Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[N:2]1([NH:1][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: C=C1CC(=O)O1
Reactant: NN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
18 ml (0.19 mol) of 4-Aminomorpholine were added dropwise to a solution of 15 g of diketene (0.18 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 26.1 g (0.14 mol, 78% yield) of a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:28])(=O)[CH2:2][CH3:3].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:30]([O:32][NH:33][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:28])[CH2:2][CH3:3])[CH3:31]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(OC(F)(F)C(F)F)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCONC(CC)=C1C(=O)CC(CCSc2ccc(OC(F)(F)C(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.21 Gram of 2-propionyl-5-[2-(4-α,α,β,β-tetrafluoroethoxyphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.06 g of ethoxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=5:1) to obtain 0.07 g of 2-(1-ethoxyaminopropylidene)-5-[2-(4-α,α,β,β-tetrafluoroethoxyphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:18][C:17]=2[CH:29]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([C:20]2[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:29][C:17]=3[S:18][C:19]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Cl)nc2)cc1
Reaction time: 16 h
Yield: 32.6 %

Procedure:
To a suspension of 2-Chloropyridine-5-carbonyl chloride (4.23 gm, 24 mmol) and 6-Methoxy-2-(4-methoxy-phenyl) -benzo[b]thiophene (5.0 gm, 18.5 mmol) in 275 mL of methylene chloride was added aluminum trichloride (18.59 g, 138.8 mmol) in three portions. The black-red reaction was stirred for 16 hrs. at room temperature. The reaction was then quenched with 400 mL of 2N NaOH (slowly and cooled in ice) and extracted into 300 mL of methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow solid which was chromatographed on silica gel using 5% to 20% Ethyl acetate/Hexanes as the gradient eluant to yield 2.47 gm of the title compound.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(C)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc(O)cc1
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a stirred solution of 38.1 (5.00 g, 17.1 mmol) in EtOH (100 mL) at room temperature was added PPTS. The resulting solution was stirred for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to give 38.2 (3.00 g, 84%) as a colorless oil. MS ESI (pos.) m/e: 226.1 (M+H2O)+.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][NH:2]1.[CH:13]([C:15]([CH3:17])=[O:16])=[CH2:14]>C(O)C>[O:16]=[C:15]([CH3:17])[CH2:13][CH2:14][N:3]1[NH:2][C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Reactant: C=CC(C)=O
Solvent: CCO
Product: CC(=O)CCn1[nH]c(=O)c2ccccc2c1=O

Procedure:
2,3-Dihydrophthalazine-1,4-dione (16.2 g; 0.1 mol) was suspended in 95 percent ethanol (200 ml). The suspension was heated to reflux and methyl vinyl ketone (8.4 g; 0.12 mol) was added to the refluxing suspension. With the ketone in the reaction mixture, the mixture was refluxed for 41 hours. The solid remaining after refluxing was filtered. The filtrate was concentrated to obtain the product which was crystallized from ethanol. The yield was determined to be 80 percent. The product had a melting point of 152°-153° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
Following the method of Example 6, (S)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid and N-chlorosuccinimide in carbon tetrachloride are reacted, yielding (S)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1.[C:20]([Cu])#[N:21].[C-]#N.[Na+]>OS(O)(=O)=O.O>[C:20]([C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1)#[N:21]
Reactant: N#C[Cu]
Reactant: CC(=O)N1CCc2ccc(N)cc2CC1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [C-]#N
Solvent: O
Product: CC(=O)N1CCc2ccc(C#N)cc2CC1
Temperature: 0 °C
Yield: 63.6 %

Procedure:
NaNO2 (0.53 g, 1.05 eq) was added portion wise to a solution of 1-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone (1.5 g, 1 eq) in 1.5 M H2SO4 (10 mL) maintained to 0° C. The obtained solution was added drop wise to a solution of CuCN (0.8 g, 1.23 eq) and NaCN (1.25 g, 3.42 eq) in H2O (5 ml), then the reaction mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic solution was washed with 5% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated to afford a crude material (1.5 g). Chromatography over silica gel (ethyl acetate/MeOH: 9/1) yielded the title compound as a pale orange solid (1.0 g, 63% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN1CC[O:18][CH2:17][CH2:16]1.C(Cl)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:17](=[O:18])[CH3:16])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(F)c2)n[nH]1
Reactant: CN1CCOCC1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1cc(-c2cccc(F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a solution of 3-(3-fluorophenyl)-1H-pyrazol-5-amine (6.5 g, 36 mmol) and N-methylmorpholine (9.7 mL, 88 mmol) in CH2Cl2 (150 mL) was added acetyl chloride (6 mL, 85 mmol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 d. The reaction mixture was concentrated in vacuo. MeOH (50 mL) and THF (50 mL) were added to the residue, followed by the addition of NaOH solution (aq. 2.5 M, 42.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 min and HCl solution was added until pH reached ˜6. The organic solvents were evaporated in vacuo. The solid from the resulting aqueous suspension was collected by filtration, yielding the title compound as a solid (7.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)[C:10]#[N:11].Cl[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[OH-].[Na+]>CS(C)=O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)#[N:11]
Reactant: CN1CCCC(CC(C#N)c2ccc(Cl)cc2Cl)C1
Reactant: ClCn1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCCC(CC(C#N)(Cn2cncn2)c2ccc(Cl)cc2Cl)C1

Procedure:
This compound (1.8 g.) was prepared using the procedure described in Example 9b except using 3.0 g. (0.010 mole) of 2-(2,4-dichlorophenyl)-3-(1-methylpiperidin-3-yl)propionitrile, 1.7 g. (0.011 mole) of 1-(chloromethyl)-1,2,4-triazole, 2.0 g. (0.025 mole) of 50% aqueous sodium hydroxide, and 30 ml. of DMSO yielding a white solid, melting point 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4C)ncc2Cl)c1
Yield: 43 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (55.06 mg, 43% yield) as a white solid. 1H-NMR (DMSO-d6) δ 9.39 (s, 1H), 9.02 (s, 1H), 8.37 (m, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.42 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.12 (s, 3H), 2.75 (d, J=4.2 Hz, 3H), 2.09 (br s, 2H), 2.09 (br s, 2H), 1.87 (br s, 2H), 1.13 (m, 6H). LC/MS (ESI+)=479 (M+H). 263-263.5° C.
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=CC=[CH:3][CH:2]=1.CC1(O)CC1>>[CH3:6][C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)Oc1ccccc1
Agent: CC1(O)CC1
Product: CC1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-methyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-methylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234) to obtain sulfamic acid 1-methyl-cyclopropyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][NH:30][CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of tert-butyl 1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (0.50 g) was added a solution of HCl in EtOAc (10 mL). The reaction mixture was continued to stir at room temperature for 2 h and filtered to afford the title compound as a solid (0.28 g, 64.00%), HPLC: 98.79%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 472.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.55-1.58 (m, 2H), 1.83-1.88 (m, 3H), 2.25 (t, J=5.7 Hz, 2H), 2.40-2.45 (m, 3H), 2.70-2.73 (m, 4H), 3.93 (s, 3H), 4.08 (t, J=5.4 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.60 (m, 1H), 7.91-7.95 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.O.CCCCCC>[F:13][C:14]1[C:19]([CH:20]([OH:23])[CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Fc1ccccn1
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cccnc1F
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of diisopropylamine (15.8 g) in tetrahydrofuran (100 mL) was added dropwise a 1.6 mol/L hexane solution (95 mL) of n-butyllithium at −78° C., and the mixture was stirred for 15 min. A solution of 2-fluoropyridine (11.6 g) in tetrahydrofuran (10 mL) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 30 min. To the obtained mixture was added a solution of propionaldehyde (11.2 mL) in tetrahydrofuran (10 mL) at the same temperature, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 12.4 g, 67%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[N:15]=[CH:16][C:17]([NH:20]C(=O)C)=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.Cl>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)Nc1cnc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3cnc(N)cn3)ccn2)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A solution of N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrazin-2-yl)acetamide (0.38 g, 1.22 mmol) in THF (10 mL) was treated with aqueous HCl (2 M, 6.12 mL, 12.24 mmol) and the solution was stirred at 60° C. for 4 h. The solvent was evaporated and the crude residue was diluted with water (40 mL), basified with solid NaHCO3, and extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to afford 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrazin-2-amine (0.32 g, 97%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.91 (d, J=1.4 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 6.44 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added MeI (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[H][H]>C(OCC)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: Nc1ccc2c(c1)C(=O)OC2=O
Temperature: 245 °C
Yield: 52.7 %

Procedure:
In 200 ml of dry ethyl ether, (C2H5)2O, was dissolved 1.93 g of 4-nitrophthalic anhydride (~1% solution) to which was added 0.10 g of 5% palladium-on-charcoal and the mixture hydrogenated in a Paar hydrogenator at 39 psi at room temperature, until no more hydrogen was consumed. The catalyst was removed by filtration and the ether removed from the filtrate, maintained at 0° to -5° C, under vacuo, yielding a yellow crystalline solid mixed with non-crystalline viscous mass. When a small sample of this mixture was placed on a metal plate heated to 245° C, the product melted and polymerized immediately to a tough polymer. Extraction of the crystalline-non-crystalline mixture with ether left 0.46 g of polymer; concentration of the ether followed by cooling, yielded 0.86 g of 4-aminophthalic anhydride.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([OH:21])=O)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.O[NH:46][C:47](=[NH:66])[C:48]1[C:58]2[O:57][CH2:56][CH2:55][N:54]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][C:52]=2[CH:51]=[CH:50][CH:49]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:21][N:46]=[C:47]([C:48]3[C:58]4[O:57][CH2:56][CH2:55][N:54]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][C:52]=4[CH:51]=[CH:50][CH:49]=3)[N:66]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 60 °C
Yield: 57 %

Procedure:
Triethylamine (0.281 ml, 2.02 mmol) was added to a stirred solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (may be prepared as described in WO9702244; 217 mg, 1.01 mmol) in N,N-dimethylformamide (20 ml) followed by hydroxybenzotriazole hydrate (185 mg, 1.21 mmol) then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (232 mg, 1.21 mmol) and lastly 1,1-dimethylethyl 9-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 65) (310 mg, 1.009 mmol). The reaction mixture was heated to 60° C. for 48 hours, then allowed to cool before diluting with ethyl acetate and washing with water. The organic phase was dried and evaporated. Purification of the residue by column chromatography, eluting with 15-25% ethyl acetate in cyclohexane to give the title compound as an amber coloured gum (280 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:26][OH:27])[N:13](C(OC(C)(C)C)=O)[CH2:14]2>ClCCl>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:26][OH:27])[NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(Br)c2C[C@@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@H]1Cc2c(Br)cccc2CN1
Reaction time: 0.5 h

Procedure:
Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.Cl.[NH2:14][C:15]([CH3:28])([CH3:27])[C:16](=[N:25][OH:26])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:14][C:15]([CH3:28])([CH3:27])[C:16](=[N:25][OH:26])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:7]=1
Reactant: CC(C)(N)C(COc1ccccc1)=NO
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(COc1ccccc1)=NO
Yield: 48.1 %

Procedure:
A mixture of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal = Cl) (1.53 g), 3-amino-1-(p-methoxy)phenoxy-3-methylbutan-2-one oxime hydrochloride (IV) (2.2 g) and dry triethylamine (1.70 g) in dry ethanol (20 ml) was refluxed for 2 hours. The mixture was cooled, water (50 ml) was added, and the resulting precipitate was filtered off and dried. Recrystallisation from a mixture of water and ethanol gave the nitropyrimidine oxime (II) (1.4 g, yield 48%) as pale yellow crystals, m.p. 242° (decomp.).