Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:45]([N+:46]([O-])=O)=[CH:44][CH:43]=[CH:42][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:7]1.[CH:49]([Mg]Br)=[CH:50][CH3:51].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH:6]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:14][CH:13]=3)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:7]2)=[CH:42][CH:43]=[C:44]2[C:45]=1[NH:46][CH:49]=[C:50]2[CH3:51]
Reactant: CC=C[Mg]Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)c[nH]c3c2Br)cc1
Reaction time: 0.25 h

Procedure:
The solution of 0.500 g of benzyl 3-(2-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 6.5 ml of tetrahydrofuran is cooled to −45° C. under argon and admixed slowly with 4.0 ml of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran). The reaction mixture is stirred over 15 minutes, subsequently poured onto saturated aqueous ammonium chloride solution (10 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with water (25 ml) and brine (25 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane); Rt=6.17.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Yield: 74 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (0.37 g, 1.16 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.30 g, 1.16 mmol) and caesium carbonate (0.45 g, 1.4 mmol) in dimethylformamide (15 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatography on silica gel (eluent: ethyl acetate/n-heptane), yielding the titled compound (0.33, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([O:19]C)=O)=[CH:4][CH:3]=1.[OH-].[Na+].[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH:25]=[N:24]1.N=C=N>CO.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:32][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[NH:23][N:24]=[CH:25]3)=[O:19])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(F)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: N=C=N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)CC(=O)N1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.4 %

Procedure:
The product of Step 1 (1.58 g, 5.70 mmol, 1 equiv) was dissolved in methanol (24 mL) and 2.5 N NaOH (8 mL) was added. The reaction was heated to 60° C. for 3 h. Upon cooling, the resulting mixture was partitioned between EtOAc and water. The aqueous layer was acidified to pH 1 and extracted with EtOAc. The phases were separated and the organic phase was concentrated in vacuo. The resulting residue (1.50 g, 5.70 mmol, 1.1 equiv) was dissolved in DMF (30 mL). 1H-indazol-5-amine (700 mg, 5.18 mmol, 1.0 equiv) and PS-carbodiimide resin (8.27 g, 7.77 mmol, 1.5 equiv) were added and the mixture stirred overnight at room temperature. The resin was removed by filtration and washed alternately with methanol and CH2Cl2, followed by diethyl ether. The filtrate was concentrated en vacuo to remove the volatile solvents. The residue was dissolved in EtOAc, washed twice with water and once with satd. NaHCO3. The organic phase was concentrated in vacuo and the residue was purified by reverse phase HPLC (Xterra Prep 19×50, 25 mL/min, 10-90% 5 mM aq. NH4HCO3/CH3CN over 9 minutes) to provide 8 mg (0.4%) of a white crystalline solid. MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [SH:1][C@@H:2]([CH3:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23].Cl>O>[C:22]([CH:21]([S:1][C@@H:2]([CH3:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:24])=[O:23]
Reactant: C[C@H](S)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(Br)CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](SC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(2S)-1-[(2S)-2-Mercaptopropanoyl]-2-pyrrolidinecarboxylic acid (2.0 g), potassium carbonate (2.8 g) and 2-bromo-4-phenylbutanoic acid (2.9 g) were dissolved in water (40 ml), and stirred overnight at room temperature. The reaction mixture was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography to give 2.3 g (62%) of the titled compound: [α]D23 -82.2° (c=1.2, MeOH). IR (KBr, cm-1): 1740, 1720, 1610, 1455, 1438, 1185, 748, 700.
Reaction SMILES: [O:1]=[C:2]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6]CC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:6][C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH2:3][C:2]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)=[O:1]
Reactant: CCCCCn1cc(C(=O)Cc2ccccc2OCC(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCn1cc(C(=O)Cc2ccccc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
t-Butyl 2-(2-(2-oxo-2-(1-pentyl-1H-indol-3-yl)ethyl)phenoxy)acetate (O-desmethyl JWH-250 t-butyl 2-CME) 6 (1.09 g, 2.50 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (10 ml) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera 4, SNAP-50 g, 50% ethyl acetate in hexane) to give 512 mg (54%) of O-desmethyl JWH-250 2-CME (Hapten 1) as a tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=S)[NH:8][NH2:9].Cl.[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[ClH:13].[CH2:18]([O:17][C:15]([C:14]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])=[N:8][NH:9][C:20]=1[CH3:22])=[O:16])[CH3:19]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CN(C)CCCNC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)n[nH]c1C
Yield: 71.4 %

Procedure:
A stirred solution of 7.05 g (0.04 mole) of 4-(3-dimethylaminopropyl)-3-thiosemicarbazide in 50 mL of absolute ethanol under nitrogen atmosphere was treated with 40 mL of 2N ethanolic hydrogen chloride and then with 6.6 g (0.04 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 2 hr and heated at reflux for 5 hr. The reaction mixture was filtered hot to remove some crystalline sulfur and the filtrate solidified on cooling to give 8.3 g of crude product. After 5 recrystallizations from methyl ethyl ketone/methanol with charcoal treatment of the final recrystallization, a crystalline product was obtained, 3,4 g, mp 195°-196° C. After drying at 82° C. under reduced pressure, it was submitted for elemental analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1C(=O)CCC1.CN.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][NH:14][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)Sc1ccc(Cl)nc1
Reactant: CN1CCCC1=O
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNc1ccc(SC(F)(F)F)cn1
Temperature: 60 °C

Procedure:
To a mixture of 2-chloro-5-trifluoromethylsulfanylpyridine (1.71 g) and NMP (16 ml), 40% of aqueous methylamine solution (1.86 g) was added dropwise, and then the mixture was heated to 60° C., and stirred with heating for 2 hours. After the mixture was cooled to room temperature, potassium carbonate (1.66 g) was added thereto, and 40% of aqueous methylamine solution (1.86 g) was added dropwise. The mixture was heated to 60° C., and stirred with heating for further 2 hours. After the mixture was cooled to room temperature, water was poured, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.52 g of methyl-(5-trifluoromethylsulfanylpyridine-2-yl)-amine.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][C:5]=1[C:12]([OH:14])=O)([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[NH:6][C:5]=1[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:14])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)O)[nH]1
Reactant: COC(=O)c1ccc(N)cc1
Product: CC(C)c1cc(C(C)C)c(C(=O)Nc2ccc(C(=O)O)cc2)[nH]1

Procedure:
In the same manner as that of Example 17, 3,5-diisopropylpyrrole-2-carboxylic acid (60 mg, 0.308 mmol) was condensed with methyl 4-aminobenzoate, the reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography [hexane-ethyl acetate (3:1)] to obtain the desired condensate (60 mg, 59%) from the high polarity portion, and the starting material substrate acid anhydride (15 mg, 26%) from the low polarity portion.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]=[CH2:33]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C=CCN
Product: C=CCNCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and allylamine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.81 (s, 1H), 5.95 (m, 1H), 5.55 (m, 2H), 3.25-3.8 (m, 14H); MS (DCI) m/z 392 (M+H)+;
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH3:49])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccccc3C)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 2-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[BH4-].[Na+].C(O)(=O)C(O)=O>COCCOCCOC>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1

Procedure:
41.5 G. of 1-carbethoxy-4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)piperazine are reacted together with 1 l. of absolute diglyme (diethyleneglycoldimethylether) with 26.5 g. of sodium borohydride and stirred at 25° for 30 minutes. The reaction mixture is then mixed dropwise at 20°-30° over a 45-minute period with a solution of 138.6 g. of oxalic acid in 800 ml. of diglyme. The reaction mixture is maintained at 100° for 15 hours. The resulting mixture is evapoated under reduced pressure. The residue is suspended in 1 l. of 2N aqueous sodium hydroxide and extracted with benzene. The benzene extract is washed with water, dried and evaporated, whereby there is obtained 1-carbethoxy-4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl)piperazine as a red-brown oil, whose nmr and ir spectra are consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C:34]([N:12]1[CH2:11][CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])([OH:15])[CH2:14][CH2:13]1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: OC1(c2ccc(Cl)cc2Cl)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-piperidin-4-ol (0.10 g, 0.40 mmol) in dichloromethane (2 mL) was added diisopropyl ethylamine (0.073 mL, 0.42 mmol) followed by benzyloxy acetyl chloride (0.078 g, 0.42 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was chromatographed on silica gel using dichloromethane/methanol from 100% to 97% dichloromethane in a gradient fashion, to give the title compound as a glassy solid. The material was used as is without further purification. 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 8H), 4.58 (m, 3H), 4.22 (m, 2H), 3.86 (bm, 1H), 3.57 (bm, 1H), 3.13 (bm, 1H), 2.64 (s, 1H), 2.26 (m, 2H), 1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Oc2ccccc2)cc1

Procedure:
Example 33 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-phenoxybenzene (24.6 μl) to give the title compound (0.0171 g). LC-MS (System A): Rt 2.62 mins, Mass Spectrum m/z 486 [MH+].
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)=[O:5])C.[OH-].[K+].Cl>C(O)C.O>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:18]([F:20])([F:21])[F:19])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH3:15]
Reactant: CCOC(=O)c1[nH]c2cc(C(F)(F)F)c(OC)cc2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(C)c(C(=O)O)[nH]c2cc1C(F)(F)F
Yield: 73 %

Procedure:
5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (3.0 g, 10 mmol) was dissolved in 10 ml absolute ethanol, and a solution of KOH (1.7 g, 30 mmol) in 7 ml water was added. The reaction mixture was heated to reflux for 2.5 hours, then cooled, acidified slowly with 6 N HCl to pH=2, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2.0 g, (73%) 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([I:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(I)c1
Yield: 64.6 %

Procedure:
A mixture of 4-chloro-2-iodo-1-methylbenzene (3.95 g, 15.6 mmol), N-bromosuccinimide (3.10 g, 17.6 mmol), and benzoyl peroxide (0.1 g) in carbon tetrachloride (100 mL) was heated to reflux for 48 hours, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexanes to provide 3.34 g (64%) of the desired product. MS (DCI/NH3) m/z 330, 332 (M+H)+; 1H NMR (CDCl3) δ 7.85 (d, 1H), 7.40-7.32 (m, 2H), 4.59 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ncccc1N
Reaction time: 15 h
Yield: 86.7 %

Procedure:
A solution of 2-methoxy-3-nitro-pyridine (70. g, 0.45 mol) in methanol (700 mL) containing palladium on carbon (7 g, 10%) was stirred under an atmosphere of hydrogen for 15 hours. The catalyst was filtered and washed with methanol. The filtrate was evaporated to dryness to give crude 2-methoxy-pyridin-3-ylamine (48 g, 0.39 mol, 87%), which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.Cl.O>CO>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2cccc(O)c2)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-hydroxybenzaldehyde 0.813 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. The solution was cooled to room temperature, water 400 ml was added and allowed to stand for one hour. Precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.20 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[N:15]=[N+]=[N-])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[CH:8]=1)[CH3:2]>CC1C=CC(C)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:12]2[C:7]([CH:6]=1)=[CH:8][C:9]([F:14])=[C:10]([CH3:13])[CH:11]=2)=[O:18])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(C)c(F)c1)N=[N+]=[N-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2cc(F)c(C)cc2[nH]1
Temperature: 15 °C
Yield: 37.1 %

Procedure:
(Z)-2-Azido-3-(3-fluoro-4-methyl-phenyl)-acrylic acid ethyl ester (9.7 g, 0.039 mol) was dissolved in 80 ml p-xylene and divided into four portions which were refluxed for 1 h. The oil bath was removed and the yellow solutions were cooled to 15° C. The resulting suspensions were filtered, washed with n-hexane and the solid material collected. The combined mother liquors were evaporated and the resulting oil was purified on silical gel (0.030–0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluent. The purified fractions together with the first precipitates were combined and chromatographed again to yield the desired product as a colorless solid (3.2 g, 37.2%). EI-MS: m/e=249.1 (M).
Reaction SMILES: C([O:8][C@H:9]([CH2:36][O:37]CC1C=CC=CC=1)[CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]([CH2:36][OH:37])[CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:33])[F:34])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC[C@@H](COCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC[C@H](O)CO
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture consisting of 26 mg (0.043 mmol) of (R)-2,3-bisbenzyloxypropyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate synthesized in Example 132; 5 mg (0.036 mmol) of palladium hydroxide; and 0.2 ml (3.49 mmol) of acetic acid, was suspended in 3 ml of ethanol, and the obtained suspension was then stirred under a hydrogen atmosphere for 2 hours. Thereafter, the reaction solution was filtrated with celite, and was then concentrated. The obtained residue was purified by silica gel chromatography (dichloromethane:methanol=10:1), so as to obtain 18 mg (100%) of (R)-2,3-dihydroxypropyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate in the form of a light yellow oily substance.