Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([Br:16])[C:7]1[C:8]([F:15])=[CH:9][C:10]([Br:14])=[CH:11][C:12]=1[F:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c(F)cc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(Br)c1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-2,6-difluorophenethyl acetate (1.182 mmol) in carbon tetrachloride (3 mL) was degassed with a stream of nitrogen for 5 min and was then treated with N-bromosuccinimide (1.301 mmol) and azobisisobutyronitrile (0.118 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was stirred in an oil bath at 80° C. overnight. The reaction was then cooled and was concentrated to dryness under a stream of nitrogen. The crude material was dissolved in ethyl acetate (50 mL) and was washed twice with water. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The product was dissolved in dichloromethane and was again concentrated to dryness in vacuo to afford the title compound as a yellow oil (403 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 3 H) 4.55-4.70 (m, 2 H) 5.50 (t, J=7.45 Hz, 1 H) 7.55-7.67 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[Br:16][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
To the solution of 21.8 g of methyl m-trifluoromethylphenylacetate in 450 ml of carbon tetrachloride a portion of 18.7 g of N-bromosuccinimide is added along with several drops of triethylamine and a pinch of azobisisobutyronitrile. The mixture is warmed to reflux with a 250 watt incandescent bulb and a precipitate is formed. Thereupon the reminder of N-bromosuccinimide is added, the light removed and the solution stirred for 3 hours. It is cooled in an ice bath and the solid formed removed by filtration. The filtrate is evaporated the residue dissolved in diethyl ether-water and the organic phase washed with aqueous sodium bicarbonate and water. It is dried, evaporated, the residue distilled and the fraction boiling at 85°-88°/0.4 mmHg collected, to yield the methyl α-bromo-m-trifluoromethylphenylacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](F)[C:15]=2[F:23])=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([F:23])=[C:16]3[C:17]([C:20]([NH2:21])=[N:27][NH:28]3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[F:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1F

Procedure:
A solution of 1.49 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in 40 mL of ethanol is admixed with 2.14 g of hydrazine hydrate and then the mixture is heated at reflux for 18 h. The reaction medium is concentrated to dryness under reduced pressure, the residue is taken up in distilled water and the solid thus obtained is isolated by filtration and then dried. This gives 1.5 g of tert-butyl[4-(3-amino-7-fluoro-1H-indazol-6-yl)-2-fluorophenyl]carbamate in the form of a white solid, whose characteristics are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:27](=[NH:30])[NH:26][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h
Yield: 33.4 %

Procedure:
7.8 g (36.4 mole) of 4-(N-tert-butyloxycarbonylaminomethyl) piperidine and 8.98 g (40 mmole) of N-benzyloxycarbonyl-S-methylisothiourea was mixed in 25 mL ethanol. The mixture was heated at 60°-70° C. for six hours and left at roomtemperature for two days. The solvent was evaporated and the residue was dissolved in CH2Cl2. The organic layer was washed twice with 0.3M KHSO4 and once with brine. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using a stepwise gradient of CH2Cl2 /MeOH (100/0, 97/3, 95/5, 90/10) as eluent to yield 5.22 g (37%) of the title product.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.O[CH:13]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:14].C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:35]([CH:13]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:14])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(C)O)s1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)N=[N+]=[N-])s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
Add DBU (1.228 g, 1.2 mL, 8.07 mmol) to a solution of (±)-2-(1-hydroxyethyl)-5-methylthiophene (0.955 g, 6.72 mmol) and diphenylphosphoryl azide (2.22 g, 1.74 mL, 8.07 mmol) in anhydrous toluene. Stir at room temperature for 18 h. Dilute the mixture with EtOAc and wash with water and 0.5N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as an oil (0.875 g, 78%). GC-MS m/z 167 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:14])=[O:13])[C@H:8]([OH:26])[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[CH3:31][S:32]([O:26][C@@H:8]1[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])[CH2:10][C@H:9]1[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Benzyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (1.00 g) was added to methylene chloride (10 ml), and the obtained solution was then cooled to approximately 0° C. Triethylamine (0.52 ml) was added to the reaction solution, and methanesulfonyl chloride (0.28 ml) was then added dropwise to the mixed solution. The obtained mixture was stirred for approximately 1 hour. The precipitated crystals were collected by filtration, and were then washed with methylene chloride (1 ml). The obtained crystals were dried under reduced pressure to obtain 866 mg of the title compound (yield: 72%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[Na+].Br[CH2:21][CH2:22][OH:23].O.CCOC(C)=O>CN(C=O)C>[OH:23][CH2:22][CH2:21][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)[O-])cc2)cs1
Reactant: OCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)CCO)cc2)cs1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Sodium 4-[2-(acetylamino)-1,3-thiazol-4-yl]phenylsulfinate (600 mg) was dissolved in DMF (2 ml) under N2 atmosphere. Then 2-bromoethanol (0.168 ml) was added to the solution at 0° C. The reaction mixture was stirred at 100° C. for 7 hours. After cooled to r.t., water and AcOEt were added to the mixture. The precipitate was filtered in vacuo to give N-(4-{4-[(2-hydroxyethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide (80.2 mg) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.C([Li])(C)(C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[CH2:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>C(OCC)C>[Cl:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:22][CH2:21][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Reactant: Clc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cccc(CN2CCC(O)(c3cccc(Cl)c3)CC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To 1-bromo-3-chlorobenzene (480 mg, 2.51 mmol) in diethyl ether (10 mL), at −78° C., was added t-butyllithium (3.0 mL of a 1.7 M solution in hexanes, 5.0 mmol) dropwise. After 1 h, a solution of 1-(3-methoxybenzyl)piperidin-4-one (500 mg, 2.28 mmol) in diethyl ether (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 h, warmed to ambient temperature and quenched with saturated ammonium chloride. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(3-chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (668 mg, 80%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.53-7.52 (m, 1H), 7.40-7.36 (m, 1H), 7.30-7.20 (m, 3H), 6.96-6.93 (m, 2H), 6.82-6.79 (m, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 2.82-2.70 (m, 2H), 2.49-2.41 (m, 2H), 2.18-2.08 (m, 2H), 1.73-1.67 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[CH:20]=1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[C:20]=1[I:27]
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)(C)C

Procedure:
A solution of Step 1 intermediate (275 mg, 5.816 mmol) was treated with N-iodosuccinimide (143 g, 6.327 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford a crude product which was purified by column chromatography using 2% ethyl acetate in chloroform as eluent to afford 510 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.58 (m, 2H), 3.81 (m, 3H), 7.07-7.12 (m, 2H), 7.30-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.94-7.96 (m, 1H), 8.23-8.29 (m, 1H); ESI-MS (m/z) 497.21 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1CN1C2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2C2N(C3CCOCC3)N=CC=2C1=O.ClC1C(OC)=NC(C)=CC=1C.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C=C(OC)C=CC=1C[N:63]1[C:72]2[CH:71]=[C:70]([C:73]3[C:74]([O:81][CH3:82])=[N:75][C:76]([CH3:80])=[CH:77][C:78]=3[CH3:79])[CH:69]=[CH:68][C:67]=2[C:66]2[N:83]([CH:86]3[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)[N:84]=[CH:85][C:65]=2[C:64]1=[O:92].COC1C=C(OC)C=CC=1CN1C2C=CC=CC=2C2N(C3CCOCC3)N=CC=2C1=O>O1CCOCC1.C(O)(C(F)(F)F)=O.O>[CH3:82][O:81][C:74]1[C:73]([C:70]2[CH:69]=[CH:68][C:67]3[C:66]4[N:83]([CH:86]5[CH2:91][CH2:90][O:89][CH2:88][CH2:87]5)[N:84]=[CH:85][C:65]=4[C:64](=[O:92])[NH:63][C:72]=3[CH:71]=2)=[C:78]([CH3:79])[CH:77]=[C:76]([CH3:80])[N:75]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)cc(C)nc4OC)cc32)c(OC)c1
Agent: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c(OC)c1
Agent: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccccc32)c(OC)c1
Agent: COc1nc(C)cc(C)c1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1nc(C)cc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-chloro-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 25 (472 mg), [(t-Bu)2P(OH)]2PdCl2 (4.6 mg), cesium carbonate (119 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for four hours. The reaction mixture was extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give a 1:1 mixture of 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4,6-dimethylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one and 5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (76 mg). The mixture (76 mg) was dissolved in TFA (1.5 mL), and the mixture was stirred at 65° C. for three hours. The reaction mixture was concentrated under reduced pressure. DCM and a saturated aqueous sodium bicarbonate solution were added to the resulting residue, followed by extraction with DCM. The organic layer was washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (22 mg).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].C(N(CC)CC)C.[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]1[O:28][CH2:27]1.O>C(O)C>[CH2:30]([O:29][CH2:25][CH:26]([OH:28])[CH2:27][N:6]1[C:4](=[O:5])[C:3]([CH2:2][CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOCC1CO1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CC)(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of phenobarbital (69.6 g, 0.3 mole) in ethanol (150 ml) containing triethylamine (2.02 g, 0.02 mole) was stirred with butyl glycidyl ether (26.0 g, 0.2 mole) (available from Merck & Co.) for 6 hours at 70° C. The reaction mixture was then poured into water (500 ml) and the precipitated product was extracted with toluene (200 ml) at 70° C. The toluene layer was separated, washed with 3% aqueous sulphuric acid (200 ml) and left overnight at 4° C. The precipitated phenobarbital was filtered off and the filtrate extracted with 5% aqueous sodium carbonate (5×100 ml). The organic layer was then extracted with 1M aqueous sodium hydroxide (2×200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (40.1 g, 55%); purity by HPLC 99% m.p. 92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals, m.p.=101-103° C.
Reaction SMILES: CO.[I:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9](OC)=[O:10].[BH4-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[OH:10][CH2:9][C:8]1[CH:13]=[C:4]([I:3])[CH:5]=[C:6]([CH:7]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(I)cc(CO)c1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Methanol (20 ml) was added dropwise to a mixture of dimethyl 5-iodoisophthalate (20.0 g) and sodium borohydride (2.4 g) in tetrahydrofuran (200 ml) for 15 minutes at 45-50° C., and the mixture was stirred for 1 hour at same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform-methanol (19:1, V/V) as an eluent. The fractions containing the desired product were collected and evaporated in vacuo to give methyl 5-hydroxymethyl-3-iodobenzoate (15.11 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=1)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.3 %

Procedure:
The 2-(3-dimethylcarbamoyl-4-nitrophenyl)malonic acid tert-butyl ester methyl ester (1.22 g) obtained in Example 2b) was dissolved in dichloromethane (10 mL), and the solution was cooled to 0° C. After addition of trifluoroacetic acid (10 mL), the mixture was stirred at room temperature for 6 hours, and concentrated, followed by azeotropic distillation with toluene. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=3:1 to give the title compound (712 mg).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[C:6]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([NH2:25])[C:18]=2[CH3:26])[CH2:14][C:15]=1[OH:16])(=[O:9])[CH2:7][CH3:8].C(Cl)Cl>C(O)C>[C:6]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([NH:25][C:4]([NH:3][CH2:1][CH3:2])=[S:5])[C:18]=2[CH3:26])[CH2:14][C:15]=1[OH:16])(=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reactant: CCN=C=S
Solvent: CCO
Solvent: ClCCl
Product: CCNC(=S)Nc1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Reaction time: 96 h
Yield: 31 %

Procedure:
Ethylisothiocyanate (0.35 g, 3.98 mmol) was added to a solution of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.32 mmol) in ethanol (5 ml). Stirring was continued at 20° for 4 days. Dilute acid and methylene chloride were added. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to yield 2-propionyl-3-hydroxy-5-(3-ethylthioureido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as an oil (0.4 g, 33%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.12 (6H,t); 2.18 (3H,s); 2.28 (3H,s); 2.39 (3H,s); 2.4-4.2 (9H,m); 5.4 (1H,brs); 6.29 (1H,s); 8.34 (1H,brs).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH:8][C:9]([CH3:17])([CH3:18])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1N

Procedure:
Mix (4-bromo-2-nitro-phenyl)-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-amine (4 g, 11.1 mmol) and 5% Pt/C(S) (100 mg) in EtOAc (215 mL) and place under 60 psi hydrogen for 18 h. Filter and concentrate to give 3.76 (100%) title compound as a pale yellow oil; MS (es) 328, 330 (M+1), HPLC (ISO80-10M) t=1.57 (95%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetyl chloride (43 uL, 0.60 mmol) in DMF (2 mL) at 0° C. and the resulted mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated and the residue was washed with water (sonicated) and the solid was collected by filtration, dried under high vacuum to give compound 186 (170 mg, 74% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.82 (1H, s), 9.27 (1H, s), 9.01 (1H, s), 8.44 (1 H, d, J=5 Hz), 8.21 (1H, d, J=10 Hz), 8.07 (1H, d, J=2 Hz), 8.04 (1H, d, J=5 Hz), 7.52 (1H, dd, J=10 Hz, J=2 Hz), 5.37 (1H, p, J=10 Hz), 3.61 (4H, q, J=5 Hz), 3.17 (2H, t, J=5 Hz), 3.10 (2H, t, J=5 Hz), (3H, s), 2.40 (2H, m), 2.08 (4H, m), 2.06 (3H, s), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 456.1, Calculated 456.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)[C:11]([CH3:15])=[CH:12][C:13]=1[CH3:14]>O1CCCC1>[NH2:7][C:8]1[CH:9]=[C:10]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:11]([CH3:15])=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1cc(C)c(N2CCCCC2=O)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCCCC2)cc1N

Procedure:
6.2 g of lithium aluminium hydride are introduced into 200 ml of absolute tetrahydrofuran. 26 g (0.12 mol) of 1-(3'-amino-4',6'-dimethylphenyl)-piperidin-2-one are added in portions, with stirring. The mixture is then refluxed for 1 hour. Excess LiAlH4 is destroyed with ethyl acetate. 2 N Hcl is added to the mixture until the pH is 4-5, ether is added and the mixture is extracted twice with 2 N KOH solution. The organic phase is washed with water and saturated NaCl solution, dried with MgSO4, clarified with active charcoal and evaporated. The residue is distilled in a bulb tube. This gives 18.2 g (73%) of a yellow oil (boiling point 140°/0.001 mm Hg).