Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1COCC1.Cl[C:47]([O:49][CH3:50])=[O:48]>O>[CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([N:14]([CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[C:47]([O:49][CH3:50])=[O:48])[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2c(c(C)nn2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(c(C)nn2C)C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3,5-Bis-trifluoromethyl-benzylamino)-6-ethyl-1,3-dimethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridine-7-carboxylic acid ethyl ester (0.02 g, 0.04 mmol) obtained in step (vi), and K2CO3 (0.016 g, 0.12 mmol) were charged to a flask under a nitrogen atmosphere. Dry THF (5 mL) was added to this mixture, and the resulting mixture was stirred at room temperature for about 30 min, after which time methyl chloroformate (0.011 g, 0.12 mmol) was added dropwise. The reaction was stirred at room temperature overnight. Water was then added to the reaction mixture and the product was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum to provide a residue. This residue was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate in petroleum ether as eluent, to afford the title compound. Yield: 0.01 g (50%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O:3][CH3:4])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O:3][CH3:4])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)OC
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(/C=C/c1scnc1CCCCCCC(=O)OC)OC(C)=O
Reaction time: 24 h

Procedure:
To the solution of 353 mg of 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, R1 = H) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added. The reaction mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated under vacuum in vacuo. The obtained 390 mg of evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. Thus, 285 mg of 4-(6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, R1 = H) of chromatographic purity were obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3c(F)cccc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Lithium hydroxide monohydrate (0.011 g, 0.26 mmol) was added to a stirred solution of {4-[4-(2,6-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.031 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,6-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.024 g, 80%) as a solid. The final product was isolated with a significant amount of water as an impurity. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.17 (d, J=7.91 Hz, 2 H), 8.01 (dd, J=9.23, 6.22 Hz, 1 H), 7.91 (s, 1 H), 7.80-7.88 (m, 1 H), 7.58 (d, J=8.48 Hz, 2 H), 7.39 (t, J=9.04 Hz, 3 H), 6.64 (d, J=11.87 Hz, 1 H), 3.83 (s, 2 H), 2.04 (s, 3 H). MS calcd. for C25H16F3O4S [(M−H)−] 469, obsd. 469.2.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Yield: 72.4 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 102.6 g of (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and using 4-nitrophenol instead of benzoic acid. Thus, 118.2 mg (72.4%) of (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline was obtained as a pale yellow amorphous substance.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:36]1C[CH2:39][CH2:38][CH2:37]1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:36])[CH:38]=[CH2:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 6 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine and tetrahydrofuran using Method G (6% yield). HPLC: 96%, RT=4.127 min. MS: m/z=423 [M+H]+, RT=3.22 min. 1H-NMR (DMSO-d6) δ 9.14 (s, 1H), 9.02 (d, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H), 7.93 (t, 1H), 7.87-7.84 (m, 3H), 7.73 (d, 2H), 7.62-7.58 (m, 3H), 7.51-7.50 (m, 3H), 6.77 (dd, 1H), 6.67 (d, 1H), 6.03 (d, 1H), 5.02 (d, 2H).
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.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:25]2
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 6-phenyl-2-oxindole (45 mg, 0.21 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 68 mg (76%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.0 g, 10.6 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add sodium hydride (305 mg, 12.7 mmol) in portions. After the vigorous gas evolution stops, add 1-bromo-propane (1.4 mL, 15.9 mmol) and stir the reaction mixture overnight at room temperature. Slowly pour the reaction into water (400 mL) and extract with diethyl ether (2×150 mL). Wash the combined organic layers with water (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to yield 2.7 g of 1-bromo-4-propylsulfanyl-benzene (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][C:11](=[O:16])[CH2:12]1
Reactant: O=C1CC(=O)CC(c2cc(F)ccc2F)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1CC(=O)CC(c2cc(F)ccc2F)C1
Yield: 92.1 %

Procedure:
A solution of 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (4.0 g) and ammonium acetate (4.1 g) in ethanol (60 ml) was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with water and dried to obtain 1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5](N)[CH:6]=[CH:7][CH:8]=1.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[BrH:22]>O>[Br:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Reactant: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
3-Methoxy-2-nitro-phenylamine (360 mg, 2.14 mmol) was dissolved in HBr (48%, 4.8 mL) at 0° C. A solution of sodium nitrite (0.16 g, 2.40 mmol) in water (360 μL) was added dropwise to the stirred solution over one hour period while the temperature was maintained at 0° C. Then a cold (0° C.) freshly prepared solution of CuBr2 (from CuSO4.5H2O (1.0 g) and HBr (48%, 1.0 mL) mixed 30 min. at room temperature to give a dark purple solution) was added at 0° C. to the reaction mixture. The resulting solution was stirred at 0° C. for 3 hours and at room temperature for 2 days. The reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 482 mg (2.08 mmol, 97%) of 1-bromo-3-methoxy-2-nitrobenzene as an orange solid.
Reaction SMILES: [OH:1][C:2]1[N+:3]([O-:26])=[C:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[NH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[Si](Cl)(C(C)(C)C)(C)[CH3:28].N1C=CN=C1>ClCCl>[CH2:22]([C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)=[C:2]([O:1][CH3:28])[N+:3]=1[O-:26])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Cc2[nH]c(=O)c(CC(C)C)[n+]([O-])c2O)cc(OC)c1OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(Cc2[nH]c(=O)c(CC(C)C)[n+]([O-])c2OC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a suspension (90 ml) of dried dichloromethane, containing 3.00 g of 5-hydroxy-3-isobutyl-6-(3,4,5-trimethoxy-benzyl)-1,2-dihydropyrazin-2-one 4-oxide, there were added 1.16 g of tert-butyldimethylsilyl chloride and 1.05 g of imidazole, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with an aqueous solution saturated with sodium chloride and was dried with magnesium sulfate. After filtration of the reaction mixture, to the filtrate was added a diethyl ether solution of diazo-methane, then this mixture was allowed to stand at room temperature for 1.5 hours. The solvent was removed by distillation under reduced pressure, the resulting residue was dissolved in 50 ml of tetrahydrofuran and 5 ml of methanol, then 5 ml of tetrahydrofuran solution of 1M-n-Bu4N⊕F⃝ was added thereto and was stirred at room temperature for 10 minutes. To this reaction mixture was added ethyl acetate and water, then the organic layer was obtained by separation and dried with magnesium sulfate. The solvent was removed by distillation, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and the pale yellow oily substance was crystallized from diethyl ether to obtain 0.74 g of 3-isobutyl-5-methoxy-6-(3,4,5-trimethoxybenzyl)-1,2dihydro pyrazin-2-one 4-oxide. Pale yellow needles
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[F:27][C:28]1([F:39])[C:32](F)=[C:31](F)[C:30]([F:36])([F:35])[C:29]1([F:38])[F:37]>C1COCC1.CCOCC>[F:27][C:28]1([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:11][CH:12]=3)[S:4][C:3]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:21][CH:22]=2)=[C:32]1[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1ccc(-c2cc(Br)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(-c2cc(C3=C(c4cc(-c5ccc(C(C)(C)C)cc5)sc4-c4ccc(C(C)(C)C)cc4)C(F)(F)C(F)(F)C3(F)F)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Reaction time: 0.25 h

Procedure:
A solution of (30) in anhydrous THF/ether cooled to −45° C. and treated with nBu—Li-(2.5 M in hexanes, 35 mL, 87 mmol) dropwise under a n argon atmosphere. The reaction mixture was stirred for a further 15 minutes followed by addition of octafluorocyclopentene (5.6 mL, 41.5 mmol) using a cooled gas tight syringe. The reaction was allowed to stir until the temperature reached −10° C., quenched by the addition of 10% HCl (50 mL). The aqueous layer was separated and extracted with ether. The organic phases were separated and pooled, dried over MgSO4, filtered and solvent removed by rotary evaporation. The crude product was stirred in MeOH for 3 hours, and the resulting precipitate filtered, dried and purified using flash chromatography (hexanes), affording 2 fractions—F1 was pure S006 (TLC), F2 contained S006 along with a fluorescent byproduct by TLC. F1, 5.35 g, 14.8%) and F2, 10.4 g (˜75% pure, 22%) as light yellow, powdery solids. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.5 Hz, 4H), 7.30 (d, J=8.5 Hz, 4H), 7.05 (d, J=8.4 Hz, 4H), 6.92 (d, J=8.4 Hz, 4H), 6.13 (s, 2H), 1.34 (s, 18H), 0.91 (s, 18H).
Reaction SMILES: [Na:1].CC1(C)O[C@H]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:18])[C:11]=2[CH3:28])CO1.[O:30]1[C:34]2([CH2:38][CH2:37][CH2:36][CH:35]2CO)[O:33][CH2:32][CH2:31]1>>[Na:1].[O:30]1[C:34]2([CH2:38][CH2:37][CH2:36][CH:35]2[CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:18])[C:11]=2[CH3:28])[O:33][CH2:32][CH2:31]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCC1CCCC12OCCO2
Agent: [Na]
Product: Cc1c(OCC2CCCC23OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (14a) to (14e) of Example 14 was repeated using the 1,4-dioxaspiro[4.4]non-6-ylmethanol obtained in the step (80b) above to obtain the title compound (383 mg, the total yield of 5 steps: 14.6%) as a light yellow solid. Note that in the same process as in the step (14c), methanol was used as a solvent instead of ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[CH:46]=[CH:45][C:13]2[N:14]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](OC4C=CC=CC=4)=[O:35])=[CH:29][C:28]=3[O:43][CH3:44])(=[O:26])=[O:25])[C:15](=[O:23])[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12]=2[CH:11]=1)[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:46]=[CH:45][C:13]2[N:14]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:35])=[CH:29][C:28]=3[O:43][CH3:44])(=[O:25])=[O:26])[C:15](=[O:23])[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12]=2[CH:11]=1)[CH3:8]
Reactant: C1CCNCC1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)N2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 ml of piperidine were added to a solution of 500 mg of the compound obtained in Example 16 step A) in 25 ml of DCM. The reaction mixture was then stirred for 18 hours at room temperature. It was concentrated to dryness and the resulting product was passed over silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.36 g of the expected product in the form of white crystals. M.p. =232° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:20][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=1)[N:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]2=[O:18]
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1ncccc1-n1c(CNc2cccc(CN3CCCC3)c2)nc2ccc(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.158 g, 0.56 mmol), 3-pyrrolidin-1-ylmethylaniline (0.050 g, 0.28 mmol), and acetic acid (0.16 mL, 2.8 mmol) in dichloroethane (15 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.297 g, 1.4 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (35 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (50 mL), nil; (75 mL), unweighed impurity; (50 mL), unweighed 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (50 mL), unweighed mixed fraction; (100 mL), 0.031 g (25%) of 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a yellow foam which had: 1H NMR δ 8.72 (d, J=5 Hz, 1H), 7.92 (dd, J=3, 8 Hz, 1H), 7.82 (dd, J=5, 9 Hz, 1H), 7.58-7.52 (m, 2H), 7.39 (dd, J=5, 8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 6.67-6.64 (m, 2H), 6.37 (d, J=8 Hz, 1H), 5.10 (s, 1H), 3.90 (dd, J=4.5, 17 Hz, 1H), 3.70 (dd, J=5, 17 Hz, 1H), 3.56 (ABq, Δv1-3=21 Hz, J=12.5 Hz, 2H), 2.54 (s, 4H), 2.36 (s, 3H), 1.78 (s, 4H); APCI MS m/z=444 (P+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cn1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 62.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 2-(5-aminopyridin-2-yloxy)ethylcarbamate (380 mg, 1.5 mmol) to afford the desired product (332 mg, 63%) as a yellow solid: ESI MS m/z 527 [C25H27BrN4O4+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>CN(C)C=O>[NH:24]1[CH:25]=[C:21]([CH2:20][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[N:22]=[CH:23]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 5.80 g. portion of diphenylacetonitrile and 1.5 g. of 50% sodium hydride were reacted for 30 minutes in 20 ml. of dimethylformamide, and 2.29 g. of 4-chloromethylimidazole hydrochloride in 20 ml. of dimethylformamide was added. The reaction mixture was stirred at ambient temperature for about 15 minutes, the solvent was evaporated from the mixture under vacuum, and the residue was worked up as described in Example 1 to obtain 3.0 g. of the desired product as the free base, which was identified by 60 mHz nuclear magnetic resonance analysis in CDCl3, showing the following characteristic peaks: δ9.05 (broad m, 1H); 7.32 (m, 11H); 6.60 (s, 1H); 3.68 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Br)c1
Yield: 81.6 %

Procedure:
2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-Bromobenzylamine (2.6 g, 18.1 mmol) and N,N-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.25 (dd, 1H), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).