Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH2:31]>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH:31][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: NCC1COc2ccccc2O1
Product: Fc1cnc(NCC2COc3ccccc3O2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.49 min.; purity: 87.6%; MS (m/e): 411.01 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.NCCCN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: NCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCCC(=O)O)CC1
Reaction time: 2 h

Procedure:
The compound (1.46 g) obtained in the above (1) is dissolved in dichloromethane (20 ml), and thereto are added glutaric anhydride (0.86 g) and triethylamine (1.14 ml), and the mixture is stirred for two hours. To the mixture is added dropwise N-(3-aminopropyl)morpholine (0.3 ml), and the mixture is further stirred for 30 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and thereto is added 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (1.54 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]I)=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][O:21][C:14]3[C:15]([Cl:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[Cl:12])=[CH:26][CH:27]=2)[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1F
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3F)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using commercially available (4-bromo-2-fluorophenyl)acetonitrile and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol 50%, afforded the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Pd].C(O)C>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1

Procedure:
In an autoclave there are added 32.5 g (0.1 moles) of 2-chloro-4'-fluoro-5,3'-dinitro benzophenone, 15.9 g (0.15 moles) of sodium carbonate, 2 g of 5% palladium/alumina catalyst (from Nihon-Engelhardt Co.) and 100 ml of ethanol. With the mixture being stirred at 30°-35° C., there is introduced hydrogen into the autoclave, at a constant pressure of 10 Kg/cm2. G, to carry out the reaction for ten hours. After the completion of the reaction, the reaction mixture is heated up to filter out the catalyst and the inorganic salt. Then, on cooling the mixture there is obtained 3,3'-diamino benzophenone in the form of yellow needle-like crystals. The crystals are filtered, washed with 10 ml of ethanol and dried. Yield 16.2 g (76.3%). M.P. 149°-151° C.
Reaction SMILES: [C:1]([CH:3](P(=O)(OCC)OCC)[CH3:4])#[N:2].[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:38]=[CH:37][C:25]2[C:26](=O)[C:27]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=3[O:29][CH2:30][C:24]=2[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[CH:38]=[CH:37][C:25]2[C:26](=[C:3]([CH3:4])[C:1]#[N:2])[C:27]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=3[O:29][CH2:30][C:24]=2[CH:23]=1
Reactant: O=C1c2ccc(Br)cc2COc2cc(F)ccc21
Reactant: CCOP(=O)(OCC)C(C)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C#N)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
[step 3] Commercially available diethyl 1-cyanoethylphosphonate (38.0 g, 199 mmol) was dissolved in THF (170 mL), LDA (99.0 mL, 199 mmol, 2.0 mol/L heptane/THF/ethylbenzene solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. 8-Bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-one (30.5 g, 99.0 mmol) obtained in step 2 and dissolved in THF (120 ml) was added to the reaction system, and the mixture was stirred at room temperature for 1 hr. To the mixture was added saturated aqueous ammonium chloride solution (500 mL), and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-80/20 v/v) to give 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (31.4 g, 92%, E/Z=1/1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](Br)=[O:20].O>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:6]1[CH:5]=[CH:4][C:3]2[O:10][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[C:7]=1[CH3:8]
Reactant: Cc1c(Br)ccc(O)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
An ice cold suspension of 2-amino-4-bromo-3-methylphenol (3.81 g, 18.86 mmol) and potassium carbonate (10.42 g, 75 mmol) in N,N-Dimethylformamide (DMF) (25 mL) was treated by dropwise addition of bromoacetyl bromide (1.971 mL, 22.63 mmol). The mixture was warmed to ambient temperature and stirred for one hour. Water was added and the mixture was diluted with ethyl acetate. There were insoluble solids, so the entire mixture was passed through a fine glass frit to afford 6-bromo-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one as an off-white solid (1.20 g, 26%). The filtrate was extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to give slightly impure 6-bromo-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one as a reddish-brown solid (3.05 g, 67%): 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (br. s., 1 H), 7.15 (d, J=8.6 Hz, 1 H), 6.79 (d, J=8.6 Hz, 1 H), 4.50 (s, 2 H), 2.30 (s, 3 H); LC/MS (m/z) ES+=242 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=O)[O:9][CH:8]2OC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC1OC(=O)c2c(F)cc(C(C)(C)C)cc21
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
To a solution of 101g (40 g, 168 mmol) in glacial acetic acid (360 mL) was added hydrazine monohydrate (240 mL) at 0-10° C. under N2 protection. The resulting slurry was stirred under nitrogen at 50° C. for 1.5 hours. The reaction mixture was poured into 300 mL of water with continuous stirring. The aqueous phase was extracted with DCM (2×500 mL), and the combined organic phase was dried over Na2SO4, filtered and concentrated to give a residue, which was purified by re-crystallization in DMC and Et2O to provide 101h (17 g, 37.6% over 2 steps) as an off-white solid. 1HNMR (300 MHz, CDCl3) δ 8.11 (d, J=2.7 Hz, 1H), 7.46 (m, 2H), 1.39 (s, 9H). LCMS (ESI) m/z 221 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(S(C)(=O)=O)ccc23)n[nH]1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 42.5 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-(methylsulfonyl)quinazolin-4-ol (76 mg, 0.21 mmol) were added phosphoryl tribromide (1.21 g), toluene (0.5 mL), and DIEA (0.072 mL, 0.42 mmol), and the mixture was heated at 100° C. for 10 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (59 mg, 0.6 mmol) in DMF (3 mL) and the mixture was stirred at rt for 20 min. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(methylsulfonyl)quinazolin-4-amine (40 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 3.39 (s, 3H) 6.06 (s, 1H) 7.97-8.05 (m, 2H) 8.09 (d, J=7.72 Hz, 1H) 8.33 (s, 1H) 8.67 (s, 1H) 8.97 (d, J=8.48 Hz, 1H) 11.10 (br s, 1H) 12.28 (br s, 1H); LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[CH2:9][CH:8](O)[C:7]=2[CH:20]=1.[Cl-].[Ca+2].[Cl-]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([Cl:1])[C:7]=2[CH:20]=1
Reactant: Cl
Reactant: COc1ccc2c(c1)Sc1cc(OC)c(Cl)cc1C(O)C2
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)Sc1cc(OC)c(Cl)cc1C(Cl)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Anhydrous hydrogen chloride was passed at 0° C. into a stirred solution of the alcohol from the above experiment (22.5 g) in methylene chloride (500 ml) for 3 hours. Anhydrous calcium chloride (5 g) was added, the mixture stirred at room temperature for 3 hours and filtered. The filtrate was evaporated under diminished pressure, yielding 23.4 g of crude 8,10-dichloro-3,7-dimethoxy-10,11-dihydrodibenzo(b,f)-thiepine. The compound was crystallized from methylene chloride and melted in the pure state at 151°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:32])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:14]=2[CH:31]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:32][S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:14]=2[CH:31]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(C)cc1

Procedure:
6-[(5-Amino-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[F-].[Cs+].Cl[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=1>O1CCOCC1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: CCc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(CC)cc3)ccc12

Procedure:
612 mg of 4-ethylphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 30 cm3 of dioxane, and the mixture is then refluxed for 16 hours. The reaction medium is diluted with 50 cm3 of ethyl acetate and 50 cm3 of water, filtered through a sinter funnel packed with Celite and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. The product, which is still impure, is repurified by HPLC (Hypurity; C18, 5 μm column; length 50 mm, diameter 21 mm, eluent: acetonitrile/water containing 0.05% trifluoroacetic acid; flow rate 10 cm3/min). After concentrating the fractions containing the expected product and drying (90 Pa; 45° C.), 240 mg of N-[6-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil. The product is used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH2:25][CH3:26])[C:5]([N+:27]([O-])=O)=[N:4]1)[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH2:25][CH3:26])[C:5]([NH2:27])=[N:4]1)[CH3:2]
Reactant: CCCOc1ccc2ccccc2c1CNc1c([N+](=O)[O-])nn(CC)c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOc1ccc2ccccc2c1CNc1c(N)nn(CC)c(=O)c1Br
Yield: 2 %

Procedure:
530 mg of 2-ethyl-4-bromo-5-(2-n-propoxy-1- naphthylmethylamino)-6-nitro-3(2H)pyridazinone (Compound No. 48) was dissolved in a mixture comprising 50 ml of ethanol and 25 ml of a 10 wt% sodium carbonate aqueous solution. Then, 1.0 g of sodium hydrosulfite was gradually added under stirring, and the mixture was then stirred at room temperature for 2.5 hours. Glacial acetic acid was added to neutralize the reaction solution. Then, the solvent was distilled off under reduced pressure. Water was poured to the residue thus obtained, and the mixture was extracted with chloroform. The extract was washed sequentially with water and with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. Then, the solvent was distilled off to obtain a residual yellowish orange solid substance. This product was purified by silica gel column chromatography by using chloroform and a mixture of chloroform/methanol (volume ratio of 10/1) as developers to obtain 10 mg of colorless crystals. This product was found to show the same behavior on the silica gel thin layer chromatography as the substance obtained in the above method (i), and was identical with it also in NMR, MS and IR spectrum.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=3[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1ccccn1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccn2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-hydroxypyridine as in Example 45 to afford 0.015 g (10%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO5F3 523, found 524 (M+1, 100%).
Reaction SMILES: [C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[H][H]>[Pd].O>[C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCCCCCC=CCCCCCCC1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCCCCCCCCCCCCC1

Procedure:
100 kg of 8-cyclohexadecenone (odoriferously good quality: GC ratio of (E) and (Z) isomers was 2.5:1), 45 kg of acetone and 100 g of palladium on activated charcoal (Pd content: 5 wt. %) with 40% water content were placed in a stirred autoclave equipped with a gassing stirrer. The reaction mixture was hydrogenated for 12 hours at 35° to 40° C. and at 15 bar hydrogen pressure and then filtered. After removing the acetone 99.2 kg of cyclohexadecanone were obtained (GC content of cyclohexadecanone: >98%). The product thereby obtained was of a good perfumery quality. The perfumery quality could be improved still further by recrystallisation from methanol.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]=1)[C:15](O)=[O:16].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>O1CCCC1>[CH2:35]([N:37]([CH2:38][CH3:39])[C:15](=[O:16])[CH:14]([CH3:13])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]=1)[CH3:36]
Reactant: CCNCC
Reactant: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C(C)Cc1nc(-c2ccccc2)nc2ccccc12
Reaction time: 0.33 h

Procedure:
Carbonyldiimidazole (1.65 g) is added to a stirred solution of dextrorotatory α-methyl-2-phenyl-4-quinazolinepropanoic acid (2 g) in tetrahydrofuran (20 cc). The mixture is stirred for about 20 minutes until the evolution of gas has ceased, and then for a further hour, and diethylamine (1.05 cc) is added. The mixture is stirred for 5 days at room temperature (approximately 20° C.) and then heated under reflux for two hours. The solvent is evaporated off under reduced pressure and the residue taken up with ethyl ether (100 cc). The organic phase is washed with water (2×10 cc), then with normal hydrochloric acid solution (2×5 cc), then with normal sodium hydroxide solution (2×5 cc) and finally with water (2×5 cc). It is then dried over magnesium sulphate and evaporated under reduced pressure. The residue is recrystallized twice in isopropyl ether. Laevorotatory N,N-diethyl-α-methyl-2phenyl-4-quinazolinepropanamide (1.1 g , m.p. 93.5° C., is thereby isolated; αD at 0.5% in EtOH at 23° C.=-17.9°±2°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:44]([NH:47][NH2:48])(=[O:46])[CH3:45]>O.CN(C)C=O>[C:44]([NH:47][NH:48][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])(=[O:46])[CH3:45]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 1H-1,2,3-benzotriazol-1-ol (0.36 g) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.51 g) at room temperature. The mixture was stirred for 10 min and acetohydrazide (0.33 g) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.65 g, yield 77%) as colorless crystals. melting point 254-256° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2C1CCCC1
Yield: 62.5 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (91.0 mg).