Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CNC
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C[C@@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 80 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.3 mmol) followed by dimethylamine (2.4 ml of a 2 M solution in tetrahydrofuran, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (160 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.31 mL, 0.43 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (190 mg, 80%) as a yellow solid: mp 210-213° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.22 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.84 (m, 5H), 7.48 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0 Hz, 2.0 Hz, 1H), 6.01 (br s, 1H), 4.58-4.49 (m, 2H), 4.40 (br s, 1H), 3.28-3.24 (m, 1H), 3.15-3.10 (m, 1H), 2.81 (d, J=4.5 Hz, 3H), 2.78 (d, J=4.5 Hz, 3H); ESI MS m/z 457 [M+H]+; HPLC (Method B) 96.5% (AUC), tR=14.4 min; [α]23D +10.4° (c 0.11, Methanol).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=1)([OH:3])=[O:2].[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[C:1]([C:4]1[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=1)([OH:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COc1cc(C(=O)O)on1
Solvent: CCO
Product: CCOC(=O)COc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Carboxyisoxazol-3-yl)oxyacetic acid (4.0 mmol, Example 74) is dissolved in ethanol (50 mL), to which is added a catalytic amount of p-toluenesulfonic acid (100 mg). After stirring overnight at room temperature, the ethanol was removed and the residue was recrystallized from ethanol/water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CN(C=O)C>[F:30][C:29]([F:32])([F:31])[CH2:28][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Yield: 106.1 %

Procedure:
To a 20 ml DMF solution of 4-benzyloxyphenol (3.35 g, 16.7 mmol) and cesium carbonate (6.02 g, 18.5 mmol) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.29 g, 18.4 mmol) upon cooling in an ice-water bath. The cooling bath was removed and the reaction mixture was heated to 50° C. for 1 hr. The reaction mixture was diluted with AcOEt and water. The organic layer was separated, washed with 1N hydrochloric acid, dried over anhydrous Na2SO4, filtered, and concentrated to give benzyl 4-(2,2,2-trifluoroethoxy)phenyl ether 5.0 g (quant.). This material was dissolved in 200 ml of ethanol and was hydrogenated in a Parr shaker with 10% Pd/C 222 mg under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by suction filtration through a pad of celite. The filtrate was concentrated to give the title compound 2.6 g (87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)[CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:29]1[N:30]=[C:26]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[S:27][CH:28]=1)=[O:32]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1csc(-c2cccnc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-3-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).
Reaction SMILES: Cl.Cl.N1CCOC([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])C1.N1C=CC=CC=1.[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1NC)[CH3:43]>C1COCC1>[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:18]=1)=[O:12])[CH3:43]
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCN1CCC[C@@H]1NC
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCc1nnc(C(=O)NC[C@H]2CCCN2CC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.18 mmol, 0.1 g) and 0.1 mL of pyridine in 2 mL of THF was added ((R)-1-ethyl-pyrrolidin-2-yl)-methylamine (0.4 mmol, 0.05 g). The mixture was shaken at room temperature, upon completion, the solvent was removed and the residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc afforded 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid ((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amide. LCMS: m/z 464.9. 1H NMR (400 MHz, CD3OD) δ 8.27 (1H, s), 7.42 (2H, d), 7.09 (2H, d), 4.44-4.40 (1H, m), 4.00-3.96 (1H, m), 3.80-3.68 (4H, m), 3.20-3.10 (4H, m), 2.34-2.28 (1H, m), 2.16-2.02 (5H, m), 1.84-1.80 (2H, m), 1.64-1.27 (13H, m), 0.83 (3H, t).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.C1C(=O)N([Cl:19])C(=O)C1.Cl.O1CCOCC1>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[N:8][OH:9])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(CCl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
4-(chloromethyl)benzaldehyde oxime 5 (15.8 g, 93.16 mmol) was dissolved in DMF (300 mL). NCS (13.69 g, 102.5 mmol) was added in portions and then HCl in dioxane (100 mL of 4 M, 400.0 mmol) was added slowly, cooling the mixture with an ice water bath to moderate the exotherm, keeping internal temperature below 33° C. The mixture was then stirred at room temperature for 1 hour. The solution was partitioned between EtOAc and water and the organic extract was washed with water and brine (5×200 ml), dried over MgSO4 and concentrated under reduced pressure to give a colourless solid (21.65 g, 95%). 1H NMR (400 MHz, CDCl3) δ 4.63 (2H, s), 7.45 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz), 8.36 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Yield: 84.7 %

Procedure:
3-Fluoro-4-nitro phenol (5 g, 0.032 moles), potassium carbonate (6.34 g, 0.047 moles) and tert-Butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (14 g, 0.04 moles) in dimethylformamide (50 mL) were stirred at 100° C. After completion of reaction, the mass was quenched on to water (100 mL) and extracted with ethyl acetate (2×100 mL). The resulting organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 0.5:9.5) to afford the title compound 9.23 g (Yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C1C(=O)N([Br:32])C(=O)C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:21])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Yield: 97.1 %

Procedure:
Combined 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (2.19 g, 6.55 mmol), NBS (1.749 g, 9.83 mmol), and sodium bicarbonate (1.651 g, 19.65 mmol) in DMF (20 mL) and stirred at 20° C. for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL, then 2×50 mL). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on a 120 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.348 g, 97% yield) as a white solid. MS m/z 369, 371 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.6 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.3 Hz, 2H) 4.05 (s, 3H) 7.79 (dd, J=8.6, 0.5 Hz, 1H) 7.85 (s, 1H) 8.38 (dd, J=8.6, 2.3 Hz, 1H) 8.74 (t, J=5.6 Hz, 1H) 8.96 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])([CH3:3])[CH3:2].Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>>[CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)/[C:11](=[N:24]\[NH:25][C:26]([NH2:28])=[O:27])/[C:9]1=[O:10])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN(C(C)C)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: Cc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCCN(C(C)C)C(C)C
Yield: 72.2 %

Procedure:
By using 1-(3-diisopropylaminopropyl)-5-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(3-diisopropylaminopropyl)-5-methylisatin 3-semicarbazone having a melting point of 145°-148° C. (yield: 72.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[B:29]([OH:32])[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1B(O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a stirred solution of 2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (197 mg, 0.526 mmol) in THF (1.3 mL) cooled to −78° C. was added n-butyl lithium (2.5 M in hexanes, 232 uL, 0.579 mmol). The solution was stirred for 15 minutes after which time trimethyl borate (235 uL, 2.11 mmol) was added and the solution was allowed to slowly warm to RT overnight. The reaction was quenched by addition of 0.1 M HCl and was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. Flash column chromatography (12 g silica, 0-100% ethyl acetate in DCM over 30 column volumes) provided (2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63 mg) as a white foam. MS=340.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.46 (m, 5H), 7.25 (d, J=1.01 Hz, 1H), 7.08 (br. s, 1H), 6.85 (d, J=1.01 Hz, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.38 (d, J=1.52 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:5]=2[N:4]=1.S(=O)(=O)(O)O.N.O.[CH3:27]O>>[CH3:27][O:18][C:17]([C:15]1[CH:14]=[CH:13][C:6]2[N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][C:5]=2[CH:16]=1)=[O:19]
Reactant: CC(C)CCn1c(CO)nc2cc(C(=O)O)ccc21
Reactant: CO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(CO)n2CCC(C)C
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid (2.4 g, 9.1 mmol) and concentrated sulfuric acid (1.1 g, 10.9 mmol) in methanol (30 mL) was heated at reflux for 40 hrs. The solution was cooled to room temperature, the pH adjusted to 8-9 with concentrated ammonia, and water was added. A white precipitate formed that was collected by filtration and washed with water. The product was dried in vacuo to yield 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (2.4 g, 96%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[Br:14].O.[NH2:17][NH2:18]>CCO>[Br:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]([O:2][NH:17][NH2:18])=[O:15]
Reactant: COC(=O)c1cc(OC)c(OC)cc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(Br)c(C(=O)ONN)cc1OC
Temperature: -20 °C
Yield: 82.1 %

Procedure:
A mixture of 0.960 g (3.48 mmol) of 7, 1.60 g (35 mmol) of hydrazine hydrate (62% hydrazine), and 5 mL of EtOH was refluxed for 15 h. The mixture was cooled to −20° C., vacuum filtered, washed with 50 mL of ice-cold 1:1 EtOH:H2O, and dried to give 0.832 g (87% yield) of (2-bromo-4,5-dimethoxy benzoyloxy) hydrazine (8) as a white, needle-like crystalline solid. The above procedure was repeated on 2.79 g of the starting ester 7 to result in 2.77 g (99% yield) of 8. 1H NMR (200 MHz, CDCl3) δ 6.97 (s, 1H), 6.86 (s, 1H), 3.85 (s, 6H). HRMS Calculated for C9H12O3N2Br 275.0031. found 275.0037.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:16][CH2:17]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 35.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g, 19 mmol), K2CO3 (5.8 g) and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) and dimethylformamide (80 ml) was heated at 75° C for 6 hours. The reaction was poured into water, and an off-white solid formed from solution. The solid was collected and dried to yield 4.5 g of crude product. The compound was recrystallized from ethanol (3 times) to afford 3.0 g of an off-white solid. The solid was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the appropriate fractions afford 2.3 g of an off-white solid, which when recrystallized from ethanol yielded 1.9 g (26%) of analytically pure 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-]-piperazinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.: 156°-158° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[S:41](Cl)(=[O:44])(=[O:43])[NH2:42].O>CN(C)C(=O)C>[S:41]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:44])(=[O:43])[NH2:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(N)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (56.2 mg, 0.105 mmol) was dissolved in N,N-dimethylacetoamide (3.9 mL), and the solution was added with sulfamoyl chloride (61 mg, 0.53 mmol), followed by stirring at room temperature for 17 hours. The reaction mixture was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-sulfamoyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.2 mg, yield 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reaction time: 2 h
Yield: 98.9 %

Procedure:
250 g of 2-nitro-4-trifluoromethylbenzoic acid (1.06 mol) were dissolved in 1 l of EtOH and 7.5 g of Pd/C (5%) were added. The mixture was hydrogenated under 1-2.5 bar of hydrogen pressure. During the hydrogen uptake, the temperature rose temporarily from 10° C. to 104° C. After 2 h, the hydrogen uptake was complete. Subsequently, the catalyst was filtered off and the solvent was removed under reduced pressure to obtain 215 g (99%) of a pale yellow solid, mp 174-176° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]([O:29][CH2:30][CH3:31])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:32][N:33]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([O:29][CH2:30][CH3:31])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:20]3)(=[O:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(Cl)c3c2)CC1)c1ccccc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(N(C)C4CCCCC4)c3c2)CC1)c1ccccc1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
In 50 ml of chloroform was dissolved 4.6 g of 1-(4-chloro-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine, and to the solution were added 1.7 g of N-methyl-N-cyclohexylamine and 1 g of anhydrous potassium carbonate, and the mixture was stirred at a temperature of 20° C. to 25° C. for 3 hours. The reaction solution thus obtained was washed with water, dried with anhydrous potassium carbonate and then chloroform was distilled therefrom. The residue was subjected to the same silica gel-column chromatography as in Example 1 using chloroform as the solvent for purification to give 4.2 g of 1-[4-(N-methyl-N-cyclohexylamino)-6-quinazolinesulfonyl]-4-(2-ethoxy-2-phenylethyl)piperazine [i.e., Compound (19)] in a yield of 79%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH2:20]([N:24]1[C:28](=[CH2:29])[C:27]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:26][C:25]1=[O:35])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][C:27]3([O:26][C:25](=[O:35])[N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[C:28]3=[CH2:29])[CH2:30][CH2:31]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(=CCCBr)c2ccc(Cl)cc2)cc1
Reactant: C=C1N(CCCC)C(=O)OC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)CC2
Reaction time: 5 h
Yield: 79 %

Procedure:
10.7 g of 4,4-bis(4-chlorophenyl)-3-butenyl bromide are added to the solution of 4.5 g of 3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of acetone containing 4.20 g of anhydrous potassium carbonate and 0.5 g of potassium iodide. The heterogeneous reaction mixture is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, water is added to the residue and extracted with benzene. The benzene phase is washed with water to halide-free, filtered through a silica gel bed and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 79.0% yield, m.p.: 110°-111° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.[CH3:18][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(Br)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-n2cnc(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(4-bromo-1H-imidazol-1-yl)-3-methoxybenzoic acid (1.90 g) in toluene (20 mL) and methanol (5 mL) was added trimethylsilyldiazomethane (2M hexane solution, 3.84 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added trimethylsilyldiazomethane (2M hexane solution, 0.96 mL), the mixture was stirred for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (1.32 g).