Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:38]=[C:39]([OH:41])[CH:40]=1>C(OCC)(=O)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[C:37]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:36]=1)[O:41][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2cc(F)cc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Yield: 34.7 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Step 3 (0.74 g, 2.2 mmol), N,N′-dimethylformamide (DMF) (20 mL), potassium carbonate (0.61 g, 4.4 ,mmol), and 4-(3-fluoro-5-hydroxyphenyl) -4-methoxy-3,4,5,6-tetrahydro-2H-pyran [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)] (0.75 g, 7.5 mmol) were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL), washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue was recrystallized from ethyl acetate/hexanes to afford 4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 35%): mp 159-161° C. 1H NMR (CDCl3) 300 MHz δ 7.9 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 7.24-7.30 (m, 2H) 7.0-7.1 (dt, J=9.5 Hz and J=1.8 Hz, 1H) 4.85 (bs, 2H) 3.85 (dd, J=9.9 Hz and J=1.8 Hz, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C27H25N2O6SF: C, 61.82; H, 4.80; N, 5.34. Found: C, 61.77; H, 4.82; N, 4.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:36][N:35]=1)([CH3:33])([CH3:32])[CH3:31].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([N:36]4[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:38][C:34]([C:30]([CH3:31])([CH3:33])[CH3:32])=[N:35]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(B(O)O)ccc32)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-(4-Methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-ylboronic acid (1.8 g, 5.8 mmol) was dissolved in CH2Cl2 (120 mL) and pyridine (10 mL) with molecular sieves (activated, 4 A) and the solution was kept overnight at RT. Commercially available ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (1.2 g, 5.8 mmol), Cu(OAc)2 (1.1 g, 5.8 mmol) and molecular sieves (4 Å activated, powder) were added to the boronic acid solution and the reaction mixture was stirred open to the air at RT for 3 days. The reaction mixture was filtered through a pad of Celite®, and the filtrate was evaporated under reduced pressureand purified by silica gel column chromatography to yield ethyl 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylate (2.5 g, 94% yield). LC-MS (EI) m/z: 460.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CS(OC)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH3:10])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C([O-])[O-]
Agent: COS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(F)c(N)nc1=O
Temperature: 85 °C
Reaction time: 21 h
Yield: 37 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (151.0 mg, 1.17 mmol), K2CO3 (289.2 mg, 2.09 mmol), 18C6 (278.6 mg, 0.901 mmol) and anhydrous DMF (10 mL). Methyl methanesulfonate (0.0814 mL, 0.961 mmol) was added, and the resulting mixture was agitated on a rotary shaker at 85° C. for 21 h. After cooling to room temperature, the crude material was concentrated in vacuo and purified by reverse phase column chromatography to afford 4-amino-5-fluoro-1-methylpyrimidin-2(1H)-one (61.9 mg, 37%) as a beige solid: mp 195° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=6.8 Hz, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 3.18 (s, 3H); ESIMS m/z 144 ([M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=1[C:18]([F:21])([F:20])[F:19])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[Br:11][C:9]1[C:8]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[N:7][C:6]([C:18]([F:21])([F:19])[F:20])=[C:5]([CH:10]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Yield: 99.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid ethyl ester (244 g, 0.61 mol) was dissolved in a mixture of tetrahydrofuran (2100 mL) and water (700 mL). Lithiumhydroxid monohydrate (77 g, 1.85 mol) was added and the mixture was stirred and heated at reflux-temperature for 1.5 h. After cooling to room temperature the mixture was acidified with hydrochloric acid (2N, 750 mL). The mixture was extracted with diethylether (1×1500 mL, 1×1000 mL), and the organic phases were washed with brine (1000 mL). The organic phases were combined, dried with MgSO4 and the solvent was evaporated to give the title compound (224 g) as off-white solid; MS (ISP) 365.9, 367.9 (M−H).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:11]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O.C(Cl)Cl>[CH2:28]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:11]([C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:13])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Yield: 108.5 %

Procedure:
A solution of KOH (720 mg, 12.8 mmol) in MeOH (5 mL) and H2O (2 mL) was added dropwise to a solution of 209 (1.90 g, 4.27 mmol) in MeOH (10 mL) and CH2Cl2 (15 mL). After 48 h at room temperature CH2Cl2 and H2O were added. The aqueous layer was separated and acidified to pH 2 with 2 M HCl. The resulting white precipitate was collected, dissolved in CH2Cl2, and the solution was washed with H2O and brine. The CH2Cl2 layer was dried, the solvent was evaporated, and the residue was dried in a vacuum desiccator. Recrystallization from CH2Cl2/petroleum ether gave 7-[(dibenzylamino)sulfonyl]-2-naphthoic acid (210) (2.00 g, 99%) as colorless crystals: mp 189-190° C.; 1H NMR (CDCl3) 8 (CO2H not observed) 8.76 (s, 1H), 8.47 (s, 1H), 8.29 (dd, J=8.6, 1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.92 (dd, J=8.7, 1.8 Hz, 1H), 7.23-7.15 (m, 6H), 7.12-7.05 (m, 4H), 5.29 (s, 1H), 4.42 (s, 4H); 13C NMR δ 170.8, 139.0, 137.0, 135.4, 133.1, 131.4, 129.7, 129.3, 128.6, 128.5, 128.4, 128.2, 128.1, 127.8, 125.3, 50.7. Anal. (C25H21NO4S) C, H, N.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@@H:9](Cl)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32OCC[O:24]3)[CH2:6]1)(=[O:3])[CH3:2].O>O1CCCC1.C(O)(=O)C.[Zn]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:30])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH:12]3[CH2:28][C@@H:13]3[C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5CC5[C@H]4[C@@H]3C=C[C@]2(O)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A solution of 21 g of 3β-acetoxy-7α-chloro-5β,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstane in 105 ml of tetrahydrofuran, 105 ml of acetic acid, and 27 ml of water is combined with 63 g of zinc dust and stirred for 1.5 hours at 80° C. The mixture is then decanted off from the zinc, washed with methylene chloride, and the organic phase is washed with sodium bicarbonate solution and water. After drying and evaporation, the residue is chromatographed on silica gel, thus obtaining 13.8 g of 3β-acetoxy-5-hydroxy-15,16β-methylene-5β-androst-6-en-17-one, mp 191°-194° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])=[CH:11][CH:10]=1)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:21][C:20]3=[O:31])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[4-(2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl)-benzyl]-carbamic acid tert-butyl ester [F] (230 mg, 0.53 mmol), in dichloromethane (5 ml) was treated with 4M hydrogen chloride in dioxane (2 ml). The reaction was stirred at room temperature for 3 hours during which time a precipitate forms. The solvent was removed in vacuo and the residue triturated with ether. The resulting solid was collected by filtration and dried to give 8-(4-aminomethyl-phenyl)-2-morpholin-4-yl-chromen-4-one [G]. Yield 189 mg, quantitative.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25]Cl)=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][I:30])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCCl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCI)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.0 g, 4.76 mmole) in dry acetone (30 ml) was added sodium iodide (3.15 g, 21 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.3 g=94%.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].C(#N)C.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24](OC)=O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>O1CCCC1>[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:24][C:1]#[N:4])[CH:28]=[CH:29][CH:30]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (18.8 ml, 37 mmol, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene) was added dropwise to a solution of acetonitrile (1.58 g, 37 mmol) in dry tetrahydrofuran (50 ml) at −78° C. After stirring the reaction mixture for 30 min., a solution of methyl 3-(2-morpholin-4-ylethoxy)benzoate in dry tetrahydrofuran (50 ml) was added dropwise over 10 min. After 15 min., water was added and the reaction mixture was allowed to warm to room temperature. The aqueous layer was separated and acidified with dilute hydrochloric acid to pH 7. The product was extracted into ethyl acetate and washed with water and brine and dried over magnesium sulfate. The organics were removed in vacuo to give 2-[3-(2-morpholin-4-ylethoxy)phenyl]acetonitrile (5.0 g) as an oil which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17](OCC)=O)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 200 °C
Yield: 82.2 %

Procedure:
A solution of sodium hydroxide (175 g) in water (800 ml) was added to a solution of diethyl (4-bromophenyl)methylmalonate (150 g) in ethanol (850 ml) and the mixture was heated under reflux for 9 hours. Volatile material was removed by evaporation and the residue was dissolved in a solution of sodium hydroxide (130 g) in water (250 ml). The solution was heated under reflux for 2.5 hours, filtered through a bed of diatomaceous earth and the filtrate was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solution was concentrated and the residue was heated at 200° C. until evolution of carbon dioxide ceased. The residue was dissolved in 1M sodium hydroxide solution (500 ml) and the solution was acidified with 6M sulphuric acid. The mixture was extracted with ether (4×500 ml) and the extracts were dried (MgSO4). The solvent material was removed by evaporation to give 3-(4-bromophenyl)-2-methylpropionic acid (91 g), m.p. 72°-73° C.; 1H NMR (d6 -DMSO): 1.0 (d, 3 H), 2.05-2.15 (m, 2 H), 2.85-2.9 (m, 1 H), 7.1 (d, 2 H), 7.4 (d, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:26]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)=[O:27]>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-bromo-3,5-dimethoxy-benzene (2.7 g, 12 mmol) in THF (20 mL) was added a solution of n-butyllitium in hexane (4.5 mL, 2.5 N, 11 mmol) at −78° C. and kept for 20 min. To the mixture was added quinoline-6-carboxylic acid methoxy-methyl-amide (2.2 g, 10 mmol) at −78° C. After 2 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and slurry in ether gave (3,5-dimethoxy-phenyl)-quinolin-6-yl-methanone as a white solid (1.48 g, 50% crude yield). The sample was used in the next step without further purification. 1H NMR (CDCl3) δ 3.84 (s, 6H, 2CH3), 6.70-6.73 (m, 1H, Ar), 6.97 (d, J=2 Hz, 1H, Ar), 7.49 (dd, J=4, 8 Hz, 1H, Ar), 8.17-8.28 (m, 4H, Ar), 9.02-9.04 (m, 1H, Ar).
Reaction SMILES: [CH:1]([C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O.[CH3:25][NH:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.ClCCCl.C(O)(=O)C>[CH3:25][N:26]([CH2:1][C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:27]
Reactant: CNC
Reactant: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C/N=c1\sc(CN(C)C)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 35a) and a 1 M solution of dimethylamine in THF (2.6 mL) were dissolved in a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C., and the mixture was mixed at room temperature overnight. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.1 g) as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@H:10]([N:11]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@H:10]([N:11]([C@@H:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1ccccc1)N1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.45 g of trans-8-tert-butoxycarbonyl -5-[(1R)-1-phenylethyl]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 9a in 50 ml of tetrahydrofuran, was added 7.1 ml of diborane tetrahydrofuran complex 1M solution dropwise at 0° C. The mixture was stirred at room temperature for 14 hours. Then, 12 ml of diborane tetrahydrofuran complex was added to the solution, and the mixture was stirred at room temperature for 24 hours. To an ice-cooled mixture, was added 10 ml of water and, then, 20 ml of saturated sodium bicarbonate aqueous solution at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was extracted from 100 ml of ethyl acetate. The organic layer was separated and washed with two 100 ml portions of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (2:1), the titled compound 10a weighing 1.85 g was obtained as an oil.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]([NH2:8])[CH2:4][C:5]([CH3:7])=[CH2:6].C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O>C1C=CC=CC=1>[F:1][CH:2]([F:9])[CH:3]([N:8]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=C(C)CC(N)C(F)F
Solvent: c1ccccc1
Product: C=C(C)CC(C(F)F)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of crude 1.1-difluoro-2-amino-4-methyl-4-pentene (20 g, evaluated 110 mmoles) prepared as in Step A above, N-carbethoxyphthalimide (24 g, 110 mmoles) in benzene (300 mL) is kept overnight at room temperature. The solution is concentrated under vacuum, the oily residue is dissolved in methylene chloride (400 mL) and treated with 8 g of triethylamine during one night at room temperature. The solution is extracted with water, twice with 1 N hydrochloric acid and twice with water again. Evaporation of the organic layer affords an oily residue which is crystallized from petroleum ether at -5° C. (19.2 g, yield based on methallyl chloride: 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55]>ClCCl>[C:39]([O:38][CH2:37][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=1)[O:12][CH2:13][CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])[CH2:25][CH2:24]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:41])[CH3:40]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cc4)CC3)CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(N(C(=O)c4ccco4)c4ccc(C)cc4)CC3)CCCCC2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,3-diacetoxymethyl-5-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethoxy]benzene (synthesized in Example 33) (222 mg) dissolved in dichloromethane (4 mL) was added triethylamine (0.11 mL). 2-Furoyl chloride (0.06 mL) was added to the solution under ice cooling. The temperature was allowed to rise to room temperature, and the solution was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give N-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (276 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[S:12]([CH2:22][N+:23]#[C-:24])([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[C-]#N.[Na+]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C@H:5]2[O:6][CH:24]=[N:23][C@@H:22]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1C
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc([C@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)cc1C

Procedure:
In a manner analogous to Preparation 1, 3-methyl-p-anisaldehyde (0.73 mL, 5.25 mmol), tosylmethylisocyanide (0.98 g, 5.00 mmol) and NaCN (24.5 mg, 0.50 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 346.7 (M+H+).