Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(Cl)(=O)=O.CNCC1C=CC=CC=1.[CH3:17][N:18]([CH3:34])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25](C)[CH2:26]C1C=CC=CC=1>[Pd].CCO.C1COCC1>[CH3:17][N:18]([CH3:34])[C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][CH3:26]
Reactant: CN(C)C1CCCCC1N(C)Cc1ccccc1
Agent: [Pd]
Agent: CNCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@@H]1CCCC[C@H]1N(C)C
Reaction time: 18 h

Procedure:
A solution of trans-2-diemthylaminocyclohexanol (61.1 g.; 0.427 mole) in 85 ml. of THF was added during 5 minutes to a suspension of NaH (17.97 g.; 0.427 mole of 57% dispersion in mineral oil) in 250 ml. of THF. and the mixture was heated at 95° for 2 hours. It was cooled to 10°, and treated dropwise with methanesulfonyl chloride (48.91 g.; 0.427 mole) during 40 minutes keeping the temperature at 15°. N-Methylbenzylamine (103.48 g.; 0.854 mole distilled) was then added, THF was evaporated and heating continued at 95° for 18 hours. The mixture was treated with 500 ml. of 20% NaOH, heated at 95°, cooled and extracted with ether (6×100 ml.). The ether solution was extracted with 10% HCl (6×100 ml.), backwashed with ether (discard ether), cooled, basified with 20% NaOH and extracted with ether. The ether extract was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated to give 48.6 g. of crude N,N,N'-trimethyl-N'-benzyl-1,2-cyclohexanediamine as an oil. A solution of this oil (46.6 g.) was hydrogenated in two portions each in 130 ml. of EtOH, with 2.6 g. of 10% Pd-C and 28.6 g. of 70% HClO4 at initial pressure of 51 p.s.i. for 22 hours. The mixture was filtered through Celite, the filtrate was evaporated, cooled in ice and basified with 40% KOH. The resulting thick suspension was extracted with ether (4×200 ml.), the ether extract was dried (MgSO4) and evaporated. The product boiled at 87°-88° (15 mm. Hg.). Vpc-mass spectrum showed that the first peak 3.4 minutes, was N,N-dimethyl-1,2-cyclohexanediamine and the second peak (4.1 minute) was the desired N,N,N'-trimethyl-1,2-cyclohexanediamine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:27][C:35](=[O:37])[CH3:36])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 4.50 mL, 13.5 mmol) was added to a stirred suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (530 mg, 1.35 mmol) in tetrahydrofuran (14 mL) at room temperature. After the resultant mixture was refluxed for 3 hr, a suspension of sodium tetrahydroborate (1.02 g, 27.0 mmol) in 2-propanol (14 mL) was added at room temperature. The resultant mixture was stirred at 50° C. for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (609 mg), which was used for the next step without further purification. To a mixture of crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (120 mg) and triethylamine (0.0742 mL, 0.532 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (0.0302 mL, 0.319 mol) at 0° C. The resultant mixture was stirred at room temperature for 10 min, diluted with aqueous sodium bicarbonate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-40% acetonitrile/water gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[C:27](=[O:28])[O:26][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)=[CH:18][CH:19]=[C:14]4[CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:29]N(C=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[Cl:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[C:27](=[O:28])[O:26][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][N:23]([CH3:29])[CH2:22][CH2:21]5)=[CH:18][CH:19]=[C:14]4[CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=c1oc2nc(N3CCNCC3)ccc2cc1-c1nc2c(Cl)cccc2s1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc3cc(-c4nc5c(Cl)cccc5s4)c(=O)oc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-chlorobenzo[d]thiazol-2-yl)-7-(piperazin-1-yl)-2H-pyrano[2,3-b]pyridin-2-one hydrochloride (890 mg, 2.0 mmol) m DMF (10 mL) were added 37% aqueous HCHO (0.4 mL, 3.4 mmol) and then NaBH(OAc)3 (636 mg, 3.0 mmol). The reaction mixture was stirred for 30 min at ambient temperature. To the mixture were added water (10 mL) and a saturated NaHCO3 solution (10 mL) to form a precipitate. The precipitate was filtered off, washed with water and dried under nitrogen, affording 680 mg (97%) of the title compound as a yellow solid. Melting point 258-260° C.; MS m/z 413.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.06 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=6.9 Hz), 7.64 (1H, m), 7.44 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=9.1 Hz), 3.79 (4H, m), 2.44 (4H, m), 2.25 (3H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C>CO.[Pd]>[NH2:13][C:9]1[C:10]([CH3:12])=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)nc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(C)c(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
A round-bottom flask, containing a solution of methyl 2-chloro-6-methyl-5-nitronicotinate (12.8 g, 55.5 mmol, 1.00 equiv) in methanol (120 mL) was purged with nitrogen. Triethylamine (15.0 g, 149 mmol, 2.68 equiv) and palladium on carbon (1.30 g) were added. After further purging the flask with nitrogen, the atmosphere was changed to hydrogen and the resulting solution was stirred for 2 days at room temperature under atmospheric pressure. After purging the system with nitrogen, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:5) as eluent to furnish 3.50 g (38%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: COc1ccc2cc(-c3nc(C(C)(C)CNS(=O)(=O)CCCCl)[nH]c3-c3ccncc3)ccc2c1
Yield: 40 %

Procedure:
The title compound (11 mg, 40%) was prepared starting from the product of Example 2 and 3-chloro-propanesulfonyl chloride using the method described in Example 4; MS(ES) m/e 514 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH3:14]>CC(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1c([N+](=O)[O-])cnc2ccsc12
Yield: 99 %

Procedure:
To a suspension of 2.55 g of 7-chloro-6-nitrothieno[3,2-b]pyridine 15 in 130 ml of 2-propanol is introduced excess anhydrous ammonia at 45° C. (bath temperature) during 4 hours and the mixture is evaporated in vacuo. The residue is suspended in water, collected by filtration, and then washed with water and ether to give 2.30 g (99%) of Compound 16. An analytical sample is recrystallized from chloroform methanol, affording yellow crystals melting at 266°-268.5° C.
Reaction SMILES: CCCCCC.C([Li])CCC.C[CH2:13][O:14]CC.[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[CH:28][CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[C:28]([CH:13]=[O:14])[CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: CCOCC
Reactant: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCOc1c(C=O)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Reaction time: 1 h

Procedure:
52 ml of a hexane solution of 1.6M n-butyl lithium was dropped in an absolute ether (110 ml) solution of 19 g of 1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene and agitated for 1 hour. After ice cooling, 8.5 ml of N,N-dimethylformamide was dropped in the reaction solution and the ice bath was removed, followed by agitation for 1 hour until room temperature was reached. Iced water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography (2% ethyl acetate/hexane) to obtain 14.1 g of the captioned compound as a brown oily substance.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[C:38]=3[CH3:52])[C:31]2=[O:53])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:32]2[C:33](=[O:36])[CH:34]=[CH:35][N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[C:31]2=[O:53])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Yield: 48.7 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 3] (135 mg, 0.354 mmol), 1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione [Intermediate 44] (164 mg, 0.389 mmol), and tetrakis(triphenylphosphine)palladium (20 mg, 0.018 mmol) in toluene (5.3 mL) and ethanol (1.8 mL) was bubbled with argon for several min. The mixture was treated with 2 M aqueous Na2CO3 (354 μl, 0.707 mmol), bubbled again with argon, and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 25-100%), to give 3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (103 mg, 49% yield). Mass spectrum m/z 579 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.52 (d, J=4.5 Hz, 1H), 8.29 (br. s., 1H), 8.13 (d, J=2.5 Hz, 1H), 7.91 (dd, J=7.9, 6.4 Hz, 1H), 7.85-7.80 (m, 1H), 7.64-7.54 (m, 3H), 7.53-7.45 (m, 2H), 7.36 (dt, J=11.9, 8.7 Hz, 2H), 7.25 (ddd, J=7.3, 4.3, 1.2 Hz, 1H), 7.03-6.83 (m, 1H), 6.73-6.47 (m, 1H), 5.97 (dd, J=7.9, 3.5 Hz, 1H), 5.04-4.92 (m, 1H), 1.75 (d, J=1.5 Hz, 3H), 1.47-1.33 (m, 6H).
Reaction SMILES: [I-].[O:2]1[C:6]2([CH2:11][CH2:10][C:9]([C:12]3[CH:17]=[CH:16][N+:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[OH-:19].[Na+]>C1COCC1>[O:2]1[C:6]2([CH2:11][CH2:10][C:9]([C:12]3[CH:13]=[CH:14][N:15]([CH3:18])[C:16](=[O:19])[CH:17]=3)=[CH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C[n+]1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(C2=CCC3(CC2)OCCO3)cc1=O

Procedure:
4-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-1-methyl-pyridinium iodide (as prepared in the previous step, 864 mg, 2.40 mmol) in THF (5 mL) and 1N NaOH (5 mL) was treated with K3Fe(CN)6 (Aldrich, 1.58 g, 4.80 mmol) at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-])=O)([CH3:14])[CH:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1.C([O-])(=O)C.[Na+].C.[H][H]>C(O)(=O)C.[Pt]=O>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc2c(c1)OCO2
Reaction time: 5 h

Procedure:
A mixture of 51.52 g (0.2 mole) of 1,1-dimethyl-2-chloro-2-(3,4-methylenedioxyphenyl)nitroethane, 2.0 g of 83.8 weight % purity platinum oxide, 18.0 g (0.22 mole) of sodium acetate and 4.0 g of "Darco" in 96 ml of acetic acid and 500 ml of SDA-30 was stirred under a hydrogen atmosphere at 1000 p.s.i. and 100° C for a period of 5 hours, after which uptake of hydrogen ceased. The solution was cooled and filtered, and the filtrate was concentrated to an oil which was treated with 400 ml of water. The mixture was extracted twice with ether, after which the aqueous layer was made alkaline by addition of 20% aqueous sodium hydroxide and extracted four times with chloroform. The combined extracts were filtered through "Dicalite" (Trade Mark), washed with water, dried and concentrated to a light yellow oil which was distilled using a 2" 19.38 distillation column to give 1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethylamine as a clear colourless oil, b.p. 68°-85° C, 0.06-0.04 mm Hg (Yield 24.4 g, 63.2%)
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1)=[O:7])(C)(C)C>Cl.O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1)([OH:7])=[O:5]
Reactant: COC(=O)C(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OCc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(OCC(=O)O)cc1)OCc1ccc(F)cc1

Procedure:
A solution of methyl 3-[4-(t-butoxycarbonylmethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate (2.8 g) in 4N hydrogen chloride/dioxane (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (2.42 g, Rf=0.10: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=5:1 as the eluant).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:28])[NH:26][NH2:27])=[CH:18][C:17]=2[O:16]1>>[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]3[C:10](=[O:11])[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:7]3=[O:8])=[CH:18][C:17]=2[O:16]1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc2c(c1)OCO2

Procedure:
ninhydrin, 4-(3,4-methylenedioxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCCCNc1ccc(Cl)c(Cl)c1
Yield: 56.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 3,4-dichloroaniline (1.62 g, 10.0 mmol) and butyraldehyde (721 mg, 10.0 mmol) were converted to the title compound (1.24 g, 57%). 1H NMR (CDCl3) δ 7.17 (d, J=8.8 Hz, 1H), 6.65 (d, J=2.9 Hz, 1H), 6.41 (dd, J=2.8, 8.7 Hz, 1H), 3.05 (t, J=7.0 Hz, 2H), 1.65-1.53 (m, 2H), 1.43 (qd, J=7.3, 15.0 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 218.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[N-:11]=[N+:12]=[N-:13].[Na+].CN[C@H]1CCCC[C@@H]1NC.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CCO.O.[Cu]I>[N:11]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])=[N+:12]=[N-:13]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1cncc(C(N)=O)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromonicotinamide (100 mg, 0.5 mmol), sodium azide (65 mg, 1.0 mmol), CuI (19.5 mg, 0.05 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (11 mg, 0.08 mmol) and sodium ascorbate (5.0 mg, 0.03 mmol) in EtOH (0.7 mL) and H2O (0.3 mL) was degassed for 5 min before heated at reflux for 1.0 h. After cooled to rt, the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After removal of the solvent, the crude was purified by silica gel column chromatography eluting with gradient EtOAc in hexanes (0-100%) to give 97A. 1H NMR (400 MHz, Methanol-d4) δ ppm 7.96-8.05 (m, 1H) 8.44 (d, J=2.64 Hz, 1H) 8.79 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCCC1CCC(CCc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(CCC3CCC(CCC)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
THF solution (5 ml) including methyltriphenylphosphonium bromide (0.25 g, 0.7 mmol) was slowly added by potassium tert-butoxide (0.07 g, 0.7 mmol) for 3 minutes and then stirred for 1 hour at a room temperature. The resulting solution was added slowly dropwise by THF solution (2 ml) of trans-4-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}cyclohexane-carbaldehyde (0.2 g, 0.58 mmol) and stirred for 24 hours with maintaining the same temperature. After the reaction termination, white precipitate was removed by filtration. The filtered solution was extracted by ether (10 ml×3 times) and the organic layer was collected and washed by distilled water (10 ml×2 times) and salt water (10 ml×2 times). The residue was purified by column chromatography (petroleum ether) to obtain a final product of 1-[2-(4-propylcyclohexyl)ethyl]-4-(4-vinylcyclohexyl)benzene (0.12 g, 65%).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[C:31]1([C:29]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:38][CH:37]=2)=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)F)C(F)F)cc1
Yield: 25 %

Procedure:
To a solution of 2,2,-bis-difluoromethyl-2-hydroxy-acetic acid (1.76 g, 10 mmole) in tetrahydrofuran (40ml) was added carbonyl diimidazole (0.81 g, 5 mmole). The flask was placed in a sonic bath and the reaction sonicated for 20 minutes followed by addition of 4-aminobenzophenone. The reaction was sonicated for 18 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The recovered pasty solid was washed with ether and the combined ether washings evaporated. The recovered solid was crystallized from ethyl acetate/hexane to give the title compound (0.89g, 25%) as yellow crystals; mp 139°-142° C. 1H--NMR (300 MHz, d6 --DMSO) : 6.48(t, J=53.7Hz, 2H, HCF2); 7.53-7.77 7H, ArH, OH); 7.95-7.98(m, 3H, ArH); 10.43 (s, 1H, NH). MS(CI,CH4) 356(M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=1>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Reactant: FC(F)(F)C(F)(F)Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(=O)c1cccc(Cl)c1
Yield: 85.6 %

Procedure:
A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (2.74 g, 12.08 mmol) in dimethoxyethane (30 ml) was ice-cooled, and sodium hydride (60%, 0.49 g, 12.08 mmol) was added, and the mixture was stirred under ice-cooling for 30 min. A solution of 1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 12.08 mmol) in dimethoxyethane (15 ml) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with 0.5N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1, 10:1) to give ethyl 3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate (4.64 g, 86%) as colorless crystals.