Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of the alcohol (25 g, 80 mmol) produced in Example 2 and pyridine (6.4 mL, 80 mmol) in 300 mL of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (16.1 g, 80 mmol) in 200 mL of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, two times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 37.3 g of an off-white solid. Recrystallization from 1:1 ethyl acetate: hexane gave 26.4 g (69%) of the title compound as an off-white solid, mp 108-109° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:27]2[CH:26]=[CH:25][N:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:23](=[O:34])[C:22]=2[C:21]([CH3:35])=[C:20]1[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:27]2[CH:26]=[CH:25][N:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:23](=[O:34])[C:22]=2[C:21]([CH3:35])=[C:20]1[C:36]1[CH:37]=[CH:38][C:39]([O:42][S:5]([CH2:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])=[CH:40][CH:41]=1
Reactant: Cc1c(-c2ccc(O)cc2)n(-c2ccc(Cl)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(OS(=O)(=O)CCC(F)(F)F)cc2)n(-c2ccc(Cl)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Reaction time: 0.25 h

Procedure:
3,3,3-Trifluoro-propane-1-sulfonyl chloride (100 mg, 0.509 mmol) was added to 1-(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (74 mg, 0.158 mmol) dissolved in pyridine (5 ml) at 0° C. The reaction was continued at 0° C. for 1 h and 15 min and then at rt. After 15 min at rt more 3,3,3-trifluoro-propane-1-sulfonyl chloride (260 mg, 1.323 mmol) was added. After 15 min the solvent was evaporated. Purified by flash chromatography (20-100% EtOAc in toluene) to yield the title compound as a white solid after evaporation (24 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:46])/[C:18](/[NH:42][C:43](=[O:45])[CH3:44])=[CH:19]\[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:30][C:29](=[O:31])[NH:28][S:27]2(=[O:33])=[O:32])=[C:22]([O:34]CC2C=CC=CC=2)[CH:21]=1>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:47])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:46])[CH:18]([NH:42][C:43](=[O:45])[CH3:44])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:30][C:29](=[O:31])[NH:28][S:27]2(=[O:32])=[O:33])=[C:22]([OH:34])[CH:21]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)/C(=C\c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)C(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)NC(C)=O

Procedure:
A solution of 2-(4-{(E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acryloylamino}-butoxy)-6-hydroxybenzoic acid methyl ester (300 mg) in 16 mL of EtOH/HOAc (1:1) is hydrogenated 1 atm over 10% Pd/C (70 mg) for 4 h. The catalyst is filtered, the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC and lyophilization to give the title compound as a white solid. This is converted to its potassium salt by addition of 1 equivalent of KHCO3: (M−1)−=577. HPLC retention time: 0-86 min. (Method A).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25]>CN(C)C=O>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[C:24]=1[CH3:25]
Reactant: Cc1nc[nH]c1C
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2nccc3[nH]c(=O)ccc23)c1C
Yield: 48 %

Procedure:
A mixture containing 12.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 300 ml of dimethylformamide, 13.8 g of anhydrous potassium carbonate, 10.8 g of 4,5-dimethylimidazole and 200 mg of cuprous bromide was refluxed with stirring for eight hours About 20 ml of the solvent was distilled off using a water separator to remove any moisture from the reaction mixture. The remaining reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in water, acidified with acetic acid and evaporated to dryness on a rotary evaporator. The residue was treated with 50 ml of water and the brown solid was collected, washed with water, recrystallized from ethanol in the presence of decolorizing charcoal. The resulting pale yellow solid was dried at 80°-85° C. to yield 6.4 g of 5-(4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 256°-258° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][CH2:23]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC1CCN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-N-propylpiperidine (18 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether to give the title compound (15 mg, 38%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL), oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops) were added and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Next, to a suspension of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) in chloroform (60 mL), a solution of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride in chloroform (60 mL) was added dropwise under ice cooling and stirred at room temperature for 1 hour, followed by addition of water and chloroform under ice cooling to separate the organic layer. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to give 4-(benzyloxy)-5-bromo-N-methoxy-N-dimethylbenzamide. To a solution of this product in THF (150 mL), lithium aluminum hydride (1.96 g, 51.7 mmol) was added at −10° C. and stirred at the same temperature for 1 hour. The reaction mixture was diluted with 1N hydrochloric acid, followed by addition of ethyl acetate to separate the organic layer. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to give 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a solution of this product in toluene (120 mL), ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol) were added and heated under reflux for 1.5 hours using a Dean-Stark apparatus. Ethyl acetate was added to the reaction mixture to separate the organic layer. The organic layer was washed with water, saturated sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) and further purified by NH-type silica gel column chromatography (chloroform) to give the titled compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:17])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(-c2ccccc2)cc(OC(C)=O)cc1-c1ccccc1
Yield: 92 %

Procedure:
A mixture of 4acetoxy-2,6diphenylphenol (6.1 g, 20 mmol; prepared as described in Ber. 101, 2519 (1968)), ethyl bromoacetate )4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) and 2-butanone (150 ml) was refluxed for 24 h, then filtered and the solvent evaporated. The residue was purified by chromatography on silica gel) 120 g, eluent benzene) to give 7.2 g (92%) of oily ethyl 4-acetoxy-2,6-diphenylphenoxyacetate.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C@H:5]1[C@@H:11]2[CH2:12][C@@H:8]([C:9](=[O:13])[O:10]2)[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[CH2:6]1.Cl>CO>[Br:4][C@H:5]1[C@@H:11]([OH:10])[CH2:12][C@@H:8]([C:9]([O:2][CH3:1])=[O:13])[C@H:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[CH2:6]1
Reactant: O=C1O[C@H]2C[C@@H]1[C@H](c1ccccc1Br)C[C@H]2Br
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)[C@H](Br)C[C@H]1c1ccccc1Br

Procedure:
Freshly prepared sodium methoxide (0.45 M in methanol) was added to a methanol (20 mL) solution of (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-6-oxabicyclo [3.2.1] octan-7-one (5.43 g, 15.1 mmol) with stirrng at rt for 1.5 hours. The mixture was then treated with 0.5 M HCl (50 ml) and the methanol was removed by rotary evaporation under reduced pressure. The residue was partitioned between water and ethyl acetate and the layers separated. The aqueous phase was extracted with additional ethyl acetate and the combined organics were washed with water, 5% Na2CO3 (2×75 mL) and brine, and dried (Na2SO4). Concentration in vacuo yielded methyl (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-5-hydroxycyclohexanecarboxylate as a faint-yellow solid after trituration with ether/hexanes.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:27])[CH3:26])[CH:23]=4)[N:18]([CH3:28])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:27])[CH3:26])[CH:23]=4)[N:18]([CH3:28])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)O)cc34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(C(C)O)cc34)nc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
In a round-bottomed flask, 2-[5-(1-hydroxy-ethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (41 mg, 0.08 mmol) was dissolved in tetrabutylammonium fluoride (1.0 M in THF, 0.90 ml, 0.90 mmol). The reaction mixture was stirred at 60° C. overnight then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then concentrated. The residue was triturated with water, ethyl acetate and a few drops of methanol to afford 21 mg (65%) of 2-[5-(1-hydroxy-ethyl)-1-methyl-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a yellow powder. MS: (M+Na)+=401; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.82 (br. s., 1H), 9.09 (s, 1H), 8.41 (s, 1H), 8.30 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 5.27 (d, J=3.8 Hz, 1H), 4.87-5.00 (m, 1H), 4.19-4.32 (m, 1H), 4.17 (s, 3H), 1.41 (d, J=6.0 Hz, 3H), 1.33 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.[F:2][C:3]([F:9])([F:8])[O:4][CH2:5][CH2:6][NH2:7].[H-].[Na+].[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].CCOC(C)=O>C1COCC1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:7][CH2:6][CH2:5][O:4][C:3]([F:9])([F:8])[F:2])=[O:17]
Reactant: O=C=NCCCl
Reactant: NCCOC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCCl)NCCOC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 139.7 %

Procedure:
A 0° C. suspension of 2-(trifluoromethoxy)ethylamine hydrochloride (0.308 g, 1.861 mmol) in THF (10 mL) was treated with NaH (60% in mineral oil, 0.082 g, 2.047 mmol), stirred at 0° C. for 0.5 h, treated drop-wise with 2-chloroethyl isocyanate (0.175 mL, 2.047 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with EtOAc, the solids removed via filtration and the filtrate concentrated to dryness to afford 1-(2-chloroethyl)-3-(2-(trifluoromethoxy)ethyl)urea (610 mg, 140%) containing EtOAc. 1H NMR (400 MHz, DMSO-d6): δ 6.29 (br s, 2 H), 4.04-3.97 (m, 2 H), 3.55 (t, J=6.2 Hz, 2 H), 3.33-3.24 (m, 4 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:19][C:14]1[C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]2[C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]=2[CH:13]=1
Reactant: BrBr
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CCCO)c(Br)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 12.3 g (49.8 mmol) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 100 mL of carbon tetrachloride at 0° C. was added a trace of iron powder followed by a solution of 8.76 g (54.8 mmol) of bromine in 80 mL of carbon tetrachloride. After 4.5 hours at 0° C. the reaction mixture was warmed to room temperature. After 3 hours at room temperature, the reaction mixture was poured into ice water and the mixture was extracted with dichloromethane. The organic fraction was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to give 10.2 g (63%) of 2-bromo-3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. (M+=324).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]#[N:30])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:70]=[N+:71]=[N-:72])(C)C>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]4[N:26]([CH2:27][CH2:28][C:29]#[N:30])[N:72]=[N:71][N:70]=4)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NCCC#N)s3)C[C@H]2OC)nc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnnn4CCC#N)s3)C[C@H]2OC)nc1Cl
Yield: 39.6 %

Procedure:
THF (2 mL) was added to cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-N-(2-cyanoethyl)-4-methyl-1,3-thiazole-5-carboxylic acid amide obtained in Example (261a) (36 mg, 0.08 mmol). While the mixture was stirred, triphenylphosphine (124 mg, 0.47 mmol), diisopropyl azodicarboxylate (0.24 mL, 0.45 mmol, 1.9 M solution in toluene) and trimethylsilyl azide (7.3 g, 55.4 mmol) were added, followed by stirring at 30° C. for four days. The reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0/10, 2/8) and preparative thin layer chromatography (developing solvent: ethyl acetate/hexane=10/1) to obtain 16 mg of the title compound as a white solid (41%).
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[C:20]([F:19])([F:29])[F:30])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCc1ccccc1C(F)(F)F
Product: CCCCCCCCC#Cc1ccc(CNCc2ccccc2C(F)(F)F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dec-1-ynylbenzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 402.3. HPLC (Condition A), Rt: 4.71 min (HPLC purity: 86.5%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([CH:9]([C:7]#[N:8])[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml of N,N-dimethylformamide, 2.17 g (21.7 mmol) of methyl cyanoacetate with a purity of 99% and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 60° C. for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of ethyl acetate was added to the mixture, and 2.9 ml (34.8 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 30 ml a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: toluene) to obtain 1.81 g (isolation yield: 84%) of methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate as a yellowish oily product with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])C.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>>[CH:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]1=[O:27])([CH3:18])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Product: COc1cccc2c1ncc1c(=O)n(C(C)C)c(=O)n(C(C)C)c12
Yield: 32.1 %

Procedure:
1,3-Diisopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (59.6 mg, 0.20 mmol) and isopropyl isocyanate (1.0 mmol) following general procedure C. LCMS: m/z 328 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][CH2:30][C:31]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18]1)=[O:32]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Yield: 91.6 %

Procedure:
The 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline material was prepared as follows: —4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (430 mg, 1.07 mmol) (Prepared as described in Example 22 under preparation of starting material), chloroacetyl chloride (126 mg, 1.12 mmol) and N,N-diisopropylethylamine (519 mg, 4.02 mmol) in methylene chloride (15 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) solvent, Removal of the solvent under vacuum gave 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a yellow gum (470 mg). This material was used without any further purification); Mass Spectrum: (M+H)+ 479.