Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:38]C)=[CH:6][C:7]([O:36]C)=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].N1C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[C:7]([OH:36])=[CH:6][C:5]=1[OH:38])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccc3ncccc3c2)n1-c1ccc2c(ccn2C)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2nnc(Nc3ccc4ncccc4c3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O
Temperature: 21 °C
Yield: 38.9 %

Procedure:
A tube was charged with N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)quinolin-6-amine (114 mg) and pyridine*HCl (4 g.), and placed under a nitrogen atmosphere. It was heated to 21° C. for 50 minutes, and then cooled. The solid was dissolved in ethyl acetate (20 mL) and washed with a saturated solution of ammonium chloride (3×20 mL). The organic layer was dried and evaporated to give 4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol (42 mg). In some cases column chromatography was necessary for purification. 1H-NMR (CDCl3): 8.69 (dd, 1H); 8.50 (d, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.45-7.36 (m, 2H), 7.33 (d, 1H), 7.27 (dd, 1H), 6.64 (d, 1H), 6.42 (s, 1H), 6.30 (s, 1H), 3.98 (s, 3H); 2.83 (q, 1H); 0.50 (m, 6H). MS: expected ion=491.4; observed ion=491.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(O)C1)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
Treat a solution of (3-hydroxy-cyclohexyl)-carbamic acid benzyl ester (15.5 g, 62.24) in dichloromethane (300 mL) with PCC (16.73 g, 77.81 mmol) and stir the mixture at room temperature for 12 hours. Filter the reaction mixture through celite. Remove the solvent in vacuo. Purify the residue on silica gel column using 25% to 50% ethyl acetate in hexanes gradient to afford 12.6 g (82%) of the title compound. MS (m/z): 248 (M+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].Cl>C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (9.45 g) in methylene chloride (100 ml) were added triethylamine (18.9 ml) and 2-nitrobenzenesulfonyl chloride (10.0 g) in succession under cooling with ice and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 1N hydrochloric acid under cooling with ice, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the precipitated crystals were washed with a mixed solvent of n-hexane and diethyl ether, collected by filtration and air-dried to obtain the title compound (10.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[F:13][C@H:14]1[CH2:16][C@H:15]1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:17]([C@@H:15]3[CH2:16][C@@H:14]3[F:13])=[O:18])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(Br)cc2cn1)[C@@H]1C[C@@H]1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 109.6 %

Procedure:
A mixture of 7-bromoisoquinolin-3-amine (4.531 g, 20.31 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (2.002 g, 19.24 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (12.148 g, 23.433 mmol), N,N-diisopropylethylamine (8.50 mL, 48.8 mmol), 4-dimethylaminopyridine (0.245 g, 2.00 mmol), and N,N-dimethylformamide (100 mL, 1000 mmol) was stirred at 50° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified via flash chromatography on silica gel (120 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane) to yield 6.5208 g of the title compound. LCMS (ESI): M+H=309.2.
Reaction SMILES: [C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25](O)=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:53]>ClCCl>[C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25]([F:53])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: NCCCC[C@@H](C(=O)O)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCCCC[C@@H](C(=O)F)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Bis-FMOC-L-Lysine (5 g, 8.46 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.69 mL, 8.46 mmol) (Aldrich) and cyanuric fluoride (1.14 g, 8.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford bis-FMOC-L-lysyl fluoride as a white powder. (Yield 1.14 g, 23%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:9][CH2:10][N:11]([C:14]([NH:16][C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27](=[O:28])[NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:13]1
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Yield: 47 %

Procedure:
Following the procedure of Example 13, using the compound obtained in Example 28 in place of 2-(4-(pyridin-2-ylmethylene)piperidine-1-carboxamido)thiazole-5-carboxylic acid and using 2-aminothiazole (30 mg, 290 μmol) in place of morpholine, the title compound (45 mg, 47%) was obtained as a white solid.
Reaction SMILES: Br.[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4]1.Cl[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:2][CH:3]1[CH2:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7][N:8]1[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1
Reactant: CC1CN(c2ccccn2)CCN1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccccn2)CCN1Cc1nc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 35.7 %

Procedure:
The product from Example 24A (0.50 g, 1.93 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was slowly treated with a solution of 2-chloromethyl-1H-benzimidazole (0.31 g, 1.83 mmol) in N,N-dimethylformamide (10 mL). After 5 minutes, the mixture was treated with cesium carbonate (0.60 mmol, 1.83 mmol) and the cooling bath was removed. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water (3×) and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (2% methanol/dichloromethane) to afford 201 mg (36% yield) of the title compound. mp 207-209° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.18 (d, J=6.0 Hz, 3H), 2.38 (m, 1H), 2.52 (m, 1H), 2.78 (m, 2H), 3.02 (m, 1H), 3.67 (d, J=14.4 Hz, 1H), 3.97 (m, 2H), 4.08 (d, J=14.4 Hz, 1H), 6.62 (dd, J=5.1, 6.9 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; Anal. calcd for C18H21N5: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.15; H, 6.92; N, 22.46.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc[nH]n1
Product: COc1ccc(Cn2cnc(N)n2)cc1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 4-methoxy benzyl chloride. The title compound was obtained as a colorless solid, MS ISP (m/e): 205.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1.C(N(CC)CC)C>CN1CCCC1>[F:37][C:35]([F:36])([F:38])[C:23]1[CH:22]=[C:21]([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[C:30]2[C:25](=[C:26]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: FC(F)(F)c1cc(Cl)c2cccc(C(F)(F)F)c2n1
Agent: CN1CCCC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(N[C@H]2CC[C@@H](Nc3ccnc4cc(Cl)ccc34)CC2)c2cccc(C(F)(F)F)c2n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in N-methylpyrrolidine (0.5 mL) at 150° C. was treated with 4-chloro-2,8-bis(trifluoromethyl)quinoline (21 mg, 0.07 mmol), and triethylamine (10 μl, 0.07 mmol). The mixture was stirred at 150° C. for 18 hours then concentrated under reduced pressure. The compound was purified by reverse phase HPLC to provide the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[CH:17]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Reactant: O=C1CCCc2cc(OCCCCl)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc2N1
Temperature: 150 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture consisting of 7-(3-chloropropoxy)-2,3,4,5-tetrahydro-1H-benzoazepin-2-one (0.304 g, 1.2 mmol) and 1-(2-quinolylmethyl)piperazine (1.091 g, 4.8 mmol) was stirred for 4 hours at a bath temperature of 150° C. under an argon gas stream. The reaction mixture was dissolved in chloroform. The thus-obtained solution was rendered basic with a dilute aqueous solution of sodium hydroxide, washed with water, and then dried over magnesium sulfate. After the resulting solution was purified by subjecting it to chromatography on a silica gel column (developer: chloroform/methanol=40/1), recrystallization was conducted from acetone. The title compound (0.270 g) was obtained as yellow prisms (yield: 50.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:28])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:53][N:54]([CH3:63])[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.C(=O)(O)[O-].[Na+]>C(#N)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:28])=[C:4]([C:5]([N:60]2[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:54]([CH3:63])[CH3:53])[CH2:58][CH2:59]2)=[O:6])[CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 90 °C
Yield: 12.4 %

Procedure:
30 mg (76 μmol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid and 46 mg (0.12 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were dissolved in a mixture of 1.8 mL of acetonitrile and 0.2 mL of DMF. 40 μL (approx. 0.2 mmol; density unknown) of 1-(2-di-methylaminoethyl)-piperazine was added and the resulting mixture heated to 90° C. for 18 h. 40 mg (0.11 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were added and the mixture heated to 100° C. for 3 days. The resulting mixture was distributed between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by mass-triggered reverse-phase HPLC to afford 5.0 mg (9.4 μmol, 12%) of {3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanone as an ivory solid. 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 7.42 (d, 1H), 7.29 (ddd, 1H), 7.13 (d, 1H), 7.06 (ddd, 1H), 3.82 (s, 3H), 3.68-3.50 (m, br. 2H), 3.08-2.90 (m, br., 2H), 2.48-2.3 (m, 8H), 2.13 (s, 6H), MS: m/z 534.2 (M+H+), 548.2 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: COc1cccc(Cc2ccncc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1cccc(CC2CCNCC2)c1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 4-(3-methoxybenzyl)pyridine (25 g, 126 mmole) and platinum oxide (2.4 g) in acetic acid (250 ml) was hydrogenated for 2 hr. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and the solution basified with sodium hydroxide. The basic mixture was extracted with ether. The extracts were dried and concentrated in vacuo. The residue was vacuum distilled to give 4-(3-methoxy-benzyl)piperidine as an oil (22.6 g, 87.6%). A sample of the hydrochloride was prepared in ether (mp: 146°-147° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>S(=O)(=O)(O)O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC2CCCCO2)cc1

Procedure:
To a solution of 0.64 mL (2 mmol) of 1-(2-trimethylsiloxyethoxy)-1-trimethylsiloxy-2-methyl-1-propene, 0.55 mL of tetrabutylammonium biacetate (0.04M in THF), and 0.06 mL of bis(dimethylamino)methylsilane in 40 mL of THF was added dropwise a solution of 20 g (72.5 mmol) of 4-tetrahydropyranyloxybenzyl methacrylate (purified by passing over a column of basic alumina in hexane solution, followed by evaporation of the hexane under reduced pressure) in 30 mL of THF. When the exothermic polymerization was finished, and the temperature had returned to room temperature, the reaction mixture was poured into methanol. Filtration gave 19 g of poly(4-tetrahydropyranyloxybenzyl methacrylate). GPD: Mn =9390, M32 =11,500, MwMn =1.23. DSC: Tg =62.3° C., with a decomposition endotherm at 250.5° C. TGA: rapid loss of 24.74% of weight at 248.1° C. The monomer was prepared from methyl 4-hydroxybenzoate by reaction with an excess of 3,4-dihydro-2 H-pyran in the presence of sulfuric acid catalyst to give methyl 4-(2-tetrahydropyranyloxy)benzoate, which was then reduced with lithium aluminum hydride in THF solution to give 4-(2-tetrahydropyranyloxy)benzyl alcohol. Esterification with methacrylyl chloride and triethylamine in dichloromethane solution gave 4-tetrahydropyranyloxybenzyl methacrylate, m.p. 36° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([C:22]2[O:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:27][C:25]2[O:26][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)=[CH:6][CH:7]=1
Reactant: Nc1nnc(-c2ccccc2)o1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNc1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 5-phenyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [F:1][C:2]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4].[NH2:27][C:28]1[C:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:31][N:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:29]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](C(C)C)(C(C)C)C(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:27][C:28]2[C:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[CH:31][N:30]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:29]=2)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4]
Reactant: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Agent: CC(C)[P+](On1nnc2ccccc21)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoic acid (65 mg, 0.18 mmol), tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (74 mg, 0.27 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in methylene chloride (1.5 mL) was added (1H-1,2,3-benzotriazol-1-yloxy)(triisopropyl)phosphonium hexafluorophosphate (0.16 g, 0.36 mmol) and the reaction was sealed and heated to 60° C. for 16 hours. The reaction was purified by flash chromatography (0-4% methanol/methylene chloride) to give crude tert-butyl {3-[(4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate. ESIMS calcd 621.2 (M++U), found 621.2 (M++H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10](=O)[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=O.[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([OH:30])C=CC=2)CCCCC1.NN>>[N:6]1([CH2:7][C:8]2[CH:15]=[C:14]([CH:13]=[CH:12][CH:9]=2)[O:30][CH2:26]/[CH:25]=[CH:24]/[CH2:23][NH2:17])[CH2:10][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Agent: NN
Product: NC/C=C/COc1cccc(CN2CCCCC2)c1

Procedure:
In the same manner as in Example 1, the N-[4-chloro(trans) 2-butenyl]phthalimide was reacted with 3-(1-piperidinomethyl)phenol, followed by hydrolysis with hydrazine to obtain 1.56 g of 4-[3-(1-piperidinomethyl)phenoxy]-(trans) 2-butenylamine. To a solution of 1 g of this amine compound in 30 ml of chloroform was added 0.9 g of the 3-chloro-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide, followed by the same treatment as in Example 1 to obtain 1.57 g of white crystalline 3-[N-[4-[3-(1-piperidinomethyl)phenoxy]-(trans) 2-butenyl]amino]-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide (compound 23, yield 90% ). M.p. 116°~120° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:17]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=1
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a mixture of 0.50 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone and 15 ml of methanol was added dropwise 15 ml of a 1 N aqueous sodium hydroxide solution under ice-cooling. After stirred for 1 hour under ice-cooling, this was concentrated under reduced pressure. The resulting residue was acidified by addition of 2 N hydrochloric acid under ice-cooling, and precipitated crystals were filtered, and washed with tetrahydrofuran to obtain 0.46 g of 4-hydroxy-3-[3-[3-(carboxymethoxy)phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (9e)] as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: N#Cc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of 3-cyano-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=2.4 Hz), 7.57-7.62 (m, 4H), 7.68 (d,1H, J=8.8 Hz), 7.80 (m,1H), 8.04 (m, 2H), 8.90 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z 398.8 (M++1).