Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1
Reactant: O=c1c2c(Cc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (273 mg, 0.69 mmol, prepared in Example 25) in DMF (14 ml) and methanol (14 ml) was added activated carbon-palladium (27 mg), the mixture was stirred under hydrogen atmosphere overnight, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(3-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (220 mg, 87%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]([C@@H:11]1[CH2:15][O:14][C:13](=[O:16])[N:12]1[C:17]1[CH:18]=[C:19]([CH:23]2[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=3)[NH:24]2)[CH:20]=[CH:21][CH:22]=1)([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH:8]([C@@H:11]1[CH2:15][O:14][C:13](=[O:16])[N:12]1[C:17]1[CH:18]=[C:19]([CH:23]2[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:36])[CH:29]=3)[NH:24]2)[CH:20]=[CH:21][CH:22]=1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (290 mg, 7.3 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (703 mg, 7.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (300 mg, 0.74 mmol) and 1,1′-carbonyldiimidazole (300 mg, 1.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (71 mg, 20%) as a white solid: LC/MS m/e calcd for C25H31N3O5S (M+H)+: 486.61, observed: 486.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[NH:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][O:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[N:34]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:17]4[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]4[CH2:24][OH:25])[N:3]=3)[CH:27]([CH2:33][CH2:32]1)[CH2:28][O:29][CH2:30]2
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 130 °C

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37 g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL) and heated in a microwave reactor for 20 minutes at 130° C. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)=[O:5])[CH3:2].[CH3:17][S:18]([NH:21][C:22]1[CH:37]=[CH:36][C:25]2[NH:26][C:27]([CH2:32][C:33](O)=[O:34])=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)(=[O:20])=[O:19].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:33](=[O:34])[CH2:32][C:27]1[NH:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][C:24]=2[S:29](=[O:30])(=[O:31])[N:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of cis-2-(2-cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester (42.7 mg, 0.189 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 94.8 mg, 0.284 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.9 mg, 0.378 mmol), and 4-dimethylaminopyridine (5.8 mg, 0.047 mmol). After stirring at 25° C. for 14 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, cis-2-{(2-cyclopropylethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C23H32N4O7S2 540.17, found 541.4 [M+H+].
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)[CH:27]=[C:28](O)[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)[CH:27]=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
Trifluoromethanesulphonic anhydride (93 μL, 0.57 mmol) was added dropwise to a stirred solution of 2-(4′-chloro-5-hydroxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) (150 mg, 0.38 mmol) and pyridine (88 μL, 1.1 mmol) in DCM (3 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h, then 1M hydrochloric acid was added. The organic layer was filtered through a polytetrafluoroethylene (PTFE) frit and concentrated in vacuo to give the title compound (205 mg, 100%) as an orange oil.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][C:6]([NH2:8])=[O:7].[P:9]([O:18][CH2:19][CH2:20][Cl:21])([O:14][CH2:15][CH2:16][Cl:17])[O:10]CCCl>>[NH:5]([CH:1]([P:9](=[O:10])([O:14][CH2:15][CH2:16][Cl:17])[O:18][CH2:19][CH2:20][Cl:21])[CH2:2][CH3:3])[C:6]([NH2:8])=[O:7]
Reactant: NC(N)=O
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CCC=O
Product: CCC(NC(N)=O)P(=O)(OCCCl)OCCCl

Procedure:
Freshly distilled propionaldehyde, 58.0g (1.0 mole), is added dropwise in 1 hr to a stirred mixture of 60.0g (1.0 mole) of powdered urea and 269.5g (1.0 mole) of crude tris (2-chloroethyl) phosphite at 105°-112° C. Heat of reaction keeps the temperature at this level without external warming during most of the aldehyde addition. The reaction mixture is warmed for 0.25 hr more, and then it is stripped to 122°/2mm, giving a viscous, yellow residue, crude bis(2-chloroethyl) 1-ureidopropylphosphonate. This is dissolved in 100ml of acetonitrile and 36g (2.0 moles) of water, and the solution is warmed at reflux for 1 hr. A solid forms during warming and is separated by filtration of the warm reaction mixture; and then it is stirred and warmed in more acetonitrile and water, and the mixture is filtered while warm to give 76.2g (42%) of white solid, mp 185°-186° dec. A 5.0-g portion is recrystallized from acetic acid-water to give 3.2g: mp 189°-191° dec; 31P nmr (CD3SOCD3) -23.0 ppm(m); 1H nmr δ 8.5 (broad, 4, OH and NH2), 6.2 (broad, 1, NH), 3.7 (broad, 1, CH), 1.6 and 0.9 (broad, 5, CH2CH3); acidity 2.01 equiv/mole, pK1 2.70, pK2 7.30.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:10]C=O)[CH:6]=[CH:7][CH:8]=1.[C:25]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27][CH2:28][CH3:29])=[O:26].[CH3:50]O>>[CH2:28]([O:27][C:25](=[O:26])/[CH:30]=[CH:50]\[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=1)[CH3:29].[CH2:28]([O:27][C:25](=[O:26])/[CH:30]=[CH:50]/[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=1)[CH3:29]
Reactant: O=CC=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: CO
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)/C=C\C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 3,3-bis[3-(trifluoromethyl)phenyl]-2-propenal (18.5 g) and (carbethoxymethylene)triphenylphosphorane (19.15 g) in methanol (100 mL) was stirred at room temperature for 1 hour. The usual work up furnished a mixture of isomeric esters that was separated by HPLC (hexane-dichloromethane; 2:1) to give 2.8 g of the less polar (Z)-5,5-bis[3-(trifluoromethyl) phenyl]-2,4-pentadienoic acid ethyl ester and 16.8 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid ethyl ester. A portion of the (E)-isomer (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid ethyl ester was crystallized from hexane to provide the analytical sample, mp 53°-55° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Se](=O)=[O:14].O1CCOCC1>O.CN(C)C=O>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH:2]=[O:14]
Reactant: O=[Se]=O
Reactant: CC(=O)c1cc2ccccc2o1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1cc2ccccc2o1
Yield: 60.1 %

Procedure:
A mixture of 2-acetylbenzofuran (100 g) and selenium dioxide (69.3 g) was dissolved in water (20 ml) and dioxan (500 ml) and heated under reflux for 24 h. The reaction mixture was filtered and the solvent evaporated to give a dark-red solid which was taken up in dimethylformamide and heated on a steam bath for 8 h. The solution was filtered, the solvent evaporated and the residue triturated with ether to give the title compound (65.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]2[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]=1[OH:22].C(N(CC)CC)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:13]([N:11]1[CH2:10][CH2:9][NH:8][C@H:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([O:22][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:4]=2)[CH2:12]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of (2R)-2-(4-chloro-3-hydroxybenzyl)-4-benzylpiperazine (3.78 g) and triethylamine (5.71 ml) in dichloromethane was added 4-dimethylaminopyridine (0.29 g) and tert-butyldimethylsilyl chloride (5.30 g) successively with ice bath cooling under nitrogen atmosphere. After stirring overnight at room temperature, water (50 ml) was added to the mixture and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and methanol (10:1) as eluent to give (2R)-4-benzyl-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]piperazine (4.11 g) as an oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]2[C:27]3[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[C:25](=O)[O:24]C2=O)=[CH:19][CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:22]([CH2:21][C:20]2[CH:35]=[CH:36][C:17]([F:16])=[CH:18][CH:19]=2)[C:27]2[C:26]([C:25]=1[OH:24])=[CH:31][C:30]([CH3:32])=[CH:29][CH:28]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Reactant: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 90 °C
Yield: 71.8 %

Procedure:
Neat diethyl malonate (3.04 mL, 20 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min and cooled to room temperature. A solution of Compound 13 (6.3 g, 22 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered, washed several times by water, and dried at room temperature under vacuum to yield 5.1 g (71%) of white solids. M.P. 130° C. 1H NMR (DMSO-d6): δ 1.31 (t, J=7.0 Hz, 3H), 2.34 (s, 3H), 4.37 (q, J=7.5 Hz, 2H), 5.94 (s, 2H), 7.09-7.32 (m, 5H), 7.45 (dd, J=1.6, 8.7 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H). EIMS m/z 356 (M+1), 378 (M+23). Anal. (C20H18FNO4) C, H, N.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(O)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]([O:10][C:6](=[O:5])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a suspension of N,N-dimethyl-formamide-di-tert-butyl acetal (25 ml, 104.4 mmol) in dry toluene (90 ml) was added p-chlorophenyl acetic acid (5.94 g, 34.8 mmol) and the whole heated at 80° C. for 1 h. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml), 3% aqueous NaHCO3 solution (50 ml) and brine (20 ml) and then dried over MgSO4 and evaporated to give an oil. This oil was purified using 35%, then 50% DCM in pentane to give the title product (2.4 g, 30%); 1HNMR (400 MHz, CDCl3) δ: 1.42 (s, 9H), 3.44 (s, 2H), 7.20 (d, 2H), 7.28 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:10]2([CH3:12])[CH3:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1=Nc2ccccc2C1(C)C
Agent: O=S(=O)(O)O
Product: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Yield: 74 %

Procedure:
5-nitro-2,3,3-trimethylindole (1) was synthesized according to a modified literature procedure (see, Noland, W. E., et al., J. Org. Chem. 3457-3469, 1965). To a solution of 2,3,3-trimethylindole (10.6 g) in concentrated sulfuric acid cooled to 0° C. using an ice/brine bath was added dropwise fuming nitric acid (5.6 mL). The resultant solution was stirred at 0° C. for 1.5 hours; then poured into crushed ice; filtered; and washed with water. The combined filtrate was neutralized to a pH greater than 7. The product precipitated from the neutralized solution and was collected by filtration, washed with water, and dried to provide the desired product 1 (10.1 g, 74% yield): ESI-MS, calculated [M+H]+ 205.1, found 205.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=[N:3]1.[H-].[Na+].[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:1][N:2]1[C:10]([CH2:11][C:20]([O:19][CH3:18])=[O:21])=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=[N:3]1
Reactant: COC(=O)OC
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Product: COC(=O)Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Temperature: 25 °C

Procedure:
To a stirred solution of Step 5 intermediate (3.8 g, 18.24 mmol) in dimethylcarbonate (91 ml) was added sodium hydride (60% dispersion in mineral oil, 4.5 g, 187.5 mmol) at room temperature. The reaction mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature, quenched into 1N HCl (200 ml), extracted with ethyl acetate (2×250 ml) and the combined organic layers were washed with water (2×250 ml), dried over Na2SO4 and concentrated. The residue obtained was triturated in hexane, solid obtained was filtered to give 5.5 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.37 (s, 3H), 3.50 (s, 3H), 3.82 (s, 5H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[OH-].[Na+].Cl>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Reaction time: 1 h
Yield: 9792.4 %

Procedure:
A solution of 10 g (47,3 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 200 ml 0,5N sodium hydroxide was ice-cooled, and then 30 ml (0,36 mmol) ethyl chloroformate was added. Stirring was continued at 0° C. for 1 h and at 25° C. for 1 h. To the reaction mixture was added IN hydrochloric acid to pH 2-3, and the precipitated product was filtered off and washed with water to give 12 g of a crude product. Recrystallization (dimethylsulfoxide-0,5N hydrochloric acid) gave 10 g (75%) 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline, m.p.>300° C. NMR (DMSO-d 6):11.9 (2H, broad s), 8.9 (lH, broad s), 7.37 (lH,s), 7.17 (lH,s), 4.1 (2H,q), 1.28 (3H,t).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8].O.Cl>CCOCC.C(N(CC)CC)C>[Cl:9][C:3]1([F:8])[C:2]([Cl:1])=[CH:5][C:4]1([F:7])[F:6]
Reactant: FC1(F)CC(Cl)(Cl)C1(F)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: FC1(F)C=C(Cl)C1(F)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1,1,2 trichloro-2,3,3-trifluorocyclobutane (55.5 g) in 100 ml of anhydrous ether, triethylamine (40 ml) was added dropwise over 30 min at room temperature, and the mixture was stirred overnight at ambient temperature. The mixture was then stirred with 120 ml H2O and 7.5 ml of concentrated HCl. The ether layer was washed with H2O (100 ml), brine (100 ml), dried over anhydrous MgSO4, and evaporated in vacuo. The residue was distilled fractionally at atmospheric pressure from 64°-68° C. to yield 36 g (79%) of a colorless liquid as pure product.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:4]=1[NH2:5].[CH3:15][CH2:16][N:17]([CH:21](C)C)[CH:18](C)C.BrCC(Cl)=[O:27].CNC>C1COCC1.CCOC(C)=O>[CH3:18][N:17]([CH3:21])[CH2:16][C:15]([NH:5][C:4]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([O:10][CH3:11])=[CH:9][C:3]=1[CH3:2])=[O:27]
Reactant: COc1cc(C)c(N)cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CBr
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 104.9 %

Procedure:
A mixture of 2-methyl-4-(methyloxy)-5-nitroaniline HCl salt (500 mg, 2.287 mmol) and Hunig's Base (1.198 ml, 6.86 mmol) was stirred in THF (20 ml). Bromoacetyl chloride (0.211 ml, 2.52 mmol) was added and the reaction let stir at rt for 40 min. LCMS analysis indicated complete conversion to the acyl bromide so a 2M solution of dimethylamine in THF (4.6 ml, 9.15 mmol) was added and let stir at rt overnight. The reaction was diluted with EtOAc and washed with a saturated brine solution. Aqueous layers were re-extracted with EtOAc. Organics were combined and dried over sodium sulfate and filtered. Solvents were removed under reduced pressure to afford N2,N2-dimethyl-N1-[2-methyl-4-(methyloxy)-5-nitrophenyl]glycinamide (0.642 mg, 2.4 mmol). ESIMS (M+H)+=268.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16](C)[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[S:35][C:34]=2[CH:42]=1.O>C(#N)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([S:38]([C:36]4[S:35][C:34]5[CH:42]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=5[CH:37]=4)(=[O:40])=[O:39])[CH2:16][C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: C[C@@H]1NCCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1ccc2c(Cl)ccnc2c1
Yield: 67.9 %

Procedure:
1-(4-chloroquinolin-7-ylmethyl)-3-(S)-methylpiperazin-2-one hydrochloride (0.49 g, 1.4 mmol), EXAMPLE 89, is treated with acetonitrile (20 mL), triethyl amine (1.2 ml, 8.4 mmol) and a solution of 6-chlorobenzo[b]thiophen-2-sulfonyl chloride (0.41 g, 1.54 mmol), EXAMPLE 1, in acetonitrile (10 mL) at 0° C. After 2 h the solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated to yielded the title compound (0.45 g, 0.95 mmol). MS m/z: 506, [M+1]+; 1H NMR (CD3OD, 300 MHz) δ8.8 (d, 1H), 8.15 (d, 1H), 7.9 (d, 2H), 7.85 (s, 1H), 7.4-7.5 (m, 2H), 6.8 (s, 1H), 4.8 (s, 2H), 4.0 (s, 2H), 3.4-3.45 (m, 4H).