 1 h
Yield: 72.9 %

Procedure:
5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield 5-bromo-benzo[b]thiophene-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C1C=CN=CC=1)C.CC#N>[C:25]([NH:29][S:21]([C:19]1[CH:18]=[CH:17][C:8]2[N:9]([CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=2[CH:20]=1)(=[O:23])=[O:22])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CC(C)(C)N
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), tert-butylamine (32 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 40 mg (41% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.17 (s, 9 H), 1.49-1.64 (m, 4 H), 1.66 (s, 9 H), 2.29-2.44 (m, 1 H), 3.29-3.38 (m, 2 H), 3.87-3.97 (m, 2 H), 4.52 (d, J=7.62 Hz, 2 H), 7.97-8.05 (m, 2 H), 8.21 (dd, J=1.46, 0.68 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C21H33N3O3S+1.200 TFA+0.20 EtOAc+0.1H2O (563.83): C, 51.55; H, 6.44; N, 7.45. Found: C, 51.59; H, 6.28; N, 7.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(OCC)(=O)C.Cl>O1CCCC1.CO.[OH-].[Na+]>[C:29]([C:27]1[CH:26]=[CH:25][C:24]([O:33][CH3:34])=[C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:35]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:36])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)[CH:28]=1)([OH:31])=[O:30]
Reactant: COC(=O)c1ccc(OC)c(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(2-methoxy-5-methoxycarbonylphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-37, 50.5 mg, 0.103 mmol) was dissolved in mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and 4N aqueous sodium hydroxide solution (0.5 mL) was added thereto and stirred at room temperature overnight. Ethyl acetate (15 mL) and 0.25N aqueous HCl solution (20 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained materials were filtered with chloroform (3 mL) to give the titled compound (20.3 mg) as a pale yellow solid. (Yield 42%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3B3OC(C)(C)C(C)(C)O3)[S:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:33]3[O:34][C:35]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][C:37](=[O:39])[CH:38]=3)[S:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Sc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)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: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 100 °C
Yield: 127.4 %

Procedure:
[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthren-2-yl]-carbamic acid tert-butyl ester (8.34 g, 18.24 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (3)(4.72 g, 21.89 mmol) and grinded K2CO3 (5.04 g, 36.48 mmol) were dissolved in dry 1,4-dioxane (100 ml). The mixture was degassed for 15 minutess and Pd(PPh3)4 (1.02 g, 0.91 mmol) was then added The dark brown mixture was heated to 100° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The brown solid was filtered, washed with water, dried overnight in a vacuum desiccator and was used without any further purification to give the title compound (11.87 g). m/z (LC-MS, ESP), RT=4.61 min, (M++1)=511.2
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.FC(F)(F)C(O)=O.[C:75]1([CH:81]([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C@H:82]([C:84]([OH:86])=[O:85])[NH2:83])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.[BH4-].[Na+]>C(Cl)Cl.CO.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:83][C@@H:82]([C:84]([OH:86])=[O:85])[CH:81]([C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=3)[C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1
Reactant: N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
TBTU (0.018 g, 0.056 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.025 g, 0.046 mmol) and N-methylmorpholine (0.023 g, 0.231 mmol) in CH2Cl2 (5 ml) at 30° C. After 1.5 h, β-phenyl-D-phenylalanine trifluoro acetic acid salt (0.033 g, 0.092 mmol) was added. The mixture was stirred for 5 minutes. Water (1 ml) was added and the mixture was concentrated. MeOH (3 ml) and NaBH4 (0.017 g, 0.462 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml) followed by concentration of the mixture. Purification by preparative HPLC using an eluent of 0-45% CH3CN in 0.1M NH4OAc buffer and lyophilisation gave the title compound (0.021 g, 59%) as a colourless solid. M/z: 764.1 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.82-2.95 (m, 2H), 3.42-3.49 (m, 1H), 3.66-3.74 (m, 1H), 4.25-4.33 (m, 2H), 4.42 (d, 1H), 4.47 (d, 1H), 4.69-4.76 (m, 1H), 5.03-5.12 (m, 2H), 6.94-7.38 (m, 2H), 8.10-8.14 (m, 1H), 8.18-8.24 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:20]=[C:21]([NH2:22])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[N:5][CH:4]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1cccc(Br)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: [Na+]
Solvent: COCCOC
Product: COc1cncc(-c2cccc(N)c2)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
3-methoxypyridine-5-boronic acid pinacol ester (0.205 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-5% MeOH/CH2Cl2). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 58% yield.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.O.[C:21](O)(=O)[CH3:22]>>[NH2:1][C:4]1[C:5]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:9]=1[CH2:21][CH3:22]
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Solvent: O
Product: CCc1c(C(F)(F)F)cnc(NS(=O)(=O)CC)c1N
Temperature: 50 °C

Procedure:
3.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was suspended in a solvent mixture comprising 30 ml of water and 30 ml of acetic acid, and 2.2 g of reduced iron was added thereto. Then, the mixture was heated to 50° C. and reacted for one hour. After completion of the reaction, the reaction product was cooled to room temperature, and excess iron was separated by filtration. The filtrate was extracted with ethyl acetate. The extract layer was washed with water and dried. Ethyl acetate was distilled off under reduced pressure to obtain 2.5 g of N-(3-amino-5-trifluoromethylethyl-2-pyridyl)ethanesulfonamide.