Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:13]O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[H-].[H-].COCCO[Al+]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([NH2:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: ON=C1CC2CCCc3cccc1c32
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC1CC2CCCc3cccc1c32
Temperature: 80 °C
Yield: 82.4 %

Procedure:
To 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-one oxime (7.00 g) was added a solution (about 65%, 50 ml) of sodium bis(2-methoxyethoxy)aluminum dihydride in toluene, and the mixture was stirred with heating at 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with chloroform. After concentration under reduced pressure, the residue was extracted with 1N hydrochloric acid. The aqueous layer was alkalified with potassium carbonate, and extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (5.34 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:24][C:23](=O)[N:22]=[CH:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccnn1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1cccc(C(F)(F)F)c1

Procedure:
5-Amino-1-(3-trifluoromethylphenyl) pyrazole (19.0 g.) and 1-acetyl-2-imidazolinone (12.9 g.) were reacted as described in Example I to give 16.85 g. product, mp 194°-197°.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]([CH3:13])=O.[CH:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.[OH-].[Na+]>O>[Cl:3][C:2]1[N:1]=[C:8]([N:16]2[CH2:15][CH:14]3[CH2:22][CH2:13][CH:11]([CH2:19][CH2:20]3)[CH2:10]2)[N:7]=[C:5]([N:16]2[CH2:17][CH:18]3[CH2:21][CH2:22][CH:14]([CH2:20][CH2:19]3)[CH2:15]2)[N:4]=1
Reactant: CC(C)=O
Reactant: C1CC2CCC1CNC2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1nc(N2CC3CCC(CC3)C2)nc(N2CC3CCC(CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Eighty grams (0.43 mole) of cyanuric chloride is dissolved in 800 ml. of acetone, cooled to less than 10° C. and then one liter of water is added followed by 120 g. (0.96 mole) of 3-azabicyclo[3.2.2]nonane. After 2 hours the reaction is allowed to warm to room temperature and after a further 2 hours 35 g. (0.87 mole) of NaOH in 200 ml. of water is added over 2 hours. The reaction is then stirred for one hour and is then heated to reflux for a further one hour. Dilution with 2 l. of water gives a white precipitate which is filtered off and washed with water. The precipitate is then dissolved in one liter of chloroform and the aqueous solution separated. The aqueous solution is extracted with chloroform, the combined chloroform extracts washed with water, dried over magnesium sulfate and filtered through Magnesol®. The Magnesol® is then washed with one liter of chloroform, the solvent removed in vacuo, and the residue recrystallized from dichloromethane-hexanes giving 120 g. of colorless prisms, m.p. 195°-200° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]=2[CH2:4][O:3]1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:23]1([CH3:24])[CH:25]=[CH:26][C:20]([S:17]([O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]3[C:2]([CH3:16])([CH3:1])[O:3][CH2:4][C:5]=23)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c3c(nc4ccccc24)C(C)(C)OC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound of formula VI, 3,4-dihydro-3,3-dimethylfuro[3,4-b]quinolin-9(1H)-one (4.3 g, described in Example 8), is added portionwise to a solution of tosyl chloride (3.8 g) in dry pyridine (50 ml) at 0° C. The solution is stirred at 0° C. for 30 minutes and saturated salt solution is added. The mixture is extracted with ether and the ether extract is evaporated. Toluene is added to the residue and the solution is evaporated. The residue is crystallized from methanol to give the title compound, mp 116°-118° C.
Reaction SMILES: [F:1][C:2]([F:34])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[F:34][C:2]([F:1])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:26]
Reactant: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 98.7 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (F) in acetonitrile (319 ml), diisopropyl ethylamine (68.9 ml, 368 mmol) and benzyl bromide (46.7 ml, 366 mmol) were added and the mixture was stirred for about 13.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (369 ml) and water (283 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (226 ml). The organic layers were combined and washed with 1M-hydrochloric acid (339 ml), saturated sodium bicarbonate water (339 ml) and saturated aqueous sodium chloride (339 ml). After drying with anhydrous magnesium sulfate (50 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane=1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-3-hydroxy-6-methyloctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]heptanoate (3) (76.16 g; 130.7 mmol; yield: 98.7%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][N:19]=1)[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O.[CH2:20]([NH:22][CH2:23][CH2:24][NH2:25])[CH3:21]>O1CCCC1>[CH2:20]([NH:22][CH2:23][CH2:24][NH:25][C:5](=[O:7])[C:4]1[CH:17]=[CH:18][N:19]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: CCNCCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnc(F)c1
Solvent: C1CCOC1
Product: CCNCCNC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
To a solution of compound 35 (4.60 g, 17.5 mmol) in anhydrous tetrahydrofuran (185 mL) was added, under argon, N-ethylethylenediamine (1.80 mL, 17.5 mmol). The mixture was stirred at room temperature for 24 h. The solvent was evaporated under vacuum and the residue was suspended in dichloromethane (95 mL). A 1.0 N aqueous sodium hydroxide solution (140 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (6×120 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 36 (3.37 g, 15.9 mmol) as a yellow solid. Yield 91%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.16; mp 51-52° C.; IR (KBr) ν 1300, 1416, 1554, 1675, 2700-3050, 3100-3600 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.07 (t, 3H, J=7.1 Hz), 2.63 (q, 2H, J=7.1 Hz), 2.76 (se, 1H), 2.83 (t, 2H, J=5.8 Hz), 3.50 (m, 2H), 7.33 (s, 1H), 7.54 (m, 1H), 7.74 (se, 1H), 8.24 (d, 1H, J=5.1 Hz); MS m/z 212 (M+H+, 1), 124 (8), 96 (15), 71 (19), 58 (100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:10]([CH3:12])[CH3:11])[NH:5][C:6]=1[C:7]([O-:9])=[O:8].[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].[CH2:29]1COC[CH2:30]1>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([CH:10]([CH3:12])[CH3:11])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[C:7]([O:9][CH2:29][CH3:30])=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: C1CCOC1
Reactant: Cc1nc(C(C)C)[nH]c1C(=O)[O-]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(C(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-methyl-2-(1-methylethyl)-1H-imidazole-5-carboxylate (83 mg, 0.42 mmol) in THF (2.0 mL) was added dropwise to a suspension of NaH (60% in oil, 19.2 mg, 0.47 mmol) in THF (3.0 mL) at 0° C. under N2. The mixture was allowed warm up to room temperature and stirred for 2 h, it was then cooled to 0° C. and {2-[(chloromethyl)oxy]ethyl}(trimethyl)silane (84 uL, 0.47 mmol) was added dropwise. The mixture was stirred overnight at room temperature and saturated sodium bicarbonate was added. DCM was added and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-2% 2M NH3 solution of MeOH in DCM) to give the title compound (133 mg, 96%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.16 (2H, s) 4.34 (2H, q, J=7.1 Hz) 3.44-3.51 (2H, m) 3.06 (1H, dt, J=13.8, 6.9 Hz) 2.54 (3H, s) 1.30-1.39 (9H, m) 0.84-0.92 (2H, m) −0.07-−0.02 (9H, m). LCMS: m/z 327 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11](O)[C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:21])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([Cl:21])[C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])cc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])cc1OC

Procedure:
A mixture of 6.2 g of 1-(3,4-dimethoxyphenyl)-2-methyl-2-nitropropanol, 3 ml of thionyl chloride and 40 ml of anhydrous benzene is refluxed for 4 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (dark brown oil) is distilled at 145° C. under reduced pressure (0.15 mm Hg). 4.6 g of 1-(3,4-dimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane are thereby obtained as pale yellow prisms.
Reaction SMILES: Br[N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:3]1[C:4]2[C:9](=[C:8]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:7]=[CH:6][CH:5]=2)[CH2:10][NH:2]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: O=C1c2ccccc2CN1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2cc(-c3cccc4c3CNC4=O)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
Bromoisoindolin-1-one (11.5 mg, 0.0542 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (43.3 mg, 0.114 mmol), Fibercat palladium catalyst (Johnson-Matthey, 21.0 mg), and K2CO3 (2 M in water, 0.1 ml, 0.2 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (0.55 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) for 10 minutes at 50 Watts and 80 C. The reaction was cooled to room temperature, diluted with water (10 ml), and extracted with dichloromethane (6×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was washed with 15:1 hexanes/EtOAc and then purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (4.9 mg, 24%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: OCCCCSc1ccccc1
Yield: 3.1 %

Procedure:
A mixture of thiophenol (121.2 g, 1.10 mole), 4-chloro-1-butanol (100.0 g, 0.921 mole), and potassium carbonate (138.2 g, 1.0 mole) was heated overnight at gentle reflux in dimethoxyethane. The reaction mixture was filtered and solvent removed by rotary evaporator. The residue obtained was dissolved in chloroform and extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil which crystallized to a white solid. The solid was vacuum distilled at 134°-140° C./0.55 mm. A six-gram sample of the distilled oil was subjected to flash chromatography on silica gel using ethyl acetate-hexanes for elution. This gave a clear oil which was dried at 80° C. overnight in vacuo. The process produced 5.2 g (57.8%) of clear oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:20]2[CH:19]=[CH:18][O:17][C:16]=2[C:15]([O:21][CH3:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2.CN(C)C=[O:26].Cl>O1CCCC1>[O:26]=[C:18]1[O:17][C:16]2[C:15]([O:21][CH3:22])=[C:14]3[C:9](=[C:8]([O:7][CH3:6])[C:20]=2[CH2:19]1)[CH:10]=[CH:11][CH:12]=[CH:13]3
Reactant: CN(C)C=O
Reactant: COc1c2ccccc2c(OC)c2occc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c2c(c(OC)c3ccccc13)OC(=O)C2
Reaction time: 0.67 h
Yield: 76.4 %

Procedure:
To a solution of 5.5 mL (12.28 mmoles) of 2.2 M n-butyl lithium diluted with 20 mL of anhydrous tetrahydrofuran in an ice bath, 1.4 gram (6.14 mmoles) of 4,9-dimethoxy-naphtho[2,3-b]furan in 20 mL of anhydrous tetrahydrofuran was added dropwise over 5 minutes. The mixture was further stirred for 40 minutes in ice bath, and then 0.95 mL (12.28 mmoles) of N,N-dimethylformamide was added dropwise over 5 minutes. The mixture was stirred for additional 30 minutes in ice bath, and then further stirred for 120 minutes at room temperature. The reaction mixture was stopped by addition of 100 mL 0.1N hydrochloric acid, and then evaporated to remove tetrahydrofuran. The remaining aqueous solution was extracted with dichloromethane twice. The combined organic phase was washed with water, dried with anhydrous sodium sulfate, and evaporated to dryness. Product was purified by silica gel chromatograph using dichloromethane as elution solvent. 1.20 gram (4.69 mmoles) of product was obtained with yield of 76% and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 4.30 (s, 3H), 4.34 (s, 3H), 7.47-7.51 (m, 1H), 7.55-7.59 (m, 1H), 7.89 (s, 1H), 8.29-8.33 (m, 2H), 9.95 (s, 1H). Mass (M+H) is 257.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][CH:12]([C:14]1([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][CH:12]([C:14]2([CH2:18][CH2:19][CH3:20])[CH2:17][O:16][CH2:15]2)[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCCC1(C(C)O)COC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCC1(C(C)OC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (3.5 g) in dry ether (25 ml) was added to a stirred solution of 3-(1-hydroxyethyl)-3-n-propyloxetane (1.7 g) and pyridine (1.8 ml) in ether (50 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (pre-eluted with 1% triethylamine in hexane) and eluted with hexane/ether mixtures. 3-[1-(4-Iodobenzoyloxy)ethyl]-3-n-propyloxetane was obtained as a colourless oil (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[C:14]=[O:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N=C=O)c(C)c1
Reaction time: 5 h

Procedure:
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5. 5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification.
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:22]([NH2:24])[S:23][C:2]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)CCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Yield: 85.9 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-4-phenyl-butan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was recrystallized with anhydrous ethanol to obtain a product as a white solid in a yield of 85.9%, mp: 143-144 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.90 (2H, t, J=7.60 Hz, CH2), 3.05 (2H, t, J=7.60 Hz, CH2), 3.82 (3H, s, OCH3), 4.99 (2H, br, NH2), 6.89 (2H, d, J=8.40 Hz, ArH), 7.12˜7.30 (5H, m, ArH), 7.35 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 310.1 (M+, 23), 219.1 (100), 177.1 (39); HREI-MS Calcd. for C18H18N2OS: 310.1140. found: 310.1140. Anal. Calcd. for C18H18N2OS: C, 69.65; H, 5.84; N, 9.02. found: C, 69.74; H, 5.86; N, 9.03.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([CH:25]3[O:29][CH2:28][CH2:27][O:26]3)[N:22]=[CH:21]2)=[CH:16][CH:15]=1.IC>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH:24]=[C:23]([CH:25]3[O:29][CH2:28][CH2:27][O:26]3)[N:22]=[C:21]2[CH3:1])=[CH:18][CH:19]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(-n2cnc(C3OCCO3)c2)cc1
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: Cc1nc(C2OCCO2)cn1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 0.37 mL, 0.60 mmol, 1.5 equiv) was added to a solution of N,N-diisopropylamine (0.085 mL, 0.60 mmol, 1.5 equiv) in THF (1.5 mL) at −78° C. The solution was stirred at −78° C. for 10 min and then a solution of 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (100 mg, 0.40 mmol) in THF (1 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min, and then iodomethane (0.042 mL, 0.68 mmol, 1.7 equiv) was added. The solution was allowed to warm to room temperature and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic extract was washed with saturated aqueous sodium chloride (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give crude 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-2-methyl-1H-imidazole. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 5.88 (s, 1H), 4.20 (m, 2H), 4.03 (m, 2H), 2.35 (s, 3H). MS m/z 265.0 (M+H)+; Rt-0.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:44][CH:39]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][CH2:37][CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCC(O)CCCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CCCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 50.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (38 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:25])[C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-tert-butyl-4-isocyanatobenzene (72 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (31 mg, 17%) as a colorless powder.