Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6][CH:5]=2.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[F:27][C:22]1[CH:21]=[C:20]([N:3]2[C:4]3[C:9](=[C:8]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Cc1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: Oc1ccc(Br)cc1F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1-c1ccc(O)c(F)c1
Temperature: 190 °C

Procedure:
To a solution of 2-methyl-4-[(phenylmethyl)oxy]-1H-indole {WO9204321} (440 mg, 1.86 mmol) in N-methyl-2-pyrrolidinone (4 mL) was added 4-bromo-2-fluorophenol (0.205 mL, 1.87 mmol), copper iodide (70 mg, 0.37 mmol) and potassium carbonate (641 mg, 4.64 mmol). The reaction mixture was heated in a Biotage Initiator™ Microwave Synthesizer at 190° C. for 6 hours. The mixture was filtered through a pad of Celite which was subsequently washed with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate, filtered and then concentrated in vacuo. The product was purified by MDAP to yield the title compound (D3) (30 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[O:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=4)[CH:18]=3)[O:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 4-[[4-(4-(1-methylethyl)phenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 268, 95.0 mg, 0.210 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 75.0 mg (84%) the title compound as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 8.05 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.36 (1H, dd, J=2.0, 8.3 Hz), 7.30-7.26 (5H, m), 6.88 (1H, d, J=8.3 Hz), 5.64 (1H, s), 2.98 (1H, hept, J=6.9 Hz), 1.51 (6H, s), 1.31 (6H, d, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: COc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(methyloxy)benzenesulfonamide: 1H-NMR (CDCl3) δ 7.77-7.73 (2H, m), 7.47-7.25 (9H, m), 6.96 (2H, d, J=9.1 Hz), 6.41 (1H, br.s), 3.85 (3H, s), 3.54-3.47 (2H, m), 2.87 (2H, t, J=6.7 Hz), 2.33 (3H, s), 2.27 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 5-fluoro-2-nitro-phenol (234 mg, 1.49 mmol) in 5 mL THF, sodium hydride (122 mg, 2.9 mmol) was added, followed by chloromethoxy methane (113 ul, 1.49 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 10 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-fluoro-2-methoxymethoxy-1-nitro-benzene.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[C@H:34]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[C:8]([C:10]2[N:11]3[C:15](=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)[CH2:14][C@@H:13]([OH:22])[CH2:12]3)[CH:9]=1.[CH2:42](Br)[CH:43]=[CH2:44]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[C@H:34]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[C:8]([C:10]2[N:11]3[C:15](=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)[CH2:14][C@@H:13]([O:22][CH2:44][CH:43]=[CH2:42])[CH2:12]3)[CH:9]=1
Reactant: COC(=O)c1cc(-c2cc(F)ccc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n2c1C[C@@H](O)C2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1Cc2c(C(=O)OC)cc(-c3cc(F)ccc3C(=O)N3Cc4ccccc4C[C@H]3CN3CCOCC3)n2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 62 mg (1.54 mmol) of sodium hydride in 8 mL of anhydrous THF cooled to 0° C. there is added a solution of the compound of Step B (820 mg; 1.54 mmol) in THF (6 mL). The suspension is stirred for 15 minutes at 0° C. There is subsequently added 0.15 mL (1.69 mmol) of allyl bromide, dropwise. The reaction mixture is stirred for 5 hours at ambient temperature, and then hydrolysed with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (gradient: dichloromethane/ammoniacal methanol) to yield the title product in solid form.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:18]C(=O)C)=[CH:12][CH:13]=3)[CH:8]([CH3:22])[C:7]=2[CH:6]=1)(=O)C.O.[OH-].[Li+].Cl>C(O)CO>[OH:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][CH:13]=3)[CH:8]([CH3:22])[C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1ccc2c(c1)C(C)c1cc(OC(C)=O)ccc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1c2cc(O)ccc2-c2ccc(O)cc21
Yield: 84.2 %

Procedure:
A mixture of 2,7-diacetyloxy-9-methylfluorene (12 g), lithium hydroxide monohydrate (3.42 g) and ethylene glycol (120 mL) was refluxed for one hour by heating. The reaction mixture was poured into 6M-hydrochloric acid and extracted with ethyl acetate. The organic layer was sufficiently washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure to obtain 2,7-dihydroxy-9-methylfluorene (7.24 g) of light brown crystal. Melting point: 191.5-196.3° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[NH2:8][CH2:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]([CH2:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH2:26][N:15]([CH2:14][C:13]1[CH:36]=[CH:37][C:10]([CH2:9][NH:8][CH2:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)=[CH:11][CH:12]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1cc[nH]n1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2cc[nH]n2)cc1)Cc1nc2ccccc2[nH]1
Yield: 59.8 %

Procedure:
Using General Procedure B: A solution of pyrazol-3-carboxaldehyde (26.6 mg, 0.28 mmol) and (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (110 mg, 0.28 mmol) in MeOH (2.0 mL) was stirred overnight at room temperature. NaBH4 (21.2 mg, 0.56 mmol) was added and the resultant mixture stirred for an additional 15 minutes. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded the desired amine (80 mg, 60%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([NH2:25])=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: N
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(N)=O)n(C)n1
Yield: 60 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of isopropylamine, to the title compound (19 mg, 60%) which was obtained as a white solid. MS: m/e=327.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1N)[CH2:3][CH:4]([CH3:6])[CH3:5].[BrH:14].N([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.[Cu].O>[Br:14][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[CH:2]([CH3:1])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: Br
Reactant: CC(C)CC(C)c1ccccc1N
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC(C)c1ccccc1Br
Reaction time: 1.5 h

Procedure:
28.4 g of 2-(1,3-dimethylbutyl)aniline in 134.9 g (667 mmol) of 40 percent hydrobromic acid in glacial acetic acid at 10° C. are admixed with 12.5 g (181 mmol) of sodium nitrite in portions with stirring within 1.5 h. Thereafter, 0.5 g of copper powder is added and the mixture is boiled under reflux for 1 h hour. Subsequently, 120 ml of water and sodium hydroxide solution are added until pH 12 is attained, and the organic phase is removed, washed with dilute hydrochloric acid and concentrated by evaporation under reduced pressure. After distillation in a Kugelrohr apparatus at 0.3 mbar/70° C. and purification of the main fraction by means of preparative HPLC, 8.3 g of a yellowish oil with a purity of 99.4% (determined by HPLC) are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])O.[Na+].[I-].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(#N)C>[CH2:18]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Yield: 55.6 %

Procedure:
To a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362 mmol) in acetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412 mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml, 470 mmol), and the resulting mixture was refluxed for 24 hours under a nitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid (400 ml) was added, and the resulting mixture was extracted with ethyl acetate (400 ml×2). The organic layer was washed successively with 3% aqueous potassium carbonate solution (300 ml×2), water (300 ml×1), 1N hydrochloric acid (300 ml×1) and saturated aqueous sodium chloride solution (300 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was recrystallized from a mixture of t-butyl methyl ether and hexane to afford the title compound (45.9 g, yield: 56%) as pale orange crystals.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[F:8]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: CNCCc1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(N(C)CCc2ccncc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (280 mg, 1.54 mmol) was dissolved in 5 mL of THF and stirred at room temperature. Methyl[2-(4-pyridinyl)ethyl]amine (210 mg, 1.54 mmol) was added, followed by triethylamine (240 μL, 1.69 mmol). The resulting reaction mixture was stirred overnight. The reaction was diluted with EtOAc, washed with brine, was dried (sodium sulfate) and was evaporated to provide 6-chloro-5-fluoro-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (350 mg, 81%) that was used without further purification. LCMS: (M+H)+: 281.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[F:32])[CH2:22][CH2:21]1>>[F:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:27][C:26]=1[CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:15])[CH2:25][CH2:24]1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 129 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.42–7.38 (m, 1H), 7.31–7.20 (m, 2H), 6.94–6.83 (m, 4H), 6.46–6.40 (m, 1H), 3.19 (q, 2H, J=5.6 Hz), 2.85–2.79 (m, 2H), 2.73–2.64 (m, 1H), 2.49–2.38 (m, 3H), 2.22 (t, 2H, J=6.4 Hz), 1.94–1.84 (m, 5H), 1.75–1.47 (m, 9H), 1.17 (d, 6H, J=6.8 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]1[C:89](=[O:90])[CH:88]=[CH:87][C:86]1=[O:91].CCN(C(C)C)C(C)C>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]3[C:89](=[O:90])[CH:88]=[CH:87][C:86]3=[O:91])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (100 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (176 mg, 0.2 mmol), and DIPEA (258 mg, 191 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (28 mg, 11%). ES(+)-HRMS m/e calcd. for C58H85Cl2N5O20 (M+H)+ 1242.5238, obsd. 1242.5248.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2>>[Br:1][C:5]1[C:4]([F:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:14])=[N:10]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Product: Cc1ccc2c(Br)c(F)ccc2n1

Procedure:
reacting bromine with 6-fluoro-2-methylquinoline to give 5-bromo-6-fluoro-2-methylquinoline, and
Reaction SMILES: [P:1]([O-:40])([O:36][CH2:37][CH2:38]Br)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[P:1]([O-:40])([O:36][CH2:37][CH2:38][N+:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1cc(-c2ccccc2)on1
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1cc(-c2ccccc2)on1

Procedure:
0.875 g of the crude (2RS)-3-hexadecyloxy-2-(5-phenyl-3-isoxazolyloxy)propyl 2-bromoethyl phosphate obtained as described in the first part of Example 7 was reacted with pyridine in a similar manner to that described in Example 3 to afford 0.507 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Cl)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-chlorophenyl)[(4-dimethylaminophenyl)methyl]amine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.64 mL) as starting materials, N-(4-chlorophenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.48 g) was obtained. melting point: 151–152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CCOCC>[CH3:19][O:16][P:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:13])[OH:15]
Reactant: C=[N+]=[N-]
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Solvent: CCOCC
Product: COP(O)C(C)NC(=O)OCc1ccccc1

Procedure:
1-Benzyloxycarbonylaminoethylphosphonous acid, prepared by the method of E. K. Baylis et al. [J. Chem. Soc., Perkin Trans, 2845-2853 (1984)] was esterified with diazomethane in an ether solution prepared by a method of F. Arndt [organic Syn. Coll. V. II 165-167 (1943)]. The compound was purified by standard chromatography on silica gel. TLC (silica, 9:1, ethyl acetate:acetonitrile) Rf =0.51 NMR (CDCl3, TMS) & 1.2 and 1.5 (2d, 3H); 2.2 and 10.1 (d, 1H); 3.6 (d, 3H); 3.9 (m, 1H); 5.0 (s, 2H); 6.0-6.6 (overlapping doublets, 1H); 7.2 (s, 5H).
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:20]=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:24])N.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+]>O1CCOCC1.O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([OH:24])=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carbaldehyde G1 (0.55 mmol) in dioxane (6.8 mL) and water (2.4 mL), sulfamic acid (0.9 mmol) and sodium dihydrogen phosphate (2.33 mmol) were added. The mixture was cooled to 0° C. and sodium chlorite (0.95 mmol, dissolved in the minimum amount of water) was added. Other two additions of an equal amount of oxidant were made during 24 h of stirring, then the reaction was filtered and the solid product was washed with water and dried, resulting in 94% yield of the title compound. ESI (+) MS: m/z 289 (MH+); MS (ES−) 287. 1H NMR: 7.35-7.41 (m, 1H), 7.45-7.56 (m, 4H), 7.96 (d, J=9.00, 1H), 8.58 (d, J=9.00, 1H), 8.68 (d, J=5.17, 1H), 8.78 (d, J=5.17, 1H), 9.57 (s, 1H), 11.47 (bs, 1H), 13.54 (bs, 1H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.CO>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2c(F)cc(F)cc2F)ccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-methanone (634 mg, 1.2 mmol) in dichloromethane (10 mL). Cool to 0° C., add HCl (2M in ether, 1.2 mL, 2.4 mmol) and stir at room temperature for 15 minutes. Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and cool to 0° C. Add boron tribromide (949 mg, 3.6 mmol) dropwise and bring to room temperature. Stir reaction for 1.5 hour and pour reaction mixture onto ice, saturated sodium bicarbonate (20 mL) and methanol (20 mL). Extract with dichloromethane, combine extracts and wash with water and saturated sodium bicarbonate. Dry with sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield 350 mg (57%) of the title compound: mass spectrum (ion spray) m/z=520 (M+H).