Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37]C(OC(C)(C)C)=O)=[CH:32][CH:31]=1)[CH:19]1[CH2:28][C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][CH2:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[CH2:28][C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20]2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCc3cccnc3C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCc3cccnc3C2)cc1
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
To a stirred solution of 2-{[[4-(tert-Butoxycarbonylamino-methyl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-7-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) in anhydrous CH2Cl2 (1 mL) was added TFA (1 mL). The resultant solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved with MeOH, and added NaHCO3. The mixture was stirred for 20 min, diluted with CH2Cl2, filtered through celite. The crude product was purified by flash chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (71 mg, 89%) as a white foam.
Reaction SMILES: [N+](C1C=CC(CC([O-])=O)=CC=1)([O-])=O.C(O)C(N)(CO)CO.Cl.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O-:32])=[CH:28][CH:27]=1)([O-:25])=[O:24]>CS(C)=O.C([O-])(=O)C.[Na+]>[CH:27]1[C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=[C:29]([OH:32])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A p-nitrophenylacetate stock solution is made by dissolving p-nitrophenylacetate in dimethylsulfoxide (DMSO) to constitute a 0.1 M solution. Before assay, a sample of the stock solution is diluted 100-fold in 50 mM sodium acetate pH 5.0 to make a 1 mM solution. A 100 μl volume of 1 mM p-nitrophenylacetate is mixed with each dilution of the enzyme and then incubated at 25° C. for 10 minutes. Substrate alone, enzyme alone, and buffer alone are run as controls. p-Nitrophenol standard solutions of 0.25, 0.2, 0.1, 0.05, and 0.02 mM are prepared by diluting a 10 mM stock solution in 50 mM sodium acetate pH 5.0. At 10 minutes, 50 μl of 1.0 M Tris-HCl pH 8.0 buffer is added to each well (including samples, substrate control, enzyme control, reagent control, and standards), mixed, and the absorbance at 405 nm immediately measured on e.g. a SPECTRAMAX™ 340 PC plate reader (Molecular Devices, Sunnyvale, Calif., USA). One unit of acetyl xylan esterase activity is defined as the amount of enzyme capable of releasing 1 μmole of p-nitrophenolate anion per minute at pH 5, 25° C.
Reaction SMILES: [ClH:1].[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[N:11](=[C:13]([CH3:17])[C:14](=O)[CH3:15])[OH:12]>C(OCC)(=O)C>[ClH:1].[CH3:17][C:13]1[N+:11]([O-:12])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[O:9][C:14]=1[CH3:15]
Reactant: CC(=O)C(C)=NO
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1

Procedure:
At 0°-5° C., dry HCl was bubble through a solution of p-tolualdehyde (125 g, 1.04 mol) and 3-oximino-2-butanone (95.6 g, 0.946 mol) in 350 ml of ethyl acetate. Title product was precipitated by dilution with ether and recovered by filtration with ether wash, 207 g; mp 198°-200° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:21]1([CH:27]2[CH2:31][C:30](=[O:32])[O:29][C:28]2=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:32])[CH2:31][CH:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:28]([OH:33])=[O:29]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(CC(C(=O)O)c1ccccc1)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.7 g, 2.6 mmol; prepared in a manner similar to that described in Example 23), 3-phenyldihydrofuran-2,5-dione (0.458 g, 2.6 mmol) and toluene (35 ml) was heated under reflux for 2 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethyl acetate (3 ml) and dried in vacuo to give N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-phenylsuccinamic acid (0.775 g) as an off-white solid, m.pt. 180–183° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.7–2.9 (m, 1H) (—CHHCHPh—), 3.1–3.3 (m, 1H) (—CHHCHPh—), 4.0–4.1 (m, 1H) (—CHPh—) 4.3 (s, 2H) (ArCH2—), 7.1–7.3 (m, 2H) (2×ArH), 7.3–7.5 (m, 5H) (5×ArH), 7.8–8.0 (m, 4H) (4×ArH), 8.3 (d, 1H) (ArH), 9.75 (s, 1H) (chain CONH), 12.5 (br s, 1H) (—CO2H), 12.65 (s, 1H) (ring CONH) ; m/z (M+H)+. 446, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH:20]2[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]2)=[CH:29][CH:28]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: CN1CCC(Oc2ccc(N)cc2)C1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C1

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (52 mg, 0.18 mmol) and 4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine•TFA (55 mg, 0.18 mmol) were stirred in N,N-dimethylformamide (1 mL) and triethylamine (100 μL) at 75° C. The reaction mixture is purified by reverse phase high performance liquid chromatography to give (4Z)-6-bromo-4-[({4-[(1-methylpyrrolidin-3-yl)oxy]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as its TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].C(Br)Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:19][N:10]3[C:11]4[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=4[CH:17]=[C:9]3[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: BrCBr
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2COc2ccc(Cl)cc2-1
Temperature: 80 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
To a solution of 4-chloro-2-(4-fluoro-1H-indol-2-yl)phenol (40 mg, 0.15 mmol) in DMF (1 mL), K2CO3 (40 mg, 0.31 mmol) and CH2Br2 (53 mg, 0.31 mmol) were added at 25° C. The mixture was stirred at 80° C. for 2 hours, and cooled to 25° C. H2O (50 mL) was added, then the mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of 2-chloro-11-fluoro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (50 mg, yield: 45%). 1H-NMR (CDCl3, 400 MHz) δ 7.68 (s, 1H), 7.14˜7.23 (m, 2H), 7.03˜7.09 (m, 2H), 6.90 (s, 1H), 6.81˜6.86 (m, 1H), 5.88 (s, 2H). MS (M+H)+: 274/276.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[CH2:26])=[CH:20][CH:19]=1)[N:6]([SiH:14]([CH3:16])[CH3:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[Li+].[OH-]>C1COCC1.O>[C:7]([N:6]([SiH:14]([CH3:16])[CH3:15])[C@H:5]([C:4]([OH:27])=[O:3])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]=[CH2:26])=[CH:22][CH:23]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=CCc1ccc(C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)[SiH](C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1ccc(C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)[SiH](C)C)cc1
Yield: 79.2 %

Procedure:
The same procedure as described for 5 Scheme 2 was followed except that (Boc)2O was used instead of FmocCl for protection of the amine group; Colorless oil (yield=64%); 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 6 H), 1.19 (t, J=7.14 Hz, 3 H), 1.39 (s, 9 H), 1.72 (d, J=11.1 Hz, 2 H), 3.04 (m, 2 H), 4.13 (t, J=7.14 Hz, 2 H), 4.54 (m, 1 H), 4.79 (m, 1 H), 4.83 (m, 1 H), 5.07 (bd, NH, 1 H); 13C NMR (75 MHz, CDCl3) −3.4 (2C), 14.1, 23.6, 28.3 (3C), 38.4, 54.4, 61.2, 79.7, 113.4, 128.8 (3C), 133.8 (2C), 134.5, 137.0, 155.1, 171.9. (b) N-Boc-4-allyldimethylsilylphenylalanine ethyl ester (190 mg, 0.5 mmol) was hydrolyzed with a LiOH (60 mg, 2.5 mmol) in THF/H2O (5:1, 15 mL) for 4 h at room temperature. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL). After neutralization of the solution with acetic acid and concentration, the residue was purified by column chromatography (5:1 ethyl acetate/MeOH) to afford a viscous solid (144 mg, 82%); 1H NMR (300 MHz, CDCl3) δ 0.29 (s, 6 H), 1.41 (s, 9 H), 1.76 (d, J=7.68 Hz, 2 H), 3.05-3.32 (2 H), 4.48 (m, 1 H), 4.86 (m, 1 H), 4.91 (m, 1 H), 5.80 (m, 1 H), 7.24 (d, J=7.29 Hz, 2 H), 7.47 (d, J=7.29 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(Cl)c(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 25 %

Procedure:
4-Chloro-3-trifluoromethylphenylboronic acid (58.3 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (17 mg, 25%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[N:9]1([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(Cn2ncc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Cn2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 1-(4-nitrobenzyl)-1H-indazole (9.25 g), 10% palladium carbon (1 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from acetone-hexane gave 4-(1H-indazol-1-ylmethyl)aniline (6.77 g, 83%) as colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[C:6]([O:17][CH3:18])[CH:5]=1)([O-])=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[C:6]([O:17][CH3:18])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NCCNC(N)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)ccc1NCCNC(N)=O

Procedure:
30 g (0.118 mole) of 4-nitro-2-methoxy-N-(β-ureidoethyl) aniline is introduced little by little, while stirring and cooling, sufficiently to avoid any increase in temperature into 300 cm3 of a 3N solution of sodium hydroxide to which 120 g of sodium hydrosulfite has been added and which has been brought to 70° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Product: Cc1nccc2c3ccc(OCc4cccc(F)c4)cc3n(Cc3cccc(F)c3)c12
Yield: 85 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.5 g, 1.587 mmol) in presence of 1-bromomethyl-3-fluorobenzene (0.6 g, 3.173 mmol) as described here above.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1ccc(F)cc1

Procedure:
142 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2-fluorophenyl)piperazine (66 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1>>[N:18]1([C:13]2[N:12]=[C:11]([NH:10][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH3:9])[CH:16]=[N:15][CH:14]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccc(Br)cc1
Product: C[C@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccc(Br)cc1
Yield: 41.8 %

Procedure:
In a procedure analogous to example 25, reaction of N-[(1S)-1-(4-bromophenyl)ethyl]-6-chloropyrazin-2-amine (125 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) furnished the product (66 mg, 42%).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:24][CH2:23][C:22](=[O:25])[CH2:21][CH:20](S(C3C=CC=CC=3)(=O)=O)[C:19]=2[CH:35]=1)(=[O:14])[CH3:13].O.Cl>ClCCl>[C:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:24][CH2:23][C:22](=[O:25])[CH:21]=[CH:20][C:19]=2[CH:35]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)CC(=O)CO2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)C=CC(=O)CO2

Procedure:
0.084 ml (1.05 equivalents) of 1,8-diazabicyclo[5.4.0]undec-7-ene is added at ambient temperature, under nitrogen, to 184 mg (0.53 mmol) of 7-acetyl-5-(phenylsulfonyl)-4,5-dihydro-1-benzoxepin-3(2H)-one, prepared according to example 14, in suspension in 20 ml of dichloromethane. From the addition of the base, the medium becomes translucent and slightly yellow. After addition of water and 1N hydrochloric acid, the phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium hydrogencarbonate solution and then brine. After drying and then concentrating under vacuum, 90 mg (83%) of 7-acetyl-1-benzoxepin-3(2H)-one are obtained in the form of a white solid; M.p.=92–93° C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Li]>C1COCC1>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5cccs5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/water) solution of 3-cyclobutyl-1-quinolin-7-ylimidazo[1,5-a]pyrazin-8-ylamine (52.7 mg, 0.167 mmol) in THF (5 mL) was added 2-thienyllithium (1 M in THF; 0.6 mL, 0.6 mmol), then the cooling bath was removed, and the solution was stirred overnight at ambient temperature. After 1d and 2d, more 2-thienyllithium (0.2 mL, 0.2 mmol) was added, and stirring was continued. The reaction was quenched by adding water and sat. NH4Cl solution, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine and dried over MgSO4. Air was bubbled into the solution for 8 h. The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-6)→1% MeOH in CH2Cl2 (7-21)→2% MeOH in CH2Cl2 (22-43)], yielding a yellow film. Further purification by preparative TLC (20×20 cm silica gel plates, 500 μM thickness, eluting with 3% MeOH in CH2Cl2 four times) yielded the title compound as a yellow solid;
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCCCN
Product: CCCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1.2 g, 5.2 mmol) and N-butylamine (2 mL) was heated at 170° C. (microwave) for 30 min. The resulting mixture was cooled to room temperature and purified by preparative HPLC (neutral) to afford 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (887 mg, 63% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.69 (d, J=9.9 Hz, 1H), 3.38 (t, J=7.1 Hz, 2H), 1.59-1.73 (m, 2H), 1.41-1.53 (m, 2H), 1.01 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 269.1 [(M+H)+, calcd for C10H14BrN4 269.0].
Reaction SMILES: [OH-].[K+].[CH2:3]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:26]S(C)=O>O>[CH3:26][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=2)[CH:22]=[C:14]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2n1C

Procedure:
Potassium hydroxide (9.0 g) was added to a solution of 2-(n-undecyl)indole-6-carboxylic acid (22.1 g) in dimethylsulphoxide (100 ml) and water (5 ml), and the mixture was stirred and warmed on a steam bath to give a suspension. After 15 minutes the suspension was removed from the steam bath, methyl iodide (15 ml) was added, and the mixture was stirred for 2 hours with occasional warming. Methyl iodide (10 ml) was added and the mixture was stirred for 1 hour. The mixture was left to cool overnight and was then poured into water and acidified with 2N hydrochloric acid. The product was collected and washed. This product was then added to a mixture of ethanol (150 ml), water (50 ml), and sodium hydroxide (6.5 g), and the mixture was heated under reflux for 1 hour and then poured into water containing acetic acid (50 ml). The product was twice recrystallised from ethanol to give 1-methyl-2-(n-undecyl)indole-6-carboxylic acid (9.6 g), in the form of a white powder, m.p. 165°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:22]I>>[F:1][C:2]1[CH:3]=[C:4]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CI
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F
Product: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from (3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250 mg, 0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a procedure similar to example 7. 1H NMR (CDCl3): 7.76 (d, J=8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H), 3.58 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3C(F)(F)F)c2)CC1
Yield: 91.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-(trifluoromethyl)benzoyl chloride (101 μl, 0.687 mmol), 81.9 mg (92%) of the title compound were recovered.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[F:8][C:9]1[C:14]2[CH2:15][CH2:16][CH:17]([N:26]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34](I)=[C:33]([O:38][CH3:39])[CH:32]=4)[N:28]=[N:27]3)[C:18](=[O:25])[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:9]1[C:14]2[CH2:15][CH2:16][CH:17]([N:26]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([NH:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[C:33]([O:38][CH3:39])[CH:32]=4)[N:28]=[N:27]3)[C:18](=[O:25])[N:19]([CH2:20][C:21]([F:22])([F:23])[F:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1Nc1cccnc1

Procedure:
A suspension of pyridin-3-amine (5.08 mg, 0.054 mmol), 6-fluoro-3-[4-(4-iodo-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (30 mg, 0.054 mmol), potassium carbonate (8.14 mg, 0.059 mmol), X-Phos (12.76 mg, 0.027 mmol), and tris(dibenzylideneacetone)dipalladium (9.81 mg, 0.011 mmol) were combined in a μwave vial and dissolved in t-amyl alcohol (1071 μl). The reaction was microwaved at 130° C. for 20 min. The reaction mixture was filtered, and the solvent was removed in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 6-fluoro-3-{4-[3-methoxy-4-(pyridin-3-ylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one