Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=120-121° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1.Cl>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]1
Reactant: COCCCCCCCOC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: COCCCCCCCOC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 25.5 h
Yield: 100.6 %

Procedure:
A mixture of 8-(7-methoxyheptyloxy)-1,4-dioxaspiro[4.5]decane (9.8 g) and 3N aqueous hydrochloric acid (34 ml) in tetrahydrofuran (68 ml) was stirred for 25.5 hours at room temperature. The solvent was evaporated in vacuo and the residue was poured into a mixture of ethyl acetate and water. Then the solution was adjusted to pH 9 with potassium carbonate. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-(7-methoxyheptyloxy)cyclohexanone (8.34 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#C[Si](C)(C)C)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 82.5 %

Procedure:
To a mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol), [1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) CH2Cl2 complex (7.9 mg, 0.01 mmol, 5 mol %) and copper(I) iodide (3.7 mg, 0.019 mmol, 10 mol %) in DMF (2 mL) under an argon atmosphere was added trimethylsilylacetylene (0.08 mL, 0.58 mmol, 3.0 equiv) and triethylamine (0.13 mL, 0.96 mmol, 5.0 equiv). The resulting mixture was heated at 90° C. for 1 h in a microwave apparatus, then concentrated under reduced pressure. The remaining material was separated between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material (112 mg) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 99% CH2Cl2/1% MeOH for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH for 5.2 min.) to give {1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (84 mg, 82%):
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diisopropylethylamine (7.8 ml, 45 mmol) was added in one portion to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (7.6 g, 41 mmol) in DCM (100 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (10.0 g, 45 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (14.9 g, 89% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 7.97 (2H, d), 3.34 (4H, obscured), 2.96-2.92 (4H, m), 1.33 (9H, s). Tr=1.91 min m/z (ES+) ([(M−100)+H]+) 272.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]=2[N:10]=[N:9]1>C(Cl)(Cl)Cl>[NH2:1][N:9]1[N:8]=[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]2=[N:10]1
Reactant: c1cnc2nn[nH]c2c1
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: Nn1nc2cccnc2n1

Procedure:
Anilines of general formula 9m or the corresponding bromides 3m with an 2-propan-2-ol group in 5-position of the triazolopyridine (see Scheme 18) can be prepared starting from ester 51 by bromination in chloroform followed by cyclization as already described in Scheme 8 to give 2-amino-triazolopyridine 53. The ester 53 can then be treated with methyl magnesium bromide to provide the tertiary alcohol 54. Conversion of the bromide by e.g. Suzuki reaction gives aniline 9m or after Sandmeyer reaction bromide 3m. The starting material 51 is either commercially available or can be synthesized by methods known in the art, e.g for R=Me, 51 can be prepared from the corresponding bromide by reaction with trimethyl boroxine in the presence of a palladium catalyst.
Reaction SMILES: [CH:1]1([C:7]2([C:20]([OH:22])=[O:21])[CH2:13][CH:12]3[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>CO.O=[Pt]=O>[CH:1]1([C:7]2([C:20]([OH:22])=[O:21])[CH2:13][CH:12]3[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1C=CCCC1)C2
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2

Procedure:
To a solution of 3-cyclohex-2-en-1-yl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-6) (1.86 g, 6.05 mmol) in MeOH (20.0 mL) was added PtO2 (68.7 mg, 0.30 mmol) and the suspension was placed on a shaker under hydrogen atmosphere (50 psi) overnight. The solid was filtered out and rinsed with MeOH; the resulting solution was concentrated to give (1-7) as white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:10][C:11](N)=[O:12]>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([NH2:10])=[O:12]
Reactant: CNCc1ccccc1
Reactant: NC(N)=O
Product: CN(Cc1ccccc1)C(N)=O
Temperature: 118 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To N-methylbenzylamine (12.1 g, 0.1 mol) was added urea (6.0 g, 0.1 mol). After stirred at 118° C. for 4 h, the mixture was cooled to room temperature. The solidified mixture was ground to a powder, washed with n-hexane and recrystallized with ethyl acetate to afford N-methyl-N-benzylurea (12.3 g, 75% yield): mp 125°-129° C.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:1]([N:4]1[C:9](=[O:10])[CH2:8][C@@H:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]([CH2:21][C:22]([OH:24])=[O:23])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)N1C(=O)C[C@@H](c2ccccc2)NC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1C(=O)C[C@@H](c2ccccc2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (S)-3-isopropyl-6-phenyldihydropyrimidine-2,4(1H,3H)-dione from Step B (310 mg, 1.34 mmol) in THF (6 mL) at 0° C. was added NaH (45.0 mg of a 60% dispersion in oil, 1.87 mmol). After 15 min, methyl bromoacetate (0.202 mL, 2.14 mmol) was added and the mixture was stirred at ambient temperature for 16 h. NaOH (4.00 mL of a 1M solution) was added and the mixture was stirred at ambient temperature for 2 h. A 10% citric acid solution (20 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=291 (M+1).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[S:14][C:15]3[CH2:22][CH2:21][O:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:16]=3[N:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].N1([CH:36]=[O:37])C2C=CC=CC=2N=N1.[OH-].[Na+]>C1COCC1>[N:17]1[C:16]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:15]=2[S:14][C:13]=1[NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:36]=[O:37])[CH2:7][CH2:8]1
Reactant: CCCNCC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Reactant: O=Cn1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C=O)CC1CCC(Nc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a solution of N2-{4-[(propylamino)methyl]cyclohexyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-amine (0.254 g, 0.68 mmol) in anhydrous THF (4 ml) was added 1H-benzotriazole-1-carboxaldehyde (0.110 g, 0.75 mmol). The solution was stirred at room temperature for 1 hour and then poured into 2N NaOH (50 ml) and extracted with EtOAc (60 ml). The extract was separated and evaporated to yield 295 mg of a viscous oil. Chromatography on silica-gel eluting with 1:1 EtOAc/hexane yielded 56% (152 mg) of the product as a white solid: 1H-NMR (CDCl3) δ 0.90 (3H, m), 1.14 (4H, m), 1.58 (2H, m), 1.78 (2H, m), 2.23 (2H, m), 3.20 (8H, m), 4.32 (2H, t, J=4.9 Hz), 5.03 (1H, m), 6.99 (1H, m), 7.12 (2H, m), 8.01 (0.5H, s), 8.11 (0.5H, s), 8.22 (1H, d); m.p. 53-55° C.; 400 (ESMS, MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[N:4]=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30](=[O:34])[CH2:31][C:32]#[N:33].C(O)(=O)C.N1CCCCC1.CCOCC>C1C=CC=CC=1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[N:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:31]([C:30](=[O:34])[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=3[F:22])[C:32]#[N:33])=[CH:14][CH:13]=2)[N:4]=1
Reactant: N#CCC(=O)c1cccc(F)c1F
Reactant: O=Cc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: N#CC(=Cc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)C(=O)c1cccc(F)c1F
Yield: 69.4 %

Procedure:
A stirred solution of 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (0.18 g, 0.58 mmol), 3-(2,3-difluoro-phenyl)-3-oxo-propionitrile (0.1 g, 0.55 mmol) and piperidine acetate (8 mg, 0.06 mmol) in dry benzene was heated at reflux for 12 hours. Volatile components were removed under reduced pressure to give a syrup. Trituration with ether gave 3-[4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-2-(2,3-difluoro-benzoyl)-acrylonitrile (0.18 g, 65% yield) as a solid: 1H-NMR (CDCl3) 6δ 7.15 (s, 1H), 7.24-7.32 (m, 1H), 7.38-7.50 (m, 2H), 7.72 (d, 2H, J=8.4), 8.11 (s, 1H), 8.20 (d, 2H, J=8.4) ppm. ESMS calculated for C21 H9F8N3O: 471.1; Found: 472.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:11]([Si:15]([CH3:17])([CH3:16])[O:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(O)ccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 508 (1.5 g, 10.7 mmol) was dissolved in dry DMF (40 mL) under an argon atmosphere. tert-Butyl-chloro-dimethyl-silane (2.43 g, 16.1 mmol) and imidazole (1.1 g, 16.1 mmol) was added. Stirred at RT for 2 h, added EtOAc (250 mL) and then washed with water (2×100 mL), 4% MgSO4 (2×75 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product as yellow oil. Purified by chromatography using EtOAc/petroleum ether (40-60)(1:20) as the eluent, affording the title compound as an colourless, clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:28](O)[CH3:29]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH2:28][CH3:29])=[O:10])[NH2:8])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1OC
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Yield: 51 %

Procedure:
A 47 g (0.21 mole) portion of 3,4-dimethoxyphenylalanine in 450 ml of absolute ethanol was treated with 31 ml of concentrated H2SO4. The reaction mixture was refluxed for 5 hours and poured into 1.6 l. of H2O. The solution was basified with a solution of 61 g of K2CO3 in 200 ml of water. The basified solution was extracted with three 600 ml portions of ethyl acetate. The combined extracts were washed with 1.4 l. of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 27 g (51%) of the desired product, a light yellow-brown viscous oil which crystallized upon refrigeration.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH:8][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:6]([F:12])[CH:5]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Under argon, sodium hydride (60%, 372 mg, 9.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67 g, 8.08 mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.3 g, 4.04 mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130 ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%) (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50° C. to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.4 g, 70%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1F>CS(C)=O.C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 60 °C
Yield: 103.1 %

Procedure:
A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and dibasic potassium phosphate (9.44 g, 54.2 mmol) in DMSO (27 mL) was treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g, 27.1 mmol) was warmed at 60° C. for 18 h. The solution was cooled and diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded the title compound (6.32 g, ca. 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J=9.0, 2.6, 0.9 Hz, 1 H), 7.92 (dd, J=13.1, 2.6 Hz, 1 H), 6.92 (t, J=8.8 Hz, 1 H), 3.88 (m, 4 H), 3.29 (dd, J=5.5, 4.0 Hz, 4 H). MS +DCI m/z (rel abundance) 227 (10, M+H), 244 (100, M+NH4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][C:33]=2[CH:39]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Yield: 24.7 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (78 mg, 0.20 mmol), 2,6-dichloro-1,3-benzothiazole (61.6 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 26.7 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (br s, 1 H), 7.75–8.05 (m, 9 H), 7.60 (d, 1 H), 7.10–7.40 (m, 6 H), 3.50 (q, 1 H), 3.10 (m, 1 H), 2.85 (m, 1 H), 2.65 (m, 2 H), 1.80 (m, 2 H). LC-MS m/z 541.3 (MH+), ret. time 4.07 min.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].[C:12]1([C:18]2[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[CH:19]=[CH:20][C:21]([CH2:22][N:7]3[C:8]4[C:4](=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:24][CH:25]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: ClCc1ccc(-c2ccccc2)cc1
Product: N#Cc1cccc2c1ccn2Cc1ccc(-c2ccccc2)cc1

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 65, but using 4-cyanoindole and 4-phenylbenzylchloride as starting materials, the title compound was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[C:3](C(Cl)(Cl)Cl)=[O:4].[C:11]1([C:21]([NH:23][NH2:24])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C(#N)C>[C:11]1([C:21]([NH:23][NH:24][C:3](=[O:4])[C:2]([Cl:10])([Cl:9])[Cl:1])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)c1cccc2ccccc12
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(NNC(=O)C(Cl)(Cl)Cl)c1cccc2ccccc12
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a mixture of 100 ml of acetonitrile and 14.6 g (0.055 mol) of hexachloroacetone was added 9.3 g of α-naphthoic acid hydrazide thus obtained and the resultant mixture was refluxed with stirring for 4 hours. The precipitates formed were recovered by filtration to provide 14.6 g (yield 88%) of N-α-naphthoyl-N'-trichloroacetylhydrazine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1.CN(C=O)C>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:26])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1CNCCN1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
In THF (30 ml) and DMF (30 ml) was dissolved 2-piperazinone (3.00 g), and to the solution was added triethylamine (5.02 ml). Under ice-cooling, to the mixture was added dropwise a solution of naphthalene-2-sulfonyl chloride (8.16 g) in THF (30 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was washed with sodium hydrogen carbonate solution, water and ethanol to give pale brown crystals of the title compound (7.15 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
5.00 g (37.3 mmol) of 5-hydroxyindazole are dissolved in 40 ml of anhydrous DMF. 5.93 g (37.3 mmol) of 3,4-difluoronitrobenzene and 5.15 g (37.3 mmol) of potassium carbonate are added, and the mixture is stirred at 40° C. overnight. For work-up, the mixture is filtered off with suction through kieselguhr, diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed 1× with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated using a rotary evaporator. The residue is chromatographed twice on silica gel using cyclohexane/ethyl acetate 3:1→1:1→1:2 and then purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:14]=4)=[C:4]2[CH:3]=1.[C:31]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])[CH:32]=[CH2:33]>>[N:35]1([C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:7]=[CH:6][C:5]3=[N:8][C:9]4[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[N:16]([CH3:23])[C:15]5[C:10]=4[C:11]([CH:12]=[C:13]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:14]=5)=[C:4]3[CH:3]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC(=O)OCCCc1cc2c3c(nc4ccc(Cl)cc4c3c1)-c1ccccc1N2C
Reactant: C=CC(=O)N1CCOCC1
Product: CC(=O)OCCCc1cc2c3c(nc4ccc(/C=C/C(=O)N5CCOCC5)cc4c3c1)-c1ccccc1N2C
Yield: 83 %

Procedure:
The general procedure (Method M) applied to acetic acid 3-(3-chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl)-propyl ester, 49 (100 mg, 0.247 mmol) and 4-acryloylmorpholine (70 mg, 63 μL, 2 eq) gave the title compound (104 mg, 0.2 mmol, 83%). Purity was checked by tlc.