Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1CCC(N)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:21]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(NC(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([NH2:8])(=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-benzylpyrrolidine-3-amine represented by Formula 102 (180 mg, 1.02 mmol) was slowly added to a solution of 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (323.88 mg, 1.12 mmol) prepared in Preparative Example 1 as well as diisopropylamine (0.71 mL, 4.09 mmol) in DMF (7 mL) at room temperature. The reaction mixture was cooled to 0° C. and, after adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 388.29 mg, 1.02 mmol) thereto, the mixture was agitated at room temperature for 24 hours. After removing the reaction solvent under reduced pressure, chloroform (20 mL) was added to the remaining concentrate to form a solution, the solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. The organic layer was dried with sodium sulfate (Na2SO4) and the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 12 as a desired product (VVZ-013; 392.9 mg, 86% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[I:12]Cl>CO>[I:12][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: ClI
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Preparation B5, Step 1: To a solution of 4-(trifluoromethyl)benzenamine (10.0 g, 0.0617 mol) in dry methanol (200 ml) was added iodine monochloride (10.49 g, 0.148 mol) in dry MDC (40 ml) at RT slowly. Reaction mixture was stirred at RT over night. The reaction mixture was concentrated, water was added and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water, brine (2×50 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 6% ethyl acetate in pet-ether to get 2-iodo-4-(trifluoromethyl)benzenamine (12.5 g, 70%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 4.42 (bs, 2H), 6.75 (d, 1H), 7.38 (d, 1H), 7.87 (s, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][CH2:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[Cl:5][CH2:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: Nc1nnc(CCl)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(CCl)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-chloromethyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the desired product 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH:19]([N:18]([CH3:24])[CH3:17])[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)C1CCN(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 4-bromobenzoyl chloride (2.2 g, 10 mmol) and pyridine (1 mLl) in CH2Cl2 at 0° C. is added 3-(dimethylamino)pyrrolidine (1.14 mL, 10 mmol). The reaction is stirred at room temperature for 2 h, diluted with ether and filtered. The filtercake is washed with ether, treated with 0.1 N sodium hydroxide, stirred and filtered. This filtercake is washed with ether and recrystallized from petroleum ether to give 1-(4-bromobenzoyl)-3-dimethylaminopyrrolidine as a white powder (1.5 g), identified by NMR analysis.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=2)[N:5]=1)[CH3:3].ClC1C(C(Cl)C)=NC2C(N=1)=CC(F)=CC=2.CN(C)C=O.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>O>[Cl:14][C:13]1[C:4]([CH:2]([N:40]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:41])[CH3:3])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([F:15])=[CH:8][CH:7]=2
Reactant: CC(Br)c1nc2ccc(F)cc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(Cl)c1nc2ccc(F)cc2nc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1nc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of 2-(1-bromoethyl)-3-chloro-6-fluoroquinoxaline (57.17 g, 197.5 mmol) containing 3-chloro-2-(1-chloroethyl)-6-fluoroquinoxaline (48.39 g, 197.5 mmol) in N,N-dimethylformamide (700.0 ml, 197.5 mmol) was added potassium phthalimide (91.43 g, 493.6 mmol) at rt and the mixture was stirred at rt for 1 h. After 1 h, to the mixture was added water (2 L). The mixture was extracted with DCM (500 mL×3). The combined organic layers were washed with brine (1 L×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red liquid. The red liquid was filtered though a plug of silica (5.5 inch diameter×5 inch height), and eluented with 20% of EtOAc in hexane, then 30% of EtOAc in hexane, and then 100% of EtOAc as eluent to give two fractions. Second fraction, desired product 2-(1-(3-chloro-6-fluoroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (53.367 g, 75.97% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (dd, J=9.4, 5.9 Hz, 1H), 7.81-7.95 (m, 6H), 5.86 (q, J=6.8 Hz, 1H), 1.86 (d, J=7.0 Hz, 3H). Mass Spectrum (ESI) m/e=356.0 (M+1).
Reaction SMILES: [N:1]([C:4]1[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Cl:9])[N:8]=1)=[N+]=[N-].[CH3:40][P:41]([CH3:43])[CH3:42]>C1COCC1>[Cl:9][C:7]1[N:8]=[C:4]([N:1]=[P:41]([CH3:43])([CH3:42])[CH3:40])[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=2)[C:15]=1[F:31])=[O:11]
Reactant: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CP(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(N=P(C)(C)C)nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a 0° C. solution of 2-azido-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1.86 g, 3.05 mmol) in THF (25 ml) was added a 1M solution of trimethylphosphine in THF (6.10 ml, 6.10 mmol). Gas evolution occurred and the reaction mixture was stirred at RT for 1 h. The reaction mixture was evaporated and taken up in EtOAc and water. The organic phase was dried (Na2SO4), filtered and evaporated to provide the title compound (1.96 g, 97%) as an off-white foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]#[N:13].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:7]1[S:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[C:9]([CH2:10][CH2:11][C:12]#[N:13])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCCc1ccsc1CCCO
Solvent: CN(C)C=O
Product: N#CCCc1cc(Br)sc1CCCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.4 %

Procedure:
To a solution of 3-[2-(3-hydroxy-propyl)-thiophen-3-yl]-propionitrile 83 (0.18 g, 0.9 mmol) in DMF (2 mL) was added NBS (0.18 g, 0.99 mmol). The mixture was then stirred at room temperature for 6 hours and then concentrated in vacuo. A solution of the residue in CH2Cl2 (80 mL) was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 50% EtOAc in hexane) afforded 84 (0.08 g). 1H NMR (400 MHz, d6-DMSO) δ: 7.06 (s, 1H), 4.53 (t, J=6.0 Hz, 1H), 3.41 (dd, J=6.0 and 11.5 Hz, 2H), 2.75 (m, 6H), 1.67 (m, 2H). MS (EI) m/z [(M+H+) (79Br)] 274, [(M+H+) (81Br)] 276, [(M−OH+) (79Br)] 256 and [(M−OH+) (881Br)] 258.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Zr+3:4].[CH-:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[Li+].CCO[CH2:18][CH3:19]>>[Cl-:1].[Cl-:1].[CH3:5][C:6]1[C:18]([CH3:19])=[C:9]([CH3:10])[C:8]([Zr+2:4][CH:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6]2)([CH3:13])[CH:7]=1
Reactant: [Zr+3]
Reactant: CCOCC
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Cl-]
Agent: [Li+]
Product: CC1=CC(C)([Zr+2]C2C=Cc3ccccc32)C(C)=C1C
Reaction time: 17 h

Procedure:
To a manila-pink suspension of tetramethylcyclopentadienyl)zirconium trichloride, (Me4Cp)ZrCl3, (5.00 g, 15.7 mmol, 1.00 equiv.) in ether (100 mL) was added lithium indenide (1.91 g, 15.6 mmol, 1.00 equiv.). The reaction turned light, creamy yellow and became thick with precipitate. The mixture was stirred 17 hours and then evaporated in vacuo, leaving light yellow solid. The solid was extracted with dichloromethane (100 mL, then 3×10 mL) and the extracts were filtered to give beige solid and a yellow solution. The solution was evaporated in vacuo, leaving fluffy yellow solid. The solid was washed with pentane (2×20 mL) and dried in vacuo. Yield 5.88 g (94%). 1H NMR(CD2Cl2): δ 1.93 (s, 12H, Me), 5.86 (s, 1H, Cp-H), 6.36 (d, 2H, Ind-H), 6.67 (t, 1H, Ind-H), 7.25 (m, 2H, Ind-H), 7.61 (m, 2H, Ind-H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OC2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a mixture of 308 mg (purity: 98.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 823 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added diphenyl ether (2.76 g) and 328 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 295 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 58%) and 3.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: Br.Cl[C:3]1[N:8]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.Cl.[SH-:14].[Na+]>>[SH:14][C:3]1[N:8]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cn2c(Cl)cccc2n1
Reactant: [SH-]
Agent: Br
Agent: Cl
Agent: [Na+]
Product: Cc1cn2c(S)cccc2n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, 17.33 g (70 mmol) of 5-chloro-2-methylimidazo[1,2-a]pyridine hydrobromide was added to 70 ml of a sodium hydrosulfide solution at room temperature, followed by stirring at 90° C. for 24 hours. After the reaction mixture was cooled, concentrated hydrochloric acid was added until the reaction mixture's pH became 3-4. The resulting precipitate was collected by filtration, washed with water and dried to yield 12.32 g (quant, yellow powder) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH2:11])=[CH:7][C:6]=2[CH:12]=1.[NH2:13][C:14]1[N:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:13][C:14]1[N:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:12][C:6]=2[CH:7]=1)=[O:17]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2cc(Br)ccc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1ccc(C(=O)NCc2cc3cc(Br)ccc3o2)c(N)n1
Reaction time: 12 h
Yield: 40.6 %

Procedure:
To an N,N-dimethylformamide (10 mL) solution of C-(5-bromo-benzofuran-2-yl)-methylamine (455 mg, 2.01 mmol) described in Production Example 56-1-4 were added 2-amino-6-methoxymethyl-nicotinic acid (293 mg, 1.61 mmol) described in Production Example 4-1-5, triethylamine (700 μL, 5.03 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.41 mmol) at room temperature, which was stirred for 12 hours. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate, filtering and concentrating the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (255 mg, 33%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=2)[N:26]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][N:21]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=5)[N:26]=4)[CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4cc(F)ccc4n3)CC2)cc1F
Temperature: 100 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide (155 mg, 0.493 mmol, prepared according to Step 2 of Example 1), 2-chloro-6-fluoroquinoline (108 mg, 0.595 mmol, Combi-blocks), and DMSO (2 mL) was added potassium carbonate (240 mg, 1.737 mmol). The solution was stirred at 100° C. After 72 h, the reaction was allowed to cool to room temperature and diluted with water (50 mL). After stirring for 30 min, the solution was filtered and the filtered solid adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0-80% EtOAc in hexane, to provide a light yellow solid, which contained residual DMSO as measure by NMR. The solids were redissolved in diethyl ether and washed with water, brine, and concentrated in vacuo to give 2-fluoro-4-(3-(1-(6-fluoroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-N-methylbenzamide (90 mg, 0.196 mmol, 39.7% yield), as a light yellow solid. m/z=460 (M+1). 1H NMR (300 MHz, CDCl3) δ ppm 8.55 (d, J=2.48 Hz, 1H), 8.49 (d, J=2.48 Hz, 1H), 8.26 (t, J=8.04 Hz, 1H), 7.82 (d, J=9.21 Hz, 1H), 7.65 (dd, J=5.26, 9.06 Hz, 1H), 7.44 (dd, J=1.61, 8.04 Hz, 1H), 7.36 (dd, J=1.61, 12.42 Hz, 1H), 7.28-7.32 (m, 1H), 7.22 (dd, J=2.92, 8.92 Hz, 1H), 7.04 (d, J=9.21 Hz, 1H), 6.77 (br. s., 1H), 4.64 (d, J=13.45 Hz, 2H), 3.14-3.31 (m, 1H), 3.03-3.14 (m, 3H), 2.81-3.02 (m, 2H), 2.05-2.21 (m, 2H), 1.82 (d, J=11.69 Hz, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CO.C(OCC)C>O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)nc3n(C3CCCC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c21
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 62.5 %

Procedure:
Compound 274 (51 mg) was dissolved in 2 mL dioxane. Dioxane (1 mL) saturated at room temperature with HCl was added, followed by 1 mL methanol to aid solution. The reaction was stirred at room temperature for 80 min. The solution was then added dropwise to diethyl ether (8 mL) and the resulting precipitate was collected and dried in vacuo to give compound 271 as a yellow solid (26 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ 11.75 (br. s., 1 H) 9.36 (br. s., 2 H) 9.20 (s, 1 H) 8.53 (d, J=8.31 Hz, 1 H) 7.91-8.01 (m, 2 H) 7.49 (d, J=9.29 Hz, 1 H) 6.83 (d, J=8.56 Hz, 1 H) 5.37 (quin, J=8.56 Hz, 1 H) 3.35-3.43 (m, 5 H) 1.94-2.13 (m, 4 H) 1.64-1.79 (m, 2 H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]1[CH:13]=[CH:14][C:15]2[C:22](=[O:23])[CH:21]=[CH:20][C:18](=[O:19])[C:16]=2[CH:17]=1>>[CH:13]1[CH:12]=[CH:17][C:16]2[C:18](=[O:19])[CH:20]=[CH:21][C:22](=[O:23])[C:15]=2[CH:14]=1.[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:19])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C1C=CC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 180 °C

Procedure:
A reaction mixture gas containing 5.0 wt. parts of phthalic anhydride and 2.4 wt. parts of naphthoquinone which was formed by a catalytic vapor phase oxidation, was cooled to 180° C. by a gas cooler and was introduced into the mother liquor (pH of 1.9) to obtain an aqueous slurry of naphthoquinone and phthalic acid. The slurry (pH 1.7) was heated to 85° C. to dissolve all of phthalic acid. Naphthoquinone was extracted from the slurry of naphthoquinone in a counter-current extraction with 8.0 wt. parts of xylene. The xylene phase was washed with hot water and concentrated and dried at 70° C. under a vacuum of 60 Torr to obtain 2.4 wt. parts of naphthoquinone having a purity of 96.7%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](O)=[O:11].[N+:15]([C:18]1[CH:22]=[CH:21][NH:20][N:19]=1)([O-:17])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[OH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([N:20]1[CH:21]=[CH:22][C:18]([N+:15]([O-:17])=[O:16])=[N:19]1)=[O:11]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(O)CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)CC(=O)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 26.8 %

Procedure:
A solution containing N,N-dimethylformamide (0.22 mL, 2.85 mmol) and tetrahydrofuran (10 mL) was chilled to 0° C. under nitrogen. While stirring, oxalyl chloride (156 μL, 1.80 mmol) was added, gas evolution was observed followed by a white precipitate. The mixture was stirred at 0° C. for 5 min and at 25° C. for 15 min. The mixture was chilled to −5° C. and the 3-hydroxy-3-methyl-butyric acid (224 mg, 1.90 mmol) was added as a solution in tetrahydrofuran (3 mL) and the mixture was allowed to stir for 10 min. 3-Nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (78 mg, 1.95 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the mixture was added to the 3-hydroxy-3-methyl-butyric acid solution at −5° C. and continued to stir at 0° C. for 2 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-hydroxy-3-methyl-1-(3-nitro-pyrazol-1-yl)-butan-1-one (101 mg, 27%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 1.42 (6H, s), 3.41 (2H, s), 7.05 (1H, d, J=2.8 Hz), 8.34 (1H, d, J=2.8 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH:1]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: N#Cc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 15.9 %

Procedure:
A mixture of 5-formyl-2-hydroxy-3-nitrobenzonitrile (Intermediate 61) (150 mg, 0.78 mmol), 1,2-diphenylethanone (153 mg, 0.78 mmol), urea (141 mg, 2.34 mmol), conc. hydrochloric acid (0.5 mL) in ethanol (3 mL) was refluxed for 37 hours. The mixture was evaporated and purified by prep.-HPLC (0.1% TFA as additive) to give Compound 122 (51 mg, yield 16%). HNMR (DMSO-d6, 400 MHz): δ 8.77 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.25-7.21 (m, 5H), 7.01-6.98 (m, 3H), 6.82-6.79 (m, 2H), 5.31 (d, J=2.8 Hz, 1H), MS (ESI): m/z 413.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].Cl[C:21]([O:23][CH3:24])=[O:22].C([O:27]CC)C>C(OCC)(=O)C>[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19].[CH3:24][O:23][C:21](=[O:27])[O-:22]
Reactant: COC(=O)Cl
Reactant: CCOCC
Agent: Cc1ccc2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[O-]
Reaction time: 1 h

Procedure:
2.64 g (26 mmole) of triethylamine were added to a stirred solution of 3.16 g (20 mmole) of 2-methyl-1-naphthol in 25 mL of ethyl acetate, while the solution was maintained in an ice bath. Then 2.36 g (25 mmole) methyl chloroformate were added portionwise to the solution. The reaction mixture was stirred for one hour and then 100 mL diethylether was added. The reaction mixture was filtered over a Celite pad and the filtrate concentrated to give 3.65 g (85% yield) of an oil which was crystallized in hexane. The resulting crystals had a melting point of 54-55° C. The following 1HNMR was obtained: (300 MHz, DMSO-d6) δ2.30 (s, 3H), 3.89 (s, 3H), 7.44 (d, 1H, J=8 Hz), 7.48-7.58 (m, 2H), 7.78 (t, 2H, J=9 Hz), 7.95 (d, 1H, J=8 Hz). The mass spectrum showed a molecular ion at m/z 216.