Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20]
Reactant: COC(=O)c1cn2c3c(c(Cl)ccc3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 74.5 %

Procedure:
To 370 mg (1.3 mmol) of the compound (145) obtained in Example 30, 2 ml of concentrated hydrochloric acid and 10 ml of acetic acid were added, and the solution was heated at reflux for 2 hours. The solvent was removed by distillation. Crystals were dispersed in ethanol and filtered and washed with ethanol and ether in this order to obtain 270 mg of the subject compound (146) in a 77% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: Cc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and α-bromo-p-xylene
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4042 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.091 g, 0.0023 mol) in DMF (2 mL) and after stirring for 20 min, p-fluorobenzyl bromide (0.28 mL, 0.0023 mol) is added. Additional DMF (1 mL) is added and the mixture is stirred for 4 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 80/20) to give 0.5519 g (92%) of the title compound; mp 207-207.75° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1628, 1511, 1467, 1448, 1360, 1226, 1218, 1145, 1096, 878, 849, 840, 804, 764, 649 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.86, 5.27, 6.99, 7.16, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found (av): C, 69.08; H, 4.50; N, 4.26.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:70]([NH2:74])([CH2:72][CH3:73])[CH3:71]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[N:7]=[C:6]([NH:74][C@H:70]([CH2:72][CH3:73])[CH3:71])[CH:5]=1
Reactant: CC[C@H](C)N
Reactant: CCCS(=O)(=O)c1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)c1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Add 2-chloro-6-propanesulfonyl-isonicotinic acid methyl ester (2.70 g, 9.71 mmol), toluene (40 mL), palladium acetate (218 mg, 0.97 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (605 mg, 0.97 mmol), cesium carbonate (4.75 g, 14.6 mmol), and (S)-sec-butylamine (1.46 mL, 14.6 mmol) to a sealed vessel flushed with nitrogen. Heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (2.47 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.OS(O)(=O)=O.O.[C:23]([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:23])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(OC)c(C(F)(F)F)cc1N

Procedure:
3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. B) 5.5 g, 23.29 mmol) was dissolved in MeOH (90 ml). H2SO4 (6.21 ml, 116 mmol) was added dropwise and the solution was heated to reflux for 4 hours. The reaction mixture was reduced in vacuo to approx. 15 ml and water (15 ml) was added. The pH was adjusted to pH 9 by careful addition of solid NaHCO3. Water (100 ml) was added and the mixture was extracted with DCM. The combined organic extracts were concentrated in vacuo to afford the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1)[CH3:21].O[C:32]1[CH:33]=[CH:34][C:35]2[CH2:41][CH2:40][CH2:39][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:37][C:36]=2[CH:46]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:20]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:32]2[CH:33]=[CH:34][C:35]3[CH2:41][CH2:40][CH2:39][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:37][C:36]=3[CH:46]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: CCOc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCC3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
To triphenylphosphine (590 mg, 2.25 mmol), 4-ethoxybenzyl alcohol (342 mg, 2.25 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in THF (6 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (0.439 ml, 2.23 mmol) in THF (2 ml), and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 50 g, ethyl acetate/hexane=1/25→1/19). The objective fractions were concentrated under reduced pressure, diisopropyl ether was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (308 mg, 0.87 mmol, 58%).
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][O:49][CH:50]([F:52])[F:51])C(O)=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>ClCCl.C(#N)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:44]([NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:48][O:49][CH:50]([F:52])[F:51])[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
A cooled (0° C.) solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (923 mg, 2.0 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL). After stirring at room temperature for 1.5 h, the volatiles were removed in vacuo and residual trifluoroacetic acid was azeotroped off with toluene. The residue was combined with (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid (260 mg, 1.02 mmol) and dissolved in anhydrous acetonitrile (10 mL). The cooled (0° C.) mixture was subsequently treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (543 mg, 1.43 mmol) and N,N-diisopropylethylamine (0.71 mL, 4.08 mmol). After stirring at room temperature for 3 days, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organics were separated, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 7:3 to provide the title compound (143 mg, 28%) as a pale Greene gum and as a complex mixture of rotamers. LCMS (m/z) 498.0, 500.0 [M+H], Tr=2.91 min.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:15]([O-:17])=[O:16])[C:3]=1[NH:4]C(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:15]([O-:17])=[O:16])[C:3]=1[NH2:4]
Reactant: CC(=O)Nc1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(F)c(N)c([N+](=O)[O-])c(F)c1F
Temperature: 0 °C
Yield: 118.7 %

Procedure:
To 2,4,5-trifluoro-3-methyl-6-nitro-N-acetylaniline (2.08 g) are added ethanol (30 ml) and 10% hydrochloric acid (30 ml) and the mixture is refluxed for 3 hours. After cooling, the reaction mixture is poured into ice-water, neutralized with potassium carbonate, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitroaniline (2.05 g), as brown crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClCCl.C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:16][S:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CO)(COCc1ccccc1)CSCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC(C=O)(COCc1ccccc1)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Benzyloxymethyl-2-benzylthiomethyl-pentan-1-ol (5 g.) was added to a stirred suspension of pyridinium chlorochromate (5 g.) and anhydrous sodium acetate (3.0 g.) in dry dichloromethane (20 ml.) at 0°, under a current of nitrogen. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (100 ml.) and the organic solution was decanted off. The oily residue was treated with ether and the combined extracts were evaporated in vacuo. The residue was chromatographed on silica eluting with ethyl acetate:hexane, 1:10. 2-Benzyloxymethyl-2-benzylthiomethyl-pentanal was obtained as a colourless oil (1.9 g.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)=[O:18])[CH:10]=[N:11][CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([C:17]([NH:16][CH2:15][CH2:14][O:13][C:9]2[CH:10]=[N:11][CH:12]=[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[CH:8]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: CN1CCC[C@H]1c1cncc(OCCNC(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@H]1c1cncc(OCCNC(=O)[C@H]2CC[C@H](N)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (trans-4-{[2-({5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}oxy)ethyl]carbamoyl}cyclohexyl)carbamate (preparation 35) (35 mg, 0.078 mmol) in DCM (3 mL) was treated with trifluoroacetic acid (1 mL). The resulting solution was stirred at ambient temperature overnight, after which time it was concentrated in vacuo. The residue was dissolved in MeOH and applied to an SCX-2 cartridge and eluted with MeOH followed by ammonia in MeOH (2M). The fractions containing product were concentrated in vacuo to give the title compound as an orange gum (17 mg, 62%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC([O:11][C:12]1[C:15](=[O:16])[C:14](=O)[C:13]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])C>C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:14]2[C:15](=[O:16])[C:12](=[O:11])[C:13]=2[Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(N2CCN(C)CC2)c(=O)c1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
1-Methylpiperazine (0.65 g, 6.49 mmols) was added to a stirred, cooled (ice/H2O bath) solution of 4-(2-propoxy)-3-(tri-n-butylstannyl)-cyclobut-3-ene-1,2-dione (2.53 g, 5.90 mmols) in diethyl ether (80 mL). Stirring was continued with cooling for 1 hr and then at ambient temperatures for 1 hr. The mixture was concentrated and the residue chromatographed on SiO2 with ethyl acetate-methylene chloride (35:65) to afford the title compound (2.1 g, 76% yield) as a golden viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CCCCCCC.[C:17](#[N:20])[CH:18]=[CH2:19]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:19][CH2:18][C:17]#[N:20])=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Solvent: CCCCCCC
Product: COc1ccc(OCCC#N)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
4-Methoxyphenol (263.0 g) was dissolved in acrylonitrile (224.8 g), and then Triton B (18 mL) was added dropwise at room temperature, with stirring at 80° C. for 48 hours. The reaction liquor was returned to room temperature while slowly stirring, and stirred for 12 hours. The reaction liquor was further left to stand at 6° C. to precipitate white prisms. The mother liquor was subjected to decantation, and cold toluene (300 mL) was added to obtain crystals, and then the resulting crude crystals were dried at room temperature under reduced pressure (3 hours) (crude crystals 232.6 g). The crude crystals were dissolved in ethyl acetate (250 mL) at 50° C., n-heptane (250 mL) was slowly added with stirring, and the resulting mixture was recrystallized with slow stirring for 12 hours. The mother liquor was subjected to decantation, n-heptane (300 mL) was added, and crystals were obtained. The crystals were washed with n-heptane (400 mL) and dried at room temperature under reduced pressure (crystal No. 1: white prisms 154.5 g). Since crystals were generated in the mother liquor, pale yellow prisms were obtained as crystal No. 2 (crystal No. 2: pale yellow prisms 56.1 g). All of the filtrate and n-heptane used for washing were recovered and concentrated under reduced pressure. Then, toluene (500 mL) was added to the residue, and the mixture was washed with 1 N aqueous sodium hydroxide solution (100 mL×3 times), water (500 mL), 1 N aqueous hydrochloric acid solution (100 mL×3 times), water (500 mL) and saturated brine (300 mL), then dried over anhydrous sodium sulfate for 30 minutes, and filtered, and subsequently the filtrate was concentrated under reduced. The residue was dissolved in ethyl acetate (150 mL) at 50° C., and n-heptane (150 mL) was slowly added with stirring, and the resulting mixture was recrystallized with slow stirring for 12 hours. The mother liquor was subjected to decantation, and n-heptane (200 mL) was added, and crystals were obtained. The crystals were washed with n-heptane (300 mL) and dried at room temperature under reduced pressure (crystal No. 3: white prisms 59.0 g). Furthermore, pale yellow prisms were obtained as crystal No. 4 (crystal No. 4: 19.0 g). Total amount obtained was 288.6 g, yield was 76.9%+ crude crystals (yellow prisms, 21.8 g, 5.8%).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28]OS(C(F)(F)F)(=O)=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].C[N+](C)(C)C.O>COCCOC>[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)C1CCC(COS(=O)(=O)C(F)(F)F)CC1
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(CC(F)(F)C(F)(F)F)CC1
Reaction time: 4 h
Yield: 18.5 %

Procedure:
(Pentafluoroethyl)trimethylsilane (105 mg, 0.548 mmol) was added to a solution of 4-trifluoromethanesulfonyloxymethyl-cyclohexanecarboxylic acid benzyl ester (cis:trans=4:1) (67.0 mg, 0.176 mmol) in DME (0.88 ml) at −30° C., and tetramethylammonium fluoride (21 mg, 0.22 mmol) was then added at −30 to −27° C. over one hour. The mixture was stirred for four hours while warming from −30° C. to 0° C. and further stirred at 0° C. for one hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=150/1) to give 4-(2,2,3,3,3-pentafluoro-propyl)-cyclohexanecarboxylic acid benzyl ester (cis:trans=11:1) (11.4 mg, 18%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[OH:18]>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: COc1cc(C(C)=O)ccc1O
Product: COC(=O)COc1ccc(C(C)=O)cc1OC

Procedure:
Methyl bromoacetate was reacted with 2-methoxy-4-acetylphenol to give methyl 2-methoxy-4-acetylphenoxyacetate by the same procedure as was used to make isopropyl 4-acetylphenoxyacetate.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]([C:12]1[S:16][C:15]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.[N+:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([O-])=O.C1COCC1.C[O-].[Na+].CO>O>[NH2:37][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][CH2:17][C:15]2[S:16][C:12]([C:10]([O:9][CH3:2])=[O:11])=[CH:13][CH:14]=2)=[CH:42][CH:41]=1
Reactant: O=C(OCc1ccccc1)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a mixture of 2.88 g of ({5-[(benzyloxy)carbonyl]-2-thienyl}methyl)(triphenyl)phosphonium bromide, 823 mg of 4-nitrobenzaldehyde and 30 mL of THF was added dropwise 1.0 mL of a 5.0 M sodium methoxide/methanol solution, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with 1.0 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:6). 10 mL of methanol and 10 mL of THF were added to the obtained residue, and 98 mg of 10% palladium carbon was added thereto under an argon flow, followed by stirring overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered using celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), thereby obtaining 765 mg of methyl 5-[2-(4-aminophenyl)ethyl]thiophene-2-carboxylate.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 5.9 %

Procedure:
Using cyclohexyl{3-ethyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.90 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.75 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (82 mg, 6%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])=[CH:4][C:3]=1[Cl:20].[Cl-].[NH4+]>[Fe]>[Cl:20][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A mixture of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene (60 g, 190.40 mmol, 1.00 equiv), Fe (53 g, 946.43 mmol, 4.97 equiv) and ammonium chloride (10 g, 188.68 mmol, 0.99 equiv) in tetrahydrofuran/water(1/2) (600 mL) was stirred overnight at 60° C. under an inert atmosphere of nitrogen. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The resulting solution was extracted with 3×500 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum to give 40 g (74%) of 4-(3,4-dichlorophenoxy)-3-methoxyaniline as a light gray solid.
Reaction SMILES: [CH3:1][Zn]C.[CH2:4]([O:11][N:12]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24](Br)[CH:25]=[C:18]3[C:19]=2[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13]1=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:4]([O:11][N:12]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([CH3:1])[CH:25]=[C:18]3[C:19]=2[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13]1=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Zn]C
Reactant: O=C1c2cccc3cc(Br)cc(c23)C(=O)N1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylzinc (4 mL, 2 eq.) was added to a suspension of 2-benzyloxy-5-bromo-benzo[de]isoquinoline-1,3-dione (1.5 g, 3.9 mmol, from Example O) and Pd(PPh3)2Cl2 (0.14 g, 0.2 mmol) in dry THF (20 mL). The mixture was stirred under nitrogen at room temperature for 8 hours, filtered, and washed with dimethylacetamide. Concentration of the filtrate gave 1.1 g of the title compound in crude form which was used as is.