Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1[C:17]2[NH:25][CH:24]=[N:23][C:18]=2[CH2:19][CH2:20][NH:21][CH:22]=1)=[O:15])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[NH:25][CH:24]=[N:23][C:18]=2[CH2:19][CH2:20][N:21]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:22]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1=CNCCc2nc[nH]c21
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2nc[nH]c21
Temperature: 25 °C

Procedure:
4-fluorobenzoyl chloride was added dropwise to a stirred solution of 3,6,7,8-tetrahydro-imidazo[4,5-d]azepine-4-carboxylic acid ethyl ester (Example 1, 60 mg, 0.29 mmol) and Et3N (0.2 mL) in dry CH2Cl2 at 0° C. under nitrogen. The resulting mixture was allowed to warm to ambient temperature overnight. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel eluting with hexane-EtOAc (80:20) to give the title compound as a yellow solid. 1H-NMR(CDCl3): δ 8.27-8.21 (3H, m), 7.16 (2H, t), 7.00 (1 H, s), 5.10 (1 H, br s), 4.35 (2H, q), 3.56 (2H, m), 3.14 (2H, t), 1.39 (3H, t); MS (ES): 330 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([NH:17][CH3:18])=[O:16].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].I[C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][CH2:42][CH2:41][C:40]=2[CH:45]=1>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:36]3[CH:37]=[CH:38][C:39]4[O:44][CH2:43][CH2:42][CH2:41][C:40]=4[CH:45]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Ic1ccc2c(c1)CCCO2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CCCO4)n2)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]-N′-methylurea (i.e. the product of Step A) (0.30 g, 1.1 mmol) in dioxane (3.0 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.07 mL, 0.45 mmol) followed by copper(I) iodide (0.085 g, 0.45 mmol), potassium carbonate (0.94 g, 6.8 mmol) and 3,4-dihydro-6-iodo-2H-1-benzopyran (0.44 g, 1.7 mmol; prepared as cited in Step E of Synthesis Example 4). The reaction mixture was heated to 110° C. for 20 h and then cooled to ambient temperature. The solvent was evaporated, and the residue was taken up in chloroform, washed with water and brine, and then dried (Na2SO4) and concentrated. The crude residue was purified by preparative TLC (1.5% methanol in dichloromethane as eluant) to provide the title product a compound of the present invention, as a solid (0.036 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@H:4]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:3]1.S(Cl)([Cl:28])(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:28][C:13]1[NH:12][C:11]2[C:17]3[C:14]=1[CH2:15][C@@H:16]1[C:6]([C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:5][C@H:4]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:3][N:2]1[CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1C[C@@H](NC(=O)C(C)(C)C)C=C2c3cccc4[nH]c(Cl)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 g 6-methyl-8α-pivaloylamino-9,10-didehydro-ergoline, 100 ml CH2Cl2 and 50 mg silica gel is cooled to 0° and treated dropwise with 0.73 ml sulfurylchloride. The mixture is then stirred for 16 hours at room temperature, and then treated with 2N Na2SO4 and CH2Cl2. The organic phase is dried (Na2SO4), evaporated and chromatographed on 100 g silica gel using 8:2 CH2Cl2 /CH3OH. The title compound is obtained on crystallisaton from ether, m.p. 157°-160°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:7][C:6]=1[NH2:22])=[O:4].COC(C1C(N)=CC(C(F)(F)F)=C(C2C=CC(Cl)=CC=2C)N=1)=O>>[NH2:22][C:6]1[CH:7]=[C:8]([C:18]([F:21])([F:20])[F:19])[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1nc(-c2ccc(C)nc2)c(C(F)(F)F)cc1N
Agent: COC(=O)c1nc(-c2ccc(Cl)cc2C)c(C(F)(F)F)cc1N
Product: Cc1ccc(-c2nc(C(=O)O)c(N)cc2C(F)(F)F)cn1

Procedure:
This compound was prepared from: 5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid methyl ester analogously to 3-amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate I); LC-MS Rt 0.90 min; [M+H]+ 298 (Method 2 minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 12.90 (1H, broad), 8.45 (1H, s), 7.72 (2H), 7.32 (1H, d), 7.12 (2H, broad), 2.51 (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].C1(C)C=CC=CC=1.[CH3:28][OH:29]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:29][CH3:28])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CO
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1

Procedure:
1 g (0.00326 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was added to 2 mL toluene at 0° C. along with stirring, followed by dropwise addition of 1 mL titanium tetrachloride, and the reaction was stirred at 0° C. for 1 hour. Later 18 mL of methanol was added, and then the reaction was stirred for 36 hour at 29° C. and later reflux for 3 hrs. The solvent was distilled under reduced pressure and the residue was added to aq. sodium carbonate at 0° C. the product was extracted with 20 mL ethyl acetate, and the organic layer was isolated, dried over anhy. Na2SO4, concentrated and purified by column chromatography using hexane:ethyl acetate as eluent. The product obtained was stored under nitrogen atmosphere and kept in refrigerator before converting into salt. The yield of titled product was 0.157 g (12-15%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:35])([CH3:34])[CH2:21]/[C:22](=[N:27]/S(C(C)(C)C)=O)/[C:23]([F:26])([F:25])[F:24])[CH:19]=1>C1COCC1.CCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([C:20]([CH3:34])([CH3:35])[CH2:21][C:22]([NH2:27])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:23]([F:26])([F:25])[F:24])[CH:19]=1
Reactant: Cc1ccccn1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
To a chilled (−78 C.) solution of 0.05 mL (0.514 mmol) of 2-methylpyridine in 3 mL of dry THF was added 0.23 mL (0.4 mmol) of a 1.7 M solution of t-BuLi in pentane. The mixture turned a bright orange. After 10 min, a solution of 98 mg (0.257 mmol) of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of anhydrous THF was added. The reaction was then warmed to room temperature, quenched with aqueous ammonium chloride, stirred for 30 min and extracted with diethyl ether.(3×) The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction was warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated to afford an oil. The residue was purified by preparative thin layer chromatography eluting with hexanes-EtOAc (95:5) to afford 24 mg (25%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(OC)c2ccccc12
Solvent: CC(=O)O
Product: COc1cc(Br)c(OC)c2ccccc12

Procedure:
The process of preparing the novel compounds of this invention comprises the steps of (1) brominating 1,4-dimethoxynaphthalene with liquid bromine in an organic solvent such as acetic acid at room temperature to form the 2-bromo-1,4-dimethoxynaphthalene, (2) converting the bromine derivative to the carboxylic acid derivative by lithiation and carboxylation. The lithiation is conducted in a known procedure, as for example, by treating the bromo derivative with n-Butyllithium in an organic solvent under anhydrous conditions at a low temperature, such as -78° C. The resulting lithium compound is not isolated, but converted into the carboxylic acid by adding dry ice to the cooled lithium compound and allowing the reaction mixture to come to room temperature. (3) The carboxylic acid derivative is then converted to the acid chloride by treating with thionyl chloride at room temperature. (4) The resulting acid chloride is condensed with the appropriate amine to form the carboxamide. The condensation reaction is carried out by treating the acid chloride in an organic solvent with the appropriate amine at room temperature in the presence of a proton acceptor.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1
Reactant: NC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(C(N)=O)cc1
Temperature: 80 °C
Yield: 17.1 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 4-bromomethyl-benzamide (89 mg, 0.419 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 17%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[C:6](Cl)[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:22][O:23][CH2:24][CH2:25][OH:26]>>[CH3:3][C:4]1[N:5]=[C:6]([O:26][CH2:25][CH2:24][O:23][CH3:22])[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(C)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Sodium hydride (80 mg of a 60% dispersion in mineral oil, 2.0 mmol) was added to 2-methoxyethanol (10 ml). The mixture was stirred at room temperature for 10 minutes. Then, 2-methyl-4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (110 mg, 0.4 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of ethanol and dichloromethane, in a volume ratio of 1:100, affording the pure title compound (110 mg, yield 88%) as a white solid which was characterised as follows: MS (m/z): 314 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:4]=1[C:10]([CH3:20])([CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH:13]2[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 3.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 288 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 90 mg of the imine is reacted by reaction with 0.4 ml of titanium tetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and 25 mg of the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 3.44 g (16.4 mmol) 2,4-dichloro-benzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 2.5 g (79%) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:13])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1>[C:18]([CH2:17][CH2:16][CH2:15][NH:13][C:3]1([CH3:2])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1)#[N:19]
Reactant: N#CCCCBr
Reactant: CC1(C)CC(C)(C)CC(C)(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(C)(NCCCC#N)C1
Yield: 78.7 %

Procedure:
A mixture of 1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (1) (2-06 g, 10 mmol) 4-bromobutyronitrile (1.55 g. 10.5 mmol) and sodium carbonate (3.18 g, 30 mmol) in tetrahydrofuran (50 ml) was refluxed for 85 h, the poured into water (100 ml) and extracted with ether (3*30 ml). The combined organic phases were washed with brine (20 ml) and dried over K2CO3. The solution was filtered and evaporated and the crude product was purified by chromatography on silica gel, eluting with hexane-ether (10:1), (6:1), (4:1) to give product 2 (1.86 g, 86%) as an colorless oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[OH:16]>C(O)(=O)C>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:5](=[O:7])[CH3:6])=[CH:11][C:10]=1[OH:16]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
Acetic anhydride (3.0 mL, 42.0 mmol) was added to a solution of 4-chloro-3-hydroxy aniline (4.0 g, 28 mmol) in acetic acid (20 mL), and the reaction was refluxed for 5 mins. The reaction mixture was cooled to room temperature and the product was solidified. It was filtered off and washed with water (10 mL) and dried to obtain the product 17a in 93% yield (4.8 g) as a creamy white solid. There was no need for further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][C:13](=O)[NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COc2ncc(-c3ccccc3)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cnc3c(c2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.3 %

Procedure:
7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (21 mg, 0.09 mmol) was dissolved in tetrahydrofuran (0.5 ml) and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (0.19 ml, 0.19 mmol) was added thereto dropwise. After stirring for 5 hours at room temperature, 0.1 ml of water, 0.2 ml of 10% aqueous solution of sodium hydroxide, and 0.3 ml of water were added in this order under stirring. After filtering precipitates, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain pale-grey solid (10 mg, 50%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].O>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([I:3])=[CH:5][CH:6]=2)[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)cccc1OCc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Sodium hydride (60%; 432 mg; 10.8 mmol) was suspended in DMF (5 mL) and cooled to 0° C. under inert atmosphere. 4-Iodobenzyl alcohol (2.53 g; 10.8 mmol) was dissolved in DMF (5 mL) and added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 15 minutes. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1 g; 7.2 mmol) in DMF (20 mL) was added dropwise to the alcohol solution and stirred for 2 hours. The solution was poured over 100 mL of cooled water. The solution was cooled for 1 hour and a precipitate was evident. The solid was collected by vacuum filtration and washed with water. Purification by recrystallization in cyclohexane yielded 1.49 grams of 2-fluoro-6-(4-iodobenzyloxy)benzonitrile.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:25])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].Cl[CH2:27][O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:27][O:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@]32O)C1
Reactant: CCOCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](OC(C)=O)CC[C@@]21C

Procedure:
A solution of 9.20 g of 3β-acetoxy-14β-hydroxy-5β-androst-15-en-17-one (G. Groszek et al., Bull. Pol. Acad. Sci., Chem., 34, 1986, 313), 11 ml of ethyl chloromethyl ether, 54 ml of diisopropylethylamine in 750 ml of dichloromethane was heated at reflux for 24 hrs. The solution was then cooled and poured into 500 ml of aq. 8% citric acid solution. The lower layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by chromatography using cyclohexane/chloroform/acetone 80/10/10 as eluant to give 6.10 g of 3β-acetoxy-14β-ethoxymethoxy-5β-androst-15-en-17-one, as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18](=[O:19])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Product: COc1ccc(NC(=O)Cc2ccc(-c3ccncc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)naphth-1-ylacetic acid (D2) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) following a similar procedure to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].CC(C)=O>C(O)C>[O:25]=[C:24]([CH3:26])[CH2:22][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: C=CC(C)=O
Solvent: CCO
Solvent: CC(C)=O
Product: CC(=O)CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (5 g) and methyl vinyl ketone (5 ml) in ethanol (100 ml) was stirred at reflux for 3 days. After cooling, the product 3-(γ-oxobutylamino)-4-phenoxy-5-sulfamylbenzoic acid was collected to give 5.05 g (82%) in two crops of colorless solid. An analytical sample from aq. acetone had m.p. 215°-215.5°; ir (Nujol) 3400, 3250, 1710, 1695, 1615, 1590, and 1570 cm-1 ; nmr (CDCl3 /d6 -DMSO/D2O-washed) 2.00 (s, CH3), 2.60 (t, CH2), 3.37 (t, CH2), 6.8-7.4 (m, C6H5), 7.60 (d, J=2, CH), and 7.93 (d, CH); mass spectrum was of decomposition products, 308 (100%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C@H:17]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][NH:19][CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.O>C(OCC)C>[CH2:23]([O:22][C@H:21]1[C@H:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:18][N:19]([Cl:1])[CH2:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CO[C@@H]2CNC[C@H]2OCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: ClN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-Chlorosuccinimide (7.05 g, 52.6 mmol) was added to a solution of (3R,4R)-3,4-dibenzyloxypyrrolidine (15 g, 52.8 mmol) in diethyl ether (300 ml). The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Addition of toluene (250 ml) and water (200 ml), washing of the organic phase with 2 M sodium thiosufate (200 ml) and water (200 ml), drying with magnesium sulphate gave a solution of (3R,4R)-3,4-dibenzyloxy-1-chloropyrrolidine in toluene. The compound is unstable and was used without further purification.