Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.C([Li])(CC)C.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1Br.O>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[C:39]=2[F:40])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCOc3cccc(F)c3F)CC2)CC1
Reactant: Fc1cccc(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCOc3ccc(-c4cccc(F)c4F)c(F)c3F)CC2)CC1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under nitrogen gas stream, 101 g (267 mmol) of the 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluorophenyl ether obtained by the procedures described above was dissolved in 1.0 l of THF and cooled down to −70° C. To this solution was added by drops 320 ml of sec-butyl lithium (1.0M, cyclohexane solution) while being maintained at the same temperature, and stirred at the same temperature for 2 hours. To the reaction mixture was added by drops 640 ml of zinc chloride (0.5M, THF solution), and stirred at the same temperature for 1 hour, the reaction temperature was gradually raised up to room temperature, and they were stirred for 1 hour. To the reaction mixture was added 1.00 g of tetrakis(triphenylphosphine)palladium (0), and a solution of 61.8 g (15.9 mmol) of 2,3-difluoro-1-bromobenzene in 600 ml of THF was added by drops thereto, and heated to reflux for 3 hours. The reaction mixture was added to 1.0 l of water to terminate the reaction, the solvent was distilled off under a reduced pressure, and the residue was extracted with 3.0 l of toluene. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 55.3 g of a crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluoro-4-(2,3-difluorophenyl)phenyl ether.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[N:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:30])[CH2:36]3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Reactant: O=C1CNCCN1
Solvent: CS(C)=O
Product: O=C1CN(c2cc(-n3ccccc3=O)ccc2-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)CCN1
Yield: 17.2 %

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg, 0.16 mmol) and 2-oxopiperazine (565 mg, 5.65 mmol) in DMSO (1 mL) was heated at 150° C. for 2 days. The mixture was purified by HPLC to give the title compound (14 mg). MS 509.0 and 511.0 (M+H, Cl pattern).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1Cl.ClCl.O>CO>[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]=1[OH:1]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1O

Procedure:
To a solution of 168 g (4 moles +5% excess) of sodium hydroxide in 1000 ml methanol there were added portionwise, at 50°-65°C internal temperature, 586 g (2 moles) 2,4-bis-trifluoromethyl-6-nitrochlorobenzene; the reaction mixture, after completion of addition (about 1 hour) of the reactive chlorine compound, was boiled under reflux for one hour. After cooling, 700 ml of water were added to the mixture and unreacted starting materials were extracted once with 400 ml methylene chloride. The aquous phase was separated off, distinct acidification was effected with 20%-strength sulfuric acid; the 2,4-bis-trifluoromethyl-6-nitrophenol which separated was taken up in methylene chloride. The organic phase was dried over sodium sulfate. The 2,4-bis-trifluoromethyl-6-nitro-phenol remaining behind after methylene chloride had been distilled off was subjected to vacuum distillation. 480 g (87%) of the boiling pont 105°-106°C/20 mm Hg were obtained; refractive index nD20 : 1.4580.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)=O.[ClH:21].C(OCC)(=O)C>[C].[Pd].CO>[ClH:21].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCCOc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)CCCOc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of ethyl 4-[(3-cyanophenyl)oxy]butanoate obtained in Reference Example 41 (8.50 g, 36.4 mmol), 10% palladium carbon (containing 50% water)(12.8 g), formic acid (98 mL) and methanol (80 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. 4N Hydrogen chloride/ethyl acetate solution (15.0 mL, 60.0 mmol) was added to the obtained residue, and the mixture was stirred, and concentrated under reduced pressure. The residue was crystallized from toluene, and the crude crystals were recrystallized from diethyl ether to give the title compound as a white powder (7.79 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.N1CCCCC1>CCO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH:19]=[CH:17][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=2)=[O:18])[CH:21]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)C=Cc2cccnc2)c1

Procedure:
A mixture of 16 (4.0 g, 16 mmol), nicotinaldehyde (1.89 mL, 20 mmol), and piperidine (4.0 mL, 40 mmol) in absolute EtOH (65 mL) was heated at reflux for 16 h. The mixture was cooled and concentrated in vacuo. Chromatography on silica gel (30-60% EtOAc/hexanes) gave a mixture of unreacted nicotinaldehyde and 17 (both have the same Rf on TLC). Washing of the mixture with hexane in a filter funnel provide 1.73 g (32%) of pure 17 as a yellow crystal. 1H NMR (CDCl3, 300 MHz) 8.87 (d, J=2.1 Hz, 1 H), 8.66 (dd, J=4.8, 1.5 Hz, 1 H), 7.97 (d, J=7.9 Hz, 1 H), 7.80 (d, J=16.7 Hz, 1 H), 7.66 (d, J=7.6 Hz, 1 H), 7.60 (d, J=15.9 Hz, 1 H), 7.55 (s, 1 H), 7.46 (t, J=7.8 Hz, 1 H), 7.38 (dd, J=7.9, 4.8 Hz, 1 H), 7.20 (dd, J=8.2, 2.6 Hz, 1 H), 4.62 (s, 2 H), 1.52 (s, 9 H); 13C NMR (CDCl3, 75 MHz) 189.7, 175.0, 168.0, 158.7, 151.6, 150.5, 141.4, 139.5, 134.9, 131.0, 130.2, 124.2, 122.3, 120.6, 114.1, 83.1, 66.2, 28.4.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[O:19]([CH2:26][CH2:27]O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([CH2:26][CH2:27][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCOc2ccccc2)cc1
Yield: 77.1 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 2-phenoxyethanol (163 μL, 1.19 mmol) to give 241 mg of the title compound
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][OH:18])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: OCc1ccccc1B(O)O
Reactant: Clc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1-c1ccn2nc(-c3ccc(Cl)cc3)cc2c1
Yield: 92.3 %

Procedure:
The procedure described in Example 3 is followed. Starting from 0.3 g (0.98 mmol) of 5-bromo-2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine, obtained according to the protocol described in Examples 1.3 or 2.3, 0.18 mg (1.18 mmol) of 2-(hydroxymethyl)phenylboronic acid, 0.975 g (2.99 mmol) of caesium carbonate, 0.085 g (0.10 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 5 ml of a THF/water (9/1) mixture and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (7/3), 0.303 g (92%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=4[CH3:25])[CH2:34][CH2:35]3)[CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(Br)c1)N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of 2-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.39 g, 1.0 mmol), 1-(2,4-dimethyl-phenyl)-piperazine (0.29 g, 1.5 mmol), palladium (II) acetate (6.73 mg, 0.03 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (0.65, 2.0 mmol) in toluene (10 mL) was heated for 3 h at 120° C. After colling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 60%) as a white solid: MS (ESI) M+1=499.3.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH:22]=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N[n+]1ccc2occc2c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3occc3c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.9 %

Procedure:
To a mixture of 5-aminofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.14 mmol) and potassium carbonate (608 mg, 4.40 mmol) in dimethylformamide (20 mL) was added methyl 3-phenylpropiolate (509 μL, 3.45 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (467 mg, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH:26]1CC[CH2:29][CH2:28][CH2:27]1>CN(C=O)C.O>[CH2:24]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)[C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: BrCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a stirred solution of tert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate (3.79 g, 16.9 mmol) in DMF, cooled to 0° C. with a brine/ice bath, was added potassium tert-butoxide (126 mg, 1.07 mmol). The mixture was stirred 5 minutes at 0° C. then 1-bromo-2cyclohexylethane (205 mg, 1.07 mmol) was added. After stirring at room temperature for 4 h, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL). The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded tert-butyl hexyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as a yellow oil [3.60 g, yield 69%; HPLC/MS: m/z=309 (M+H); log P(HCOOH)=3.94].
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[C:17]([CH3:40])=[CH:18][C:19]([F:39])=[C:20]([CH:38]=1)[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34]CCO)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:5]([O:4][CH2:1][CH2:2][O:34][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:20]3[CH:38]=[C:16]([O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:17]([CH3:40])=[CH:18][C:19]=3[F:39])=[N:23][CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])(=[O:7])[CH3:6]
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Acetic anhydride (55 ml, 0.58 mmol) was added to a mixture of 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (233 mg, 0.52 mmol), triethylamine (80 ml, 0.57 mmol) and 4-(N,N-dimethylamino)pyridine (5 mg) in ethyl acetate (50 ml). The mixture was stirred for 2 hours at ambient temperature, water was added, the organic layer separated, washed with water and brine and dried (MgSO4). Most of the solvent was removed by evaporation and hexane added. The precipitated product was collected by filtration to give 7-(2-acetoxyethoxy)-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (110 mg, 43%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:9][O:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[F:37][C:28]1[CH:29]=[C:30]([C:33]([OH:36])([CH3:34])[CH3:35])[CH:31]=[CH:32][C:27]=1[C:21]1[S:20][C:19]([NH:18][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:9][O:10][CH3:11])[N:7]=2)=[C:23]([C:24]([NH2:26])=[O:25])[CH:22]=1
Reactant: COCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COCC(c1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[1-(6-bromopyridin-2-yl)-2-methoxyethyl]morpholine (111 mg, 0.37 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (108 mg, 0.37 mmol) as the starting materials.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O>>[OH:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: COc1ccc(C=O)c(O)c1
Product: COc1ccc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(O)c1
Yield: 68 %

Procedure:
6-Phenyl-2-oxindole (50 mg, 0.3 mmol) was condensed with 2-hydroxy-4-methoxybenzaldehyde (50 mg, 0.33 mmol) using method B to give 70 mg (68%) of 3-(2-hydroxy-4-methoxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[NH:6][C:7]=1[CH3:8].[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].[Br-].[Li+]>C(O)C.O>[C:29]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]3[N:4]=[C:5]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=4)[NH:6][C:7]=3[CH3:8])[CH2:27][CH2:28]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2nc(CO)c(C)[nH]2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c(C)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
One mole of 4-hydroxymethyl-2-(4-methylpheny)-5-methyl-1H-imidazole (202 g) was dissolved in 2 liters of 95% ethanol, then 252 g (1 mole) of N-(diphenylmethyl)piperazine was added portionwise. This was followed by the addition of 1 liter of water, 60 g (1.5 mole) of sodium hydroxide (as 12N solution) and 8.7 g (0.1 mole) of lithium bromide. The reaction medium was refluxed for 5 hours, allowed to cool to room temperature, and was stirred overnight. The precipitate that formed was filtered and purified by reslurrying from 1.2 liters of an ethanol-water mixture (60/40) to produce the 383.6 g of the title compound (0.88 mole, 88% yield), having a melting point of 238° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[NH2:55][C@@H:56]([CH3:72])[CH2:57][N:58]1[CH:62]=[CH:61][C:60]([C:63]2[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[C:65]([Cl:71])[CH:64]=2)=[N:59]1>CN(C)C=O.O>[Cl:71][C:65]1[CH:64]=[C:63]([C:60]2[CH:61]=[CH:62][N:58]([CH2:57][C@@H:56]([NH:55][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[CH3:72])[N:59]=2)[CH:70]=[CH:69][C:66]=1[C:67]#[N:68]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid (1.364 g, 10.82 mmol) was suspended in N,N-Dimethyl formamide (25 ml). 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.342 g, 0.901 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.073 g, 10.82 mmol), DIPEA (3.14 ml, 18.03 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (2.5 g, 9.01 mmol) were rapidly added into the mixture, respectively. The reaction mixture was stirred at RT overnight. Next day water was slowly added and the mixture was extracted twice with DCM. The combined organic phases were extracted three times with water and the DCM-layer was evaporated. The product was crystallized from acetonitrile/water mixture and finally dried with vacuum at 40° C. Yield 71.6%. 1H-NMR (400 MHz; d6-DMSO): δ 1.08 (d, 3H), 2.31 (s, 3H), 4.27 (dd, 1H), 4.32-4.48 (m, 2H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H), 7.95-8.02 (m, 2H), 8.04 (d, 1H), 8.10 (m, 1H), 12.10 (bs, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].C(OCC)(=O)C.[C:33](#[N:35])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][C:33]#[N:35])[CH2:2][CH2:3][CH3:4]
Reactant: CC#N
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC#N
Temperature: 25 °C

Procedure:
3.0 g 4-Butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole were dissolved in 50 ml acetonitrile. To this solution was added 2.89 g tetrabutylammoniumcyanide. The reaction mixture was stirred at room temperature for thirty minutes. Then a mixture of saturated NaHCO3 solution, ice and ethyl acetate was added. The aqueous phase was separated and extracted three times with portions of 30 ml ethylacetate. The combined organic layers were washed with ice cold water and brine and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane:ethyl acetate=5:1 to provide 1.1 g [4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetonitrile as oil.
Reaction SMILES: [C:1]([C:4]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:24](OCC)(=O)[C:25]([O:27]CC)=[O:26].[O-]CC.[Na+]>CCOCC>[C:25]([C:24]1[O:23][C:22]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:19]=[CH:20][CH:21]=2)([OH:27])=[O:26]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Br)cc3)cccc2o1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-bromophenoxypropane (15.2 g) and diethyl oxalate (15 ml) was added to a suspension of sodium ethoxide (prepared from 3.0 sodium) in absolute ether. The mixture was heated under reflux for 1.5 hours and then poured onto ice (100 g). After acidification with a solution of acetic acid (12 ml) in water (80 ml), the ether layer was separated and the aqueous layer was extracted with ether (3 × 25 ml). The combined ether solutions were evaporated and the residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. Recrystallization from acetic acid yielded crude 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-bromophenoxypropane, (14.7 g), as a white solid, m.p. 188°-190°, which was converted to the ethyl ester employing absolute ethyl alcohol and concentrated sulphuric acid as catalyst. 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-2-p-bromophenoxypropane was obtained as white crystals, m.p. 79°-80° after recrystallization from aqueous dioxane.