Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:19]([O-:22])(=[O:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+].S(Cl)(Cl)=O.[CH:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([OH:35])[CH:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([S:19]([NH:34][C:33]1[CH:28]=[CH:29][C:30]([OH:35])=[CH:31][CH:32]=1)(=[O:21])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCS(=O)(=O)[O-]
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(O)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, sodium octadecanesulfonate (357 g) was suspended in dimethylformamide (600 ml) and thereto was added dropwise thionyl chloride (119 g) over a period of about 30 minutes. After completion of the addition, the suspension was heated at 80° C. for 1 hour to prepare the corresponding sulfonic acid chloride. The reaction mixture was cooled and thereto were added p-aminophenol (109 g) and triethylamine (202 g), followed by refluxing with heating for 3 hours. After completion of the reaction, the reaction mixture was poured into water to precipitate a white solid. Thereto was added 5% hydrochloric acid to adjust the pH to acidic state and then, the white solid was filtered off under reduced pressure and then recrystallized from methyl ethyl ketone to obtain the desired product (302 g). Yield 71%; m.p. 142° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCOC(=O)CCCCBr
Reactant: O=c1c2ccccc2oc2ccc(O)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-hydroxyxanthone (7.7 g, 36 mmol) prepared as described in Example 1, was dissolved in DMF (50 mL), and potassium tert-butoxide (4.6 g, 41 mmol) was added in one portion. The mixture was stirred under N2 at 25° C. for 1.5 hours, and then ethyl 5-bromovalerate (8.74 g, 42 mmol) in DMF (20 mL) was added dropwise over 20 minutes. The reaction mixture was heated at 115° C. for 11 hours, then cooled, filtered, and washed with EtOAc (2×10 mL). The filtrate was concentrated to provide a light-brown oily residue, which slowly solidified at room temperature. Light-beige crystals were collected and washed with n-hexane (3×10 mL). TLC pure, Rf =0.79 benzene-EtOH 10:9. Yield: 9.70 g (79%). A small amount of the product was recrystallized from n-hexane-EtOH (10:1) for elemental analysis. White needles, 1H-NMR (CDCl3 δ: 8.34 (dd, J=1.6 and 8.0 Hz, 1H), 7.66-7.76 (m, 2H, 7.3-7.5 (m, 4H), 4.14 (q, J=7.1 Hz, 2H), 2.40 [t,J=6.9 Hz, 2H, CH2 (C=0)] 1.85 (m, 4H), 1.26 (t,J=7.1 Hz, 3H-CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:30])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:17](=[O:22])[C:18]#[C:19][CH2:20][CH3:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:30])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCC#CC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1
Reactant: FCc1cccc(Br)n1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1cccc(CF)n1)c1ccc(F)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol, Example 190(E)) and (4-fluoro-phenyl)-pentynoyl-carbamic acid tert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 300 mg (0.75 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12]>CCO.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(O)ccc1F
Reaction time: 12 h
Yield: 69.9 %

Procedure:
2-Chloro-4-fluoro-5-nitrophenol (85 g, 0.45 mol) and 10% Pd/C (25 g, 0.023 mol) were combined in EtOH and hydrogenated (50 psi) for 12 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography to provide 3-amino-4-fluorophenol (40 g 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 6.70 (dd, J=11.2, 8.8 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 5.84 (m, 1H), 4.92 (s, 2H); MS (ESI) m/z: 128.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C[N:14](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To indole-2-carboxylic acid (1e) (500 μL, 0.2 M in anhydrous DMF) was added HATU (250 μL, 0.4 M in anhydrous DMF) and Et3N (50 μL, 2.0 M in anhydrous DMF) and stirred for 5 minutes at room temperature. The desired amine (R6—NH2) was dissolved in 520 μL anhydrous DMF and added to the reaction mixture. The reaction mixture was stirred for two hours at 45° C. and the solvent was evaporated in vacuo and the residue was purified via preparative HPLC to obtain the desired product indole-2-carboxamide (I).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH3:20][NH:21][CH3:22]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:21]([CH3:22])[CH3:20]
Reactant: CNC
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Solvent: CO
Product: CN(C)c1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 79 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine 627 mg, 2.2 g of 20% methanolic dimethylamine and 50 ml of methanol were treated in the same manner as Example 2. By the above procedure there was obtained 504 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-dimethylaminopurine as colorless needles, m.p. 174°-175° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.Br[CH2:29][CH2:30][OH:31].CCN(C(C)C)C(C)C>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([CH2:29][CH2:30][OH:31])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: OCCBr
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(CCO)C1
Temperature: 70 °C
Reaction time: 20 h
Yield: 4.8 %

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), 2-bromoethanol (30 μL, 0.414 mmol) and DIPEA (215 μL, 1.24 mmol) in IMS (2 mL) was stirred in a sealed vial at 70° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) followed by sonication in cyclohexane and HPLC purification (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-50% 0.1% NH4OH in acetonitrile/water). The product containing fractions were concentrated in vacuo affording 150 as a white solid (8 mg, 5%). LCMS: RT 1.72 min [M+H]+ 407.1. 1H NMR (DMSO, 400 MHz): 8.30-8.07 (2H, m), 7.95 (1H, bs), 7.73-7.68 (1H, m), 7.63-7.58 (1H, m), 7.20-7.11 (2H, m), 5.93 (1H, bs), 4.68-4.57 (1H, m), 4.36 (1H, bs), 3.48 (2H, bs), 3.03-2.97 (1H, m), 2.89-2.77 (2H, m), 2.52-2.39 (3H, m), 2.14-2.98 (2H, m), 1.74-1.66 (4H, m), 1.61-1.53 (1H, m), 1.24-1.10 (1H, m)
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(O)C>O>[NH2:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 4 g of benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature in the region of 20° C. for 2 hours. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 50 cm3 of water and washed with twice 100 cm3 of diethyl ether. The aqueous phase is separated out after settling has taken place, basified with sodium carbonate to pH 9-10 and then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with aqueous sodium chloride solution and then dried on magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 82° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)=[CH:4][CH:3]=1.[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cc2ccccc2C2=CCNCC2)cc1
Reactant: BrCC=Cc1ccccc1
Product: Fc1ccc(Cc2ccccc2C2=CCN(C/C=C/c3ccccc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using 4-(2-(4-fluorophenyl)methylphenyl]-1,2,3,6-tetrahydropyridine and cinnamyl bromide to produce the above.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8](CO)[CH2:9][O:10][CH2:11][N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2>O>[NH:16]1[C:17](=[O:21])[C:18]2[N:19]=[CH:20][N:12]([CH2:11][O:10][CH2:9][CH:8]=[O:7])[C:13]=2[N:14]=[C:15]1[NH2:22]
Reactant: Nc1nc2c(ncn2COCC(O)CO)c(=O)[nH]1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: Nc1nc2c(ncn2COCC=O)c(=O)[nH]1
Reaction time: 1.5 h

Procedure:
To a vigorously stirred solution of 1.42 g (6.66 mmole) of sodium periodate in 14 ml of water at room temperature was added 1.34 g (5 mmole) of 9-(2,3-dihydroxy-1-propoxymethyl)guanine. The addition was accompanied by a mild exotherm. The reaction flask was stoppered, and stirring was continued at ambient temperature. After 1.5 hours, by which time the reaction was judged to be complete by high pressure liquid chromatography, the mixture was filtered. The solid on the filter was washed with small volumes of cold water and then with acetone. After air-drying overnight, yield of white powder was 1.13 g (90%), m.p. 350° (darkened beginning at about 250° without melting). Satisfactory purity was confirmed by TLC (80:20:2 CHCl3 -methanol-H2O) and analytical high pressure liquid chromatography (H2O, C8 reverse phase). By NMR (DMSO-d6) the material existed as a mixture of free aldehyde and covalent hydrate in a ratio of approximately 1:3 (This ratio was variable in different preparations).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reaction time: 1.5 h

Procedure:
6.8 g tert-butyl 5-nitro-indole-1-carboxylate are dissolved in 120 ml of methanol. 600 mg palladium on charcoal (10%) are added thereto and the mixture is hydrogenated for 1.5 hours at ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.Cl.Cl.[CH3:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:22])=[NH:19])=[CH:14][CH:13]=1>CC(C)=O>[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([CH3:11])=[CH:33][CH:32]=2)=[N:19][C:5]([CH3:6])([CH3:4])[N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(C)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C)cc2)N1
Yield: 47.2 %

Procedure:
40 ml of methanol, 80 ml of acetone and 16 ml (16.2 mmol) of piperidine were added to 3.0 g (7.7 mmol) of N1-(4-methylbenzyl)-N5-octyl-biguanide dihydrochloride, and the mixture was refluxed for 23 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform, methanol and acetic acid (9:0.5:0.5)). 50 ml of ethanol and 50 ml of water were added to the resulting colorless resinous solid, and the pH of the mixture was adjusted to 11 to 12 with 5N sodium hydroxide. The mixture was refluxed for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with water, and dried well under reduced pressure to obtain 1.3 g of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.C(Cl)CCl.N.O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:40])=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (156 mg, 0.29 mmol), HOBT (59 mg, 0.44 mmol), EDC (84 mg, 0.44 mmol), and NH3—H2O (28-30% NH3 basis, 2×4 ml, excess) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40-100% EtOAc in hexane) to yield the title compound (69 mg, 45%).
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:23]=2)[CH:34]=[N:35][CH:36]=1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.1) and (5-fluoropyridin-3-yl)boronic acid to afford a beige solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=497.4 [M+H]+, m/z=495.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 1H) 1.85 (m, J=9.05 Hz, 1H) 2.88 (d, J=11.25 Hz, 1H) 3.18-3.29 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.67 (d, J=8.80 Hz, 2H) 7.84 (dt, J=9.66, 2.26 Hz, 1H) 8.00 (d, J=8.80 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.49-8.53 (m, 1H) 8.60 (d, J=2.93 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 10.33 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48])#[N:40]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][S:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:39]#[N:40])(=[O:49])=[O:48])[CH:29]=3
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example B136, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and -cyanobenzenesulfonyl chloride as the starting materials in 27% yield. LCMS for C25H20ClN6O2S (M+H)+: m/z=503.1.
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[Cl:29][C:30]1[C:31]([OH:54])=[C:32]([C:51](=[O:53])[CH3:52])[CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[O:42][N:41]=[C:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)[N:39]=1>>[C:51]([C:32]1[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]2[O:42][N:41]=[C:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:19]([OH:21])=[O:20])=[CH:46][CH:45]=3)[N:39]=2)=[C:30]([Cl:29])[C:31]=1[OH:54])(=[O:53])[CH3:52]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(Cl)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid of Example 146, employing 1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 13.05 (s, 1H), 12.86 (s, 1H), 7.92 (d, 1H), 7.85 (m, 2H), 7.38 (d, 2H), 6.84 (d, 1H), 5.72 (s, 2H), 4.18 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([Cl:20])=[O:9]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Product: COc1cc(C=CC(=O)Cl)cc(OC)c1OC

Procedure:
0.86 gram (3.62 millimoles) of 3,4,5-trimethoxycinnamic acid and 16.3 grams (137 millimoles) of thionyl chloride were heated together at reflux temperature for 45 minutes to obtain 3,4,5-trimethoxycinnamoyl chloride. The reaction mixture was subjected to reduced pressure to vaporize excess thionyl chloride and to recover the acid chloride as residue. The acid chloride was purified by repeated dissolution in benzene and vaporizing the volatile matter. The purified acid chloride residue was dissolved in 15 milliliters of dry methylene chloride and the solution cooled to 0° C. To the solution was added a solution of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine and triethylamine in 15 milliliters of methylene chloride. The resulting mixture was allowed to warm to room temperature and then stirred overnight. As the end of this time, the mixture was diluted with methylene chloride and washed successively with 2N hydrochloric acid, aqueous sodium bicarbonate and brine and thereafter dried. The dried solution was subject to reduced pressure to remove the solvent and to obtain 1.84 grams of 4-(5H-dibenzo-[a,d]cyclohepten-5-yl) 1-(3,4,5-trimethoxyphenyl)prop-2-enoyl)piperidine as a light brown foamy solid. The latter was flash chromatographed on 80 grams of silica gel employing 40/60 ethyl acetate/hexane as eluant to obtain 1.06 grams of the product as an oil.
Reaction SMILES: [H-].[Na+].C(OC([NH:10][C@H:11]([C:27]([OH:29])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=O)(C)(C)C.CI.Cl.CCOCC>C1COCC1.CO>[C:21]1([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C@@H:11]([C:27]([OH:29])=[O:28])[NH2:10])=[CH:18][CH:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CI
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH in THF (5 mL) cooled to 0° C. was added dropwise a solution of N-(tert-butyloxycarbonyl)-O-(phenylmethyl)-L-tyrosine, 1-[4-(2,3-dichlorophenyl)methyl]piperazine amide (N-Boc derivative of Example 159) (339 mg, 1.0 equiv). Methyl iodide (402 mg, 5 equiv) was then added to the reaction mixture via syringe. After the reaction was stirred at 0° C. for 30 minutes, it was warmed up to room temperature and stirred for 3 hours. An excess of methyl iodide and NaH was added to the reaction mixture (to achieve approximately 70% conversion) over 48 hours. After aqueous work up, the mixture was directly treated with HCl/Et2O in MeOH to afford the racemized titled product along with racemized O-(phenylmethyl)-L-tyrosine, 1-[4-(2,3-dichlorophenyl)methyl]piperazine amide (wherein the amine was not methylated). The mixture was then stirred with polymer bound benzaldehyde resin and filtered, thereby removing the racemized O-(phenylmethyl)-L-tyrosine, 1-[4-(2,3-dichlorophenyl)methyl]piperazine amide. The filtrate was concentrated in vacuo and the residue was further purified by preparative HPLC to afford the racemic titled compound, bis trifluoroacetic acid salt (100 mg) as a colorless oil (HPLC purity:100%): MS Calcd for [C28H31Cl2N3O2+H]+: 512. found: 512.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[CH2:5][N:6]2C(=O)C.C(=O)(O)[O-].[Na+]>Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[CH2:5][NH:6]2
Reactant: CC(=O)N1CC(C)(C)c2c(F)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)CNc2cccc(F)c21
Yield: 72.4 %

Procedure:
A solution of 520 mg of 1-(4-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone in 10 ml of concentrated hydrochloric acid is heated at 90° C. for 2 hours. The solution is then treated with sodium bicarbonate until the pH is 7, and extracted with dichloromethane. The organic phase is filtered on a phase-separation column and concentrated under reduced pressure, so as to give 300 mg of 4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole in the form of a brown oil, the characteristics of which are the following: