Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:5][CH:4]=1.[C:42]1(=[O:48])[O:47][C:45](=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]2[N:13]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:14][CH:15]([O:17][C:42](=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(c2ccccc2)C2CC(OC(=O)CCC(=O)O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 25, Compound 94 (1.2 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.476 g, 0.64 mL, 4 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL) The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 96.
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2].[C:26]([O-:29])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH2:34]CBr>CS(C)=O>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:33][CH2:34][CH2:26][OH:29])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2]
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Reactant: O=C([O-])[O-]
Reactant: BrCCCBr
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCCO)c(OC)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
A mixture of 4-(2-ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.12 g, 0.35 mmol), DMSO (15 ml), Cs2CO3 (0.34 g, 1.0 mmol), and 1,3-dibromopropane was stirred at 100° C. for 2 h. The reaction mixture was poured out on NaHCO3 (aq) and extracted with CH2Cl2. The substance was chromatographed on furnishing the title compound (0.012 g, 9%).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[CH:9][C:10]=1[OH:11].C(OC(=O)C)(=O)C>O>[OH:11][C:10]1[CH:9]=[C:8]([CH3:12])[CH:7]=[CH:6][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C)cc1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a mixture of 40 ml of ethanol with 60 ml of water, there was added 20.0 g (16.3 mmol) of 6-amino-m-cresol, followed by heating to 80° C. To the obtained solution, there was added dropwise 17.4 g (17.1 mmol) of acetic anhydride over 10 minutes and the mixture was stirred at 80° C. for 15 minutes. After the completion of the reaction, the mixture was cooled to 10° C. The crystals thus precipitated were filtered, washed with water and dried. Thus 23.9 g (15.0 mmol) of N-(2-hydroxy-4-methylphenyl)acetamide was obtained as pale brown crystals. The yield was 89%. A 20.0 g portion of this product was recrystallized from acetonitrile to thereby give 17.9 g of N-(2-hydroxy-4-methylphenyl)acetamide as colorless crystals. The recovering yield was 90%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-:17])[O-:16].C[Mg+2].Cl.C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[CH:7]([C:15]([OH:17])=[O:16])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: CN1CC(=O)c2ccccc2S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: C[Mg+2]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To 6.34 g (0.03 mole) 3,4-dihydro-2-methyl-4-oxo-1,2-benzothiazine 1,1-dioxide, 19.5 g (0.15 mole) methylmagnesiumcarbonate in 150 ml N,N-dimethyl formamide were added. The mixture was stirred at 140°-150° C. for 2 hours. The resulting solution was poured quickly into a mixture of 200 ml conc-hydrochloric acid, 200 g ice chips and 500 ml diethyl ether. After stirring the mixture for 10 minutes, the diethylether layer was separated and the separated diethyl ether solution was evaporated in vacuo. The precipitated pale yellow crystals were filtered and recrystallized in dilute methanol solution to obtain 7.21 g of the title compound as white crystals. Yield: 94%
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15]O)=[CH:5][CH:4]=1.ClC(F)C(N(CC)CC)(F)[F:20]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15][F:20])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C2OC(=O)NC2CO)cc1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccc(C2OC(=O)NC2CF)cc1
Yield: 62 %

Procedure:
To a solution of 250 mg (1.0 mmole) of 5-(4-methylthiophenyl)-4-hydroxymethyl-oxazolidin-2-one in 30 ml of methylene chloride was added 0.21 ml (1.3 moles) of N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine. The reaction mixture was heated in a teflon bomb at 110° C for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed twice with water, dried and concentrated. Chromatography on silica gel afforded 150 mg (0.62 mmole), 62% of 5-(4-methylthiophenyl)-4-fluoromethyl-oxazolidin-2-one.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.O>[O:26]=[C:20]([NH:9][CH2:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
Triethylamine (36 mL, 262.1 mmol) was added to a solution of 2-aminoacetophenone hydrochloride (15.0 g, 87.39 mmol) in dry CH2Cl2 (300 mL), followed by ethyl chlorooxoacetate (10 mL, 87.39 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-30% EtOAc in petroleum ether) to afford ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, yield 66%). 1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1H), 8.02-8.00 (m, 2H), 7.68-7.64 (m, 1H), 7.55-7.51 (m, 2H), 4.85-4.84 (d, J=4.9 Hz, 2H), 4.44-4.39 (q, J=7.0 Hz, 2H), 1.44-1.41 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H13NO4: 235.08. found: 236.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 83188.9 %

Procedure:
To a stirred solution of ethyl(2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (15) (7.75 g, 0.0185 mmol) in THF (100 mL) and EtOH (100 mL) was slowly added 1 N NaOH (93 mL) solution at RT. The reaction mixture was heated to 70° C. and stirred at that temperature for 4.5 h. Reaction mixture was cooled to room temperature and then poured into 20% aqueous HCl (350 mL). The product was separated out as an off-white solid. The suspension was filtered and the filtered solid was dried to afford 6.01 g (83%) of compound 16 as an off-white solid. mp 219-220° C. 1H NMR (300 MHz, DMSO-d6): δ 0.89 (s, 6 H), 0.90 (s, 6 H), 1.27 (s, 2 H), 1.91 (s, 2 H), 1.94 (s, 2 H), 6.47 (d, J=15.9 Hz, 1 H), 6.68 (d, J=8.1 Hz, 2 H), 6.95 (d, J=8.4 Hz, 2 H), 7.16 (d, J=8.1 Hz, 2 H), 7.52 (d, J=15.9 Hz, 1 H), 7.60 (d, J=8.1 Hz, 2 H), 9.31 (s, 1 H), 12.35 (s, 1H). LRMS (ESI): m/z 389 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][S:6]1)=[O:4].[SH:10][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:19]([CH2:18][C:17]([NH:16][C@H:12]1[C@@H:11]([S:10][CH2:2][C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][S:6]2)=[O:4])[NH:14][C:13]1=[O:15])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCl)C1CCCS1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCS1
Yield: 72.6 %

Procedure:
(RS)-2-Chloroacetyltetrahydrothiophene (2.50 g), (3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-one (4.60 g) and potassium carbonate (2.52 g) in DMF (30 ml) were stirred at room temperature for 2.5 h. T.l.c. analysis (ethyl acetate) showed completion of the reaction. The reaction mixture was diluted with ethyl acetate, washed with water (3×), brine and then dried. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 80% ethyl acetate/hexane to give the title compound as a pale yellow solid (4.194 g, 73%); m.p. 123° C., ethyl acetate/hexane; (Found: C, 53.51; H, 5.00; N, 7.39; S, 17.06%. C17H20N2O4S2 requires C, 53.66; H, 5.30; N, 7.36; S, 16.85%); νmax (CH2Cl2) 3405, 1785 and 1695 cm-1 ; δH (CDCl3), 1.81-1.95 (1H, m), 2.01-2.12 (2H, m), 2.28-2.42 (1H, m), 2.88 (2H, t, J 6.5 Hz), 3.39 and 3.56 with 3.39 and 3.45 (2H, 2 ABq, J 5.9 Hz), 4.07 and 4.09 (1H, 2 t, J 3.8 and 3.7 Hz), 4.58 (2H, s), 5.00 and 5.04 (1H, 2d, J 4.6 Hz), 5.58 and 5.60 (1H, 2 dd's,J 4.6, 9.2 Hz), 6.55 and 6.64 (1H, 2 br s), 6.94-7.07 (3H, m), 7.27-7.36 (2H, m), and 7.46 and 7.47 (1H, 2 br d, J 9.2 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:9]([O:11][CH2:12][Cl:13])C>CC(C)=O.O>[Cl-:13].[CH3:9][O:11][CH2:12][N+:4]1([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCOCCl
Reactant: CCCN1CCCC1
Solvent: O
Solvent: CC(C)=O
Product: CCC[N+]1(COC)CCCC1
Product: [Cl-]
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A 36.33 g quantity of N-propylpyrrolidine was dissolved in 186 g of dehydrated acetone (up to 0.1% in water content), followed by replacement with nitrogen. To the solution was added dropwise 25.76 g of chloromethyl ethyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 1 hour. The mixture was stirred at 5° C. for 5 hours, whereby the reaction was terminated. The reaction mixture was filtered, washed with 100 g of acetone and dried in a vacuum, giving 58.10 g of a white solid product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Reactant: O=CCCC(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 3.11 g (12.0 mmol) 1-benzyl-4-piperidin-4-yl-piperazine and 7.50 mL (12.0 mmol, 15% in water) 4-oxo-butyric acid in 70 mL THF was adjusted to a pH of 5 with AcOH and stirred for 1 h at RT. After cooling to 0° C., 5.35 g (24.0 mmol) sodium triacetoxyborohydride were added batchwise and the reaction mixture was stirred overnight at RT. Within 15 min 80 mL of 30% K2CO3 solution were added dropwise, the aqueous phase was washed twice with EtOAc and evaporated down by half i. vac. 1 M KHSO4 solution was added, the precipitate formed was removed by suction filtering, the filtrate was washed with EtOAc and the aqueous phase was evaporated to dryness i. vac. The residue was taken up in 150 mL ethanolic HCl (1.25 M) and the reaction mixture was stirred overnight at RT. It was evaporated down i. vac., the residue was taken up in a little 15% K2CO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:29]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2O[C:37]([CH3:53])=[C:38]([CH2:40][CH2:41]OS(C3C=CC(C)=CC=3)(=O)=O)[N:39]=2)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].[OH-:66].[Na+]>C(O)C>[C:29]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:66][C:37]([CH3:53])=[C:38]([CH2:40][CH2:41][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)=[CH:18][CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:28])=[CH:12][CH:11]=3)[N:39]=2)[CH:30]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C3CCCCC3)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 29, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part P) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-cyclohexyl-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.96–7.93 (m, 1H), 7.64 (t, 3H, J=8.21 Hz), 7.50–7.43 (m, 3H), 7.37 (d, 1H, J=8.21 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.07 (d, 2H, J=8.60 Hz), 6.83 (dd, 4H, J=8.60 Hz, 5.47 Hz), 4.22 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.16 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 2.17 (s, 1H), 1.81 (d, 4H, J=9.78 Hz), 1.41 (s, 3H), 1.37–1.22 (m, 5H). MS (ES+) m/z mass calcd for C40H42NO5 616.31, found 616.3.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21]Br>O>[Br:19][CH2:20][CH2:21][N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.9 g of succinimide and 50 ml of N,N-dimethylformamide were put into a 200-ml three-necked flask equipped with a stirrer and a thermometer. 14 g of potassium carbonate was added to the mixture. The admixture was then stirred at room temperature for 30 minutes. 39.6 g of 1,2-dibromoethane was added to the admixture. The admixture was allowed to react at a temperature of 40° to 50° C. for 2 hours. The reaction mixture was poured into water. The aqueous mixture was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with hexane. The resulting crystal was filtered off and then air-dried. Yield: 16.7 g (81%); m.p. 55° to 56° C.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O-:12])=O.[Na+].Cl.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:10]([C:2]3[S:3][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=3)=[O:12])[CH2:33][CH2:34]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: O=C([O-])c1nc2ccncc2s1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Agent: [Na+]
Product: O=C(c1nc2ccncc2s1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of sodium thiazolo[5,4-c]pyridine-2-carboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:10][CH:5]1[C:3]([OH:2])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mmol of Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester were dissolved in 20 ml methylenchloride. 1.05 eq of DIPEA and mesylchloride were added. The reaction mixture was stirred at room temperature for 30 min. The product was extracted from etylacetate/water. The crude material was redissolved in methanol and treated with 2N NaOH. The reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized with HCl and the product isolated via extraction from ethylacetate/water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)cc(Cl)c1
Temperature: 35 °C
Yield: 97 %

Procedure:
147.2 g (0.86 mole) of 3-chloro-5-methylbenzoic acid previously prepared were suspended in 250 ml of methanol and warmed up to 35° C. with stirring. To the resulting suspension were added slowly 113 g (0.95 mole) of thionyl chloride keeping the temperature below 60° C. (cooling by ice bath). When addition was completed, the resulting mixture was refluxed for 1 hour, then stirred and cooled down to room temperature. The solvent was removed in the rotovap and the residue poured into water. The resulting aqueous suspension was extracted with ethyl ether (2×750 ml). The combined organic extracts were washed with 2% aqueous sodium hydroxide (3×150 ml), followed by water (1×200 ml), and then brine (1×200 ml), dried over anhydrous sodium sulfate and then concentrated in the rotavap to give the expected Methyl-3-chloro-5-methylbenzoate (154.6 g, 97% purity), used as such in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[CH:24]([N:27]([CH:30](C)C)[CH2:28]C)(C)C.ClC(Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.CNC>O1CCCC1.O.ClCCl>[CH3:24][N:27]([CH3:30])[C:28]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12]([N:9]2[CH2:10][CH2:11][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)=[O:13])[CH2:15][CH2:16]1)=[O:36]
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21
Temperature: 25 °C

Procedure:
0.25 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline, 8.1 ml of dichloromethane and 0.5 ml of diisopropylethylamine are placed in a 50 ml round-bottomed flask under a nitrogen atmosphere. 0.12 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for one and a half hours. 0.5 ml of diisopropylethylamine and 2.03 ml of a 2N solution of dimethylamine in tetrahydrofuran are subsequently added and the reaction mixture is stirred for eighteen hours. Water is added and then the aqueous phase is extracted three times with dichloromethane. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 90/10 mixture. 0.22 g of N,N-dimethyl-4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydroquinoxaline-1(2H)-carboxamide is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:33](F)(F)C(O)=O.[CH3:39][N:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[CH2:41][CH2:42][NH2:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:33][N:43]([CH2:42][CH2:41][N:40]([CH3:39])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:13][CH2:12]4)=[N:15][N:16]=3)[N:19]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CCN)c1ccccn1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCN(C)c1ccccn1)C(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02 mmol), N-methyl-N-pyridin-2-ylethane-1,2-diamine trifluoroacetate (6.1 mg, 0.037 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (13 mg, 0.029 mmol), and N,N-diisopropylethylamine (13 μL, 0.073 mmol) in methylene chloride (0.5 mL) was stirred at RT for 2 h. The solvent was evaporated. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=556.2.