Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(O)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
A 250 mL round bottom flask containing 5.6 g (30 mmol) of p-chlorophenyl-α-hydroxyacetic acid and 100 mL of concentrated HCl:MeOH (1:9) was warmed to reflux for 12 hours. The solution was concentrated under reduced pressure, diluted with 250 mL of Et2O and washed once with 30 mL of H2O, twice with 30 mL of NaHCO3 solution, once with 30 mL of H2O and once with 30 mL of brine. The organic layer was dried (Na2SO4) and concentrated leaving 5.0 g (83%) of methyl p-chlorophenyl-α-hydroxyacetate lit m.p. 55° C.)
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:15][NH:16][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: CCO
Solvent: O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
4.0 g (23 mmole) of 3-phenylfuran-2,5-dione was added to a 100 ml single-necked round bottom flask followed by 2.9 g (27.6 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (95%). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 degree (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45 degree. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of Milli-Q water, and dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of white solid. Yield, 91%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:11]2)=[N:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCc2ccccc2)CC1
Reactant: NCc1ccc(F)cc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(CN=C(c2ccc(F)cc2)C2CCN(CCc3ccccc3)CC2)cc1
Yield: 80.5 %

Procedure:
A mixture of 11.4 g (0.037 mol) of N-(2-phenylethyl)-4-(4-fluorobenzoyl)piperidine, 6.79 g (0.054 mol) of 4-fluorobenzylamine and 0.54 g (0.0034 mol) of benzenesulfonic acid in 400 mL of xylene was heated at reflux for 24 h. Water was removed from the reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo to give 12.46 g (81.2%) a-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-piperidinemethanimine as an oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].BrC[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([O:21][CH2:22]C)=O)[CH:10]=1.Cl>CO.O>[CH3:22][O:21][CH2:19][C:11]1[N:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=[C:9]([C:1]([OH:2])=[O:4])[CH:10]=1
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
Potassium carbonate (1.2 g, 8.7 mmol) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.65 g, 1.2 mmol, prepared in the manner outlined in Example 47, Step A) in methanol (10 mL). After stirring for 2 hours, the reaction was then treated with 1N HCl to achieve pH 4, was diluted with water and extracted with six portions of 10% isopropanol in chloroform. The combined extracts were dried over sodium sulfate and concentrated to afford product as an oil which was used without further purification (0.25 g, 88%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 4.74 (s, 2H), 3.58 (s, 3H); LCMS (M+H)+: 237.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N:8]([O-:10])=[O:9].CN([S+](N(C)C)N(C)C)C.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[N+](CCCCCC)([O-])=O>C(#N)C>[N:8]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:9]
Reactant: CCCCCCBr
Reactant: O=N[O-]
Agent: CCCCCC[N+](=O)[O-]
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC#N
Product: CCCCCCON=O
Reaction time: 0.25 h

Procedure:
A 165-mg (1 mmole) sample of 1-bromohexane was added to 0.5 ml (1 mmole) of 2M tris(dimethylamino)sulfonium nitrite in acetonitrile. The course of the reaction was followed by glc analysis. No further reaction occurred after 15 min. Glc analysis showed that 1-nitrohexane and 1-hexyl nitrite were formed in a 70:30 ratio.
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CCCCCC>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:19][N+:20]1([CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN1CCCC1
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Product: C[N+]1(C)CCCC1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (3.15 g; 10.0 mmol) is slowly added dropwise to dry, cooled (0° C.) N-methylpyrrolidine (0.85 g; 10.0 mmol) (exothermic) in a 25 ml glass flask. A white suspension forms. The reaction mixture is diluted with 2 ml of n-hexane, warmed to room temperature and stirred for 30 min. The readily volatile constituents are removed in vacuo (10−3 mbar) at 35° C. N,N-Dimethylpyrrolidinium bis(pentafluoroethyl)phosphinate, [MMPL][(C2F5)2P(O)O], (2.72 g; 6.8 mmol) is isolated as white solid in a yield of 68% and a purity of 98%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[NH2:25][C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH2:39])=[O:38])[CH:32]=2)=[CH:28][CH:27]=1.CCOC(C)=O>ClC(Cl)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:13]([NH:25][C:26]2[CH:41]=[CH:40][C:29]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:38])[NH2:39])[CH:32]=3)=[CH:28][CH:27]=2)=[O:14])=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 65 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of 4-chloro-5-trifluoromethylaniline (451 mg, 2.31 mmol, 1.1 equiv.) and 1,1′-carbonyl diimidazole (419 mg, 2.54 mmol, 1.2 equiv.) in anh dichloroethane (5.5 mL) was stirred under argon at 65° C. for 16 h. Once cooled to room temperature, a solution of 4-(4-aminophenoxy)-2-pyridinecarboxamide (480 mg, 2.09 mmol) in anh THF (4.0 mL) was added, and the reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water (2×) and a saturated NaCl solution (1×), dried (MgSO4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage®; gradient from 100% EtOAc to 2% MeOH/EtOAc) gave N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea as a white solid (770 mg, 82%): TLC (EtOAc) Rf 0.11, 100% ethyl acetate 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 8.99 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.69 (broad s, 1H), 7.64 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.61 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.39 (d, J=2.5 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 7.14 (m, 1H); MS LC-MS (MH+=451). Anal. calcd for C20H14ClF3N4O3: C, 53.29% H, 3.13% N, 12.43%. Found: C, 53.33% H, 3.21% N, 12.60%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH2:24])=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH2:24])=[N:21][C:22]([O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(N)nc32)CC1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)nc(N)nc32)CC1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
A mixture of: 4-(6-amino-4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 33; 224 mg, 0.64 mmol), 2-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA; 95.2 mg, 0.8 mmol), and potassium carbonate (220 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was heated at 80° C. for 3 h, and then cooled. Volatiles were evaporated and the residue was chromatographed (50-65% ethyl acetate/hexanes) to give 4-[6-Amino-4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (261 mg, 94%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]1[CH3:19])=[N:7][N:6]=[CH:5]2.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]3[CH3:19])=[N:7][N:6]=[CH:5]4)[CH:26]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1C(=O)NCCN1c1nncc2cc(Br)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC(=O)C3C)nncc2c1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
This compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of 4-(6-bromophthalazin-1-yl)-3-methylpiperazin-2-one (0.200 g, 0.62 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.245 g, 0.81 mmol), sodium carbonate (0.270 g, 2.5 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.040 g, 0.050 mmol) in DME (7 mL)/H2O (3 mL)/EtOH (2 mL) was heated at 90° C. The reaction was purified by flash chromatography eluting with 2M NH3 in MeOH/CH2Cl2 (0:1-1:19) to give 126 mg of a brown amorphous solid. The material was further purified by reverse phase HPLC (10→100% CH3CN [0.1% TFA]) to give the title compound as a light yellow amorphous solid. Found MS m/z: 416.2 [M+1].
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:13]([CH3:12])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCc1ccccc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCOc1ccc(O)cc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Compound 8a (0.25 g, 1.15 mmol) and N-methyl-1-phenylmethanamine (0.18 g, 1.38 mmol) were stirred in acetonitrile (12.0 mL) for 20 mins before diisopropylethylamine was added (0.40 mL, 2.30 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 8 as a brownish oil (0.20 g, 0.77 mmol, 67% yield). MS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.15, found: 257.98. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.37 (m, 4H), 6.74-6.82 (m, 5H), 4.05 (t, J=6 Hz, 2H), 3.78 (s, 1H), 3.645 (s, 2H), 2.83 (t, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CCCN2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccccc2)cc1

Procedure:
The title compound, white solid, m.p. 109° C. and MS: m/e=301 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-phenyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:52][O:53][C:54]1[CH:66]=[CH:65][C:57]([CH2:58][C:59]2[S:63][C:62]([NH2:64])=[N:61][CH:60]=2)=[CH:56][CH:55]=1>CN(C=O)C.O>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:64][C:62]1[S:63][C:59]([CH2:58][C:57]2[CH:65]=[CH:66][C:54]([O:53][CH3:52])=[CH:55][CH:56]=2)=[CH:60][N:61]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(Cc2cnc(N)s2)cc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2cnc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Z-Pro-OH (0.96 g, 3.84 mmol), HATU (1.46 g, 3.84 mmol), and DIEA (0.094 mL, 5.4 mmol) in DMF (30 mL) was stirred at room temperature for 1 hour. 1 mL of this solution was added to 10 mg of 5-(4-Methoxy-benzyl)-thiazol-2-ylamine and reaction mixture stirred at room temperature overnight. The resulting mixture was diluted with DMF (5 mL) and water (0.5 mL) and purified using reverse phase HPLC to furnish the corresponding product. MS: 452.1 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][S:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)Cc1ccccc1Br
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3Br)cc2)c2ccc3ccccc3c2N1
Yield: 46 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-bromophenyl)methanesulfonyl chloride, the title compound (yield 46%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[OH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[OH:25])[CH2:20][NH-:21].[NH2:26][CH2:27][CH2:28][C:29](O)=[O:30].O>C(O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[OH:25])[CH2:20][NH:21][C:29](/[C:28](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:27]#[N:26])=[O:30]
Reactant: [NH-]Cc1ccc(O)c(O)c1
Reactant: NCCC(=O)O
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)cc(OC)c1O
Yield: 75 %

Procedure:
To 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.042 g, 0.2 mmol) and N-cyanoacetyl)3,4-dihydroxybenzylamide (Example 2, 0.042 g, 0.2 mmol) in 10 ml of ethanol 3 mg of β-alanine was added and the reaction was refluxed for 6 h. Water was added and the solid was recrystallized from 5 ml of ethanol twice to give 0.06 g (75%) of a red solid. The product gave the following analytical data:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[C:20]([C@H:22]4[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]4)[CH:19]=[CH:18][C:17]=3[Cl:33])[CH:13]=[CH:14][C:7]=2[O:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:33][C:17]1[CH:18]=[CH:19][C:20]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]2)=[CH:21][C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][NH:9][C:8]=2[CH:11]=1
Reactant: COC(=O)C1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a stirred solution of 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid methyl ester (190 mg) in THF: Methanol:water (1:1:1 mixture, 1.5 mL) was added lithium hydroxide (17 mg). After stirring at room temperature overnight, the reaction mixture was concentrated, and the resulting residue was taken up in 50% methanol in ethyl acetate. The solution was filtered through a celite bed, and the filtrate was concentrated to a residue which was purified by preparative HPLC to furnish 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (23 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5].NC1C(C)=C(Cl)C=C2C=1N=C(Cl)C(Cl)=N2.[NH2:21][C:22]1[C:31]([Cl:32])=[C:30]([CH3:33])[CH:29]=[C:28]2[C:23]=1[N:24]=[C:25](Cl)[C:26](Cl)=[N:27]2>O1CCCC1.C(OCC)(=O)C>[NH2:21][C:22]1[C:31]([Cl:32])=[C:30]([CH3:33])[CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([O:5][CH3:4])[C:26]([O:2][CH3:1])=[N:27]2
Reactant: Cc1cc2nc(Cl)c(Cl)nc2c(N)c1Cl
Reactant: C[O-]
Reactant: CO
Agent: Cc1c(Cl)cc2nc(Cl)c(Cl)nc2c1N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2cc(C)c(Cl)c(N)c2nc1OC
Reaction time: 4 h

Procedure:
A 25% solution of sodium methoxide in methanol (433 μl, 1.89 mmol) was added dropwise to a solution of 5-amino-2,3,7-trichloro-6-methylquinoxaline and 5-amino-2,3,6-trichloro-7-methylquinoxaline (200 mg, 0.788 mmol) in dry tetrahydrofuran (7.9 ml) at 0° C. under nitrogen. The mixture was stirred for 31/4 hours and then diluted with ethyl acetate (30 ml) and washed with water (2×10 ml) and brine (10 ml) and then dried (MgSO4) filtered and concentrated under reduced pressure. The solid residue was purified by flash chromatography on silica gel, eluting with a hexane/ethyl acetate gradient giving 5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline as an off-white solid, mp 169°-170° C.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl>N1C=CC=CC=1>[S:9]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: OCC1CC=CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 67.2 g (0.60 mol) 3-cyclohexene-1-methanol, and 170 mL of pyridine. The mixture was cooled to 0° C. Tosyl chloride (120.8 g, 0.63 mol) was slowly added to above mixture at 0–5° C. The reaction was carried out for 3 hrs. The reaction mixture was poured into 1.2 L of HCl solution (1 M), extracted with chloroform (3×200 mL), washed with water (3×200 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled under vacuum to give a tosylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[N:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)c2cc([N+](=O)[O-])ccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a pre-dried flask were added 5-nitro-3-oxo-2,3-dihydroindazole-1-carboxylic acid tert-butyl ester (0.65 g, 2.33 mmol), triphenylphosphine (0.92 g, 3.50 mmol), methanol (115 μL, 2.80 mmol) and anhydrous THF (10 mL). The flask was evacuated and purged with N2 then cooled to 0° C. and diisopropylazodicarboxylate (690 μL, 3.50 mmol) added dropwise over 5 min. The mixture was stirred at rt overnight then diluted with EtOAc and partitioned over water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by column chromatography on silica gel (Jones, 50 g) loading and eluting in DCM revealed the title compound as a white powder. 1H NMR (400 MHz, CDCl3): δ=1.68 (s, 9H), 4.21 (s, 3H), 8.10 (d, J=8.8 Hz, 1H), 8.39 (dd, J=9.2 Hz, 2.4 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H). MS (ES+): m/z 294.3 (20) [MH+]. The N-alkylation product methyl-5-nitro-3-oxo-2,3-dihydroindazole-1-carboxylic acid tert-butyl ester was also isolated. 1H NMR (400 MHz, CDCl3): δ=1.68 (s, 9H), 3.69 (s, 3H), 8.02 (d, J=9.2 Hz, 1H), 8.48 (dd, J=9.2, 2.4 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:36]=[CH:35][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:56]=[CH:55][C:52]([CH2:53][Cl:54])=[CH:51][CH:50]=2)[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46]>>[ClH:54].[ClH:54].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:53][C:52]2[CH:55]=[CH:56][C:49]([C:41]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=3)=[CH:50][CH:51]=2)=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Product: CCCCc1ccc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)cc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.