Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5](Cl)[C:3]=1[NH2:4].[N+](C1C=CC(N)=CC=1)([O-])=O.ClCl.Cl>O.[N+]([O-])(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: ClCl
Agent: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: O=[N+]([O-])O
Product: Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
A process for the preparation of 2,6-dichloro-4-nitroaniline by chlorination of 4-nitroaniline with chlorine bleaching liquor in water using acids, which comprises chlorinating 1 mole of 4-nitroaniline in 3-6 moles of hydrochloric acid (HCl) or nitric acid (HNO3) in the form of a dilute, aqueous acid in the presence of a dispersing agent which is stable under the reaction conditions, the chlorination initially being carried out at 5° to 10° C. and then at 15°-20° C. and, finally, after 90-95% of the 2-chloro-4-nitroaniline intermediately formed has been converted into 2,6-dichloro-4-nitroaniline, the temperature of the aqueous suspension being increased from 15°-20° C. to 70° C., without further addition of chlorine bleaching liquor, and then by post-chlorinating, by renewed addition of chlorine bleaching liquor, at temperatures between 20° and 70° C., bringing the pH of the aqueous suspension to 9.0 and filtering off the 2,6-dichloro-4-nitroaniline formed and washing it with dilute mineral acid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC.C(Cl)(=O)C([Cl:30])=O>CN(C=O)C.O.C(Cl)Cl.[Cu]I>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[C:3]([CH:7]=1)[C:4]([Cl:30])=[O:6]
Reactant: c1c[nH]nn1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. A solution of the acid (3.56 g, 17.52 mmol) in 150 mL of DCM was stirred and cooled to 0° C. The solution was treated with oxalyl chloride (1.9 mL, 21.9 mmol) and DMF (68 μL, 0.878 mmol). The solution was slowly warmed to room temperature and stirred overnight. Solvent was concentrated and the resulting solid was azetroped with DCM and concentrated to provide A-7 as a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][C:4]([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.CCO>O>[CH2:9]([O:8][C:6]([C:4]1([C:11]([OH:13])=[O:12])[CH2:3][C:2]([F:1])([F:16])[CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(F)(F)C1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 3,3-difluorocyclobutane-1,1-dicarboxylate (161) (2.8 g, 12 mmol) was dissolved in ice cooled ethanolic potassium hydroxide solution (0.5 M, 11 mL) and water (2.2 mL). The mixture was stirred at room temperature overnight. An additional 0.5 eq was added to the solution at room temperature and the mixture was stirred at room temperature overnight. Water was added and most of the EtOH was removed under reduced pressure. The mixture was acidified with 2M HCl and extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to yield 1-(ethoxycarbonyl)-3,3-difluorocyclobutanecarboxylic acid (162). 1H NMR (400 MHz, CD2Cl2) δ 4.33-4.24 (m, 2H), 3.26-3.13 (m, 4H), 1.34-1.27 (m, 3H). MS m/z 209.2 (M+1)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:16]([NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:23]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1[nH]c2cccc(OCC3CO3)c2[nH]1
Reactant: Oc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Solvent: CCO
Product: O=c1[nH]c2cccc(OCC(O)CN(Cc3ccccc3)C3CCCc4cc(O)ccc4C3)c2[nH]1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 4-oxiranylmethoxy-1,3-dihydro-2-benzimidazolone (82.5 mg) and N-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (107 mg) in ethanol (1.5 ml) was stirred under reflux for 13 hours, cooled to room temperature and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol)by silica gel (4.2 g) to afford 1-[N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-(1,3-dihydro-2-benzoimidazolon-4-yloxy)-2-propanol (123 mg) as a colorless powder.
Reaction SMILES: [Si:1]([O:18][CH:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)[CH3:20])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]1[C:34](=[O:35])[C@@H:33]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:32]1[CH2:47]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:1]([O:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:47][C@@H:32]2[C@H:33]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34](=[O:35])[N:31]2[CH2:30][C:29]2[CH:49]=[CH:50][C:51]([O:53][CH3:54])=[CH:52][C:28]=2[O:27][CH3:26])[N:22]=1)[CH3:20])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c[nH]nn1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(C(C)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 4-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1H-1,2,3-triazole (2.42 g, 6.88 mmol), benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (2.76 g, 6.88 mmol), and PPh3 (2.17 mg, 8.26 mmol) in THF (35 ml) at 0° C. was added DIAD (1.60 ml, 8.26 mmol) dropwise. The reaction was stirred at room temperature for 5 h then concentrated in vacuo. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 30-60%) afforded the title compound (4.32 g, 85%) as a solid. LCMS: Rt=1.12 min, m/z=734 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([N:7]([CH3:38])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=3)[CH:17]=2)[CH2:12][NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:39](N1C=CN=C1)([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40]>ClCCl>[CH2:1]([N:7]([CH3:38])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=3)[CH:17]=2)[CH2:12][N:11]1[C:39]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)n1ccnc1
Reaction time: 0.67 h
Yield: 99 %

Procedure:
Compound 127 (18.35 g) was dissolved in anhydrous dichloromethane (37 mL) under argon. 1,1′-Carbonyldiimidazole (2 eq.) was added at room temperature. The reaction mixture was stirred for 40 min. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and concentrated under vacuum. Compound 128 (19.39 g) was recovered as a pale yellow foam in 99% yield over two steps and in 98% purity (HPLC).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC#N.[O-]S([O-])(=O)=O.O=[V+2]>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: OCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=[V+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl sulfate (8.2 mg, 0.05 mmol) in 3 mL of anhydrous CH3CN was placed. To the above mixture, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH3CN (2 mL) was slowly added to the above bluish solution with residual suspended vanadyl sulfate, and the reaction mixture was stirred for 24 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 150.9 mg of 2-phenethyl acetate (92%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 3 of the following Table 1.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:36]3[CH2:38][CH2:37]3)[CH2:28][NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:17](=[O:39])[C@:16]([CH2:42][CH:43]([OH:46])CO)([CH2:40][CH3:41])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.CO>O.C1COCC1.[Na+].[Cl-]>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:18]([C@@H:27]([CH:36]3[CH2:38][CH2:37]3)[CH2:28][NH:29][S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[C:17](=[O:39])[C@@:16]([CH2:40][CH3:41])([CH2:42][CH:43]=[O:46])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Reaction time: 0.5 h
Yield: 116.3 %

Procedure:
Sodium periodate (89 mg, 0.418 mmol) was added to a clear solution of N-((2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide (Example 254, Step B, 85 mg, 0.14 mmol) in water (0.5 mL) and THF (1 mL). After several minutes, a solid formed. Methanol (1 ml) was added and the resulting emulsion was stirred for 30 min. The reaction was diluted with sat. aq. NaCl solution and extracted twice with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate and concentrated under the reduced pressure to provide the title compound (94 mg) which was used without purification in the next step. Mass Spectrum (ESI) m/z=577.0 (M+1)
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=O)[CH2:3][CH2:2]1.N[C:9]1N=C[CH:12]=[CH:11][N:10]=1.CC(C)=[O:17]>C1(C)C=CC=CC=1>[CH3:12][C:11]1[N:10]([CH3:9])[CH:4]=[CH:3][C:2](=[O:17])[C:1]=1[OH:7]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ncccn1
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(O)c(=O)ccn1C
Temperature: 85 °C
Yield: 32 %

Procedure:
Referring to FIG. 3, to 42.0 g (0.42 mol) of succinic anhydride (17) dissolved in 300 mL of toluene was added 20 g (0.21 mol) of 2-aminopyrimidine (21), (0.21 mol) dissolved in 200 mL of acetone, and the mixture was heated to 85° C. for 3 days. After cooling to r.t. (room temperature), the product precipitated and was filtrated and washed with toluene. The filtrate was dried in vacuo, and the dried product was then dissolved in 300 mL of anhydrous Ac2O and again heated to 85° C. for 3 hrs. After removal of the remaining Ac2O under vacuum, the product was purified by silica gel column chromatograph with CHCl3 and recrystallized from EtOAc to give HK-1 as a white solid, mp 148.5-149.5° C. in 32% yield. 1H NMR (CDCl3) δ 8.92 (d, J=4.88 Hz, 2H), 7.42 (t, J=4.88 Hz, 1H), 2.96 (s, 4H); Anal. Calcd for C8H7N3O2; C, 54.24; H, 3.98; N, 23.72. Found: C, 54.29; H, 4.19; N, 23.90.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[Cl:16][CH:17](Cl)C>>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:17][Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)Cl
Reactant: O=C(OCCO)c1ccccc1
Agent: C=O
Agent: Cl
Product: O=C(OCCOCCl)c1ccccc1
Reaction time: 3 h

Procedure:
A cold (0° C.) mixture of ethylene glycol monobenzoate (166 g) and paraformaldehyde (30 g) in dry dichloroethane was saturated with dry HCl with stirring for 3 hours. The pinkish red liquid was dried over calcium chloride and the volatile components removed on a rotary evaporator at 30° C. to give 1-benzoyloxy-2-chloromethoxyethane (215 g). The Infra-Red spectrum indicated the absence of a hydroxyl group.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][N:8]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:7]=1)=[O:5])C.[OH-].[Na+].CO>CO.O>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(CCN(C)C)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Yield: 63 %

Procedure:
A solution of 1-(2-Dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester, D22 (610 mg, 2 mmol) in methanol/water (15 ml/10 ml) was treated with 2N sodium hydroxide (4 ml). After stirring at room temperature for 16 h the methanol was removed in vacuo and the residue treated with 2N HCl (4 ml). The water was removed in vacuo. Dichloromethane was added to the residue and the inorganic solid was removed by filtration. Removal of the solvent form the filtrate in vacuo afforded the title compound as a white solid (350 mg, 63%).
Reaction SMILES: ClC(O[C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[O:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[S:24][C:20]=2[C:19]=1[C:33]#[N:34].C(N(CC)CC)C.[F:45][C:46]([F:55])([F:54])[C:47]1[N:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:19]1[C:20]2[S:24][C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])=[N:22][C:21]=2[CH:31]=[CH:32][C:18]=1[O:17][C:16]1[CH:35]=[CH:36][CH:37]=[C:14]([NH:13][C:6](=[O:12])[NH:53][C:50]2[CH:51]=[N:52][C:47]([C:46]([F:55])([F:45])[F:54])=[CH:48][CH:49]=2)[CH:15]=1)#[N:34]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)Nc3ccc(C(F)(F)F)nc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of bis(trichloromethyl)carbonate (59.3 mg, 0.200 mmol) in tetrahydrofuran (2 mL) were added N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (200 mg, 0.571 mmol) produced in Example 3(vi) and triethylamine (158 μL, 1.14 mmol) at 4° C., and the mixture was stirred at the same temperature for 30 min. 6-(Trifluoromethyl)pyridine-3-amine (185 mg, 1.14 mmol) was added to the reaction mixture, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→10/90), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (79 mg, 26%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: O=CCCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCC(O)c1ccccc1

Procedure:
By the general method described in Step 7 of Example 1, 6-(3-nitroquinolin-4-ylamino)hexanal (9.9 g, 34.5 mmol) was reacted with phenylmagnesium bromide (36.2 mL of a 1 M solution in THF, 36.2 mmol) to provide 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-ol (4.4 g) as a bright yellow solid after chromatography on silica gel (elution with ethyl acetate and hexane, 1:1, volume:volume).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2]2
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1
Yield: 92.7 %

Procedure:
A solution of 52.9 g of ethyl 4-chloro-6,7-difluoroquinoline-3-carboxylate in 750 cm3 of ethanol, in the presence of 19.7 g of triethylamine, was hydrogenated at atmospheric pressure, at a temperature in the region of 20° C., for 1 hour in the presence of 3 g of 5% palladium on carbon (type D). After removing the catalyst by filtration at high temperature, being concentrated to dryness under reduced pressure (5.2 kPa) at about 50° C., the residue was taken up, with stirring, in 1.2 liters of water, dewatered, and washed 3 times with 200 cm3 of water. It was dissolved in 1 liter of diethyl ether; the ethereal extracts were washed twice with 100 cm3 of water and were dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was recrystallized from 600 cm3 of diisopropyl ether. 42.8 g of ethyl 6,7-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 135° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]#[N:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC#N)c3=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.14 mmol) in dry DMF (1 ml) was added potassium carbonate (57 mg, 0.41 mmol) and bromoacetonitrile (29 μl, 0.41 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 35% EtOAc in cyclohexane) to give the title compound (45 mg, 60%). 1H NMR (500 MHz, CDCl3): 8.43 (1H, s), 7.26-7.19 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.72 (2H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCCC1=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a 0° C. solution of 1-(3-aminopropyl)-2-pyrrolidinone (25.0 g; 176 mmol) and triethylamine (26.7 g; 264 mmol) in CH2Cl2 (500 mL) was added benzyl chloroformate (33.1 g; 194 mmol) dropwise over a period of 15 minutes. The mixture was stirred for 1.5 hr. at 0° C. and then for 15 hr. at ambient temperature, before the mixture was diluted with CH2Cl2 and extracted with 5% aqueous HCl (200 mL), H2O (200 mL), and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure, then the oil which resulted was flash chromatographed (SiO2 ; 2-5% MeOH/Ch2Cl2) to give the title compound as a colorless oil (42.7 g; 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][CH3:25])[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CSc1ccccc1C1CCNCC1
Product: CCN1C(=O)c2ccccc2C1C(CCN1CCC(c2ccccc2SC)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 106.8 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.724 g) was coupled to 4-(2-methylthiophenyl)piperidine (0.414 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the hydrochloride salt to afford the title compound (0.63 g); mp 110-140° C. (d); MS: m/z=553(M+1); NMR (CDCl3): 1.19 (m,3), 2.0 (m,2), 2.45 (s,3), 2.68 (m,7), 3.16 (m,3), 3.56 (m,4), 4.18 (m,1), 4.86 (d,1, J=3.7), 6.56-7.79 (m,11). Analysis for C31H34Cl2N2OS.HCl: Calculated: C, 63.1; H, 5.97, N, 4.75; Found: C, 62.94; H, 5.94; N, 4.82.