Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(ccn2Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68.8 %

Procedure:
Indole-5-carboaldehyde (1.0 g) was dissolved in DMF (14 mL), and potassium hydroxide (460 mg) and 4-fluorobenzyl bromide (1.4 g) were sequentially added thereto under ice cooling. The mixture was stirred for 65 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (20% to 50% ethyl acetate/hexane), and the title compound (1.2 g) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnn(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Step K (2): 10% Palladium on carbon (1.0 g) was added under an atmosphere of nitrogen to a solution of 4-(2-methoxy-4-nitrophenyl)-1-methyl-1H-pyrazole (10.0 g, 42.9 mmol) in methanol (100 mL). The flask was repeated evacuated and flushed with hydrogen gas. The resulting mixture was allowed to stir at rt for 16 h under. The reaction vessel was purged with nitrogen gas. The crude reaction mixture was filtered through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (6.8 g, 78% yield). LC-MS (M+H)+ 204.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (s, 1 H) 7.66 (s, 1 H) 7.19 (d, J=8.2 Hz, 1 H) 6.28 (s, 1 H), 6.18 (d, J=8.2 Hz, 1 H) 5.31 (br s, 1 H), 3.88 (s, 3 H), 3.74 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[C:12]([C:13]#N)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[PH2]([O-])=[O:17].[Na+]>[Ni].O.CC(O)=O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[C:12]([CH:13]=[O:17])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1C#N
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ncccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
(3-Cyanopyridin-2-ylamino)acetic acid ethyl ester (2.6 g, 12.6 mmol) was dissolved into a 1:1:2 mixture of H2O/CH3COOH/pyridine (75 mL) under argon. Sodium hypophosphite (5.0 g) and Raney nickel (2.0 g) were added and the mixture was stirred at room temperature for 3 h. The slurry was filtered through a bed of celite and the filter cake was washed with water. Concentrated NH4OH was added to the filtrate until pH 10 was reached. The solution was extracted with ethyl acetate (4×50 mL). The organic phase was washed with brine (50 mL), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography (CH2Cl2/EtOAc 9:1) to give the title compound as a clear yellow oil (2.16 g, 83%). 1H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 8.69 (bs, 1H), 8.31 (dd, J=4.8, 1.9 Hz, 1H), 7.79 (dd, J=7.6, 2.0 Hz, 1H), 6.72 (dd, J=7.6, 4.8 Hz, 1H), 4.32 (d, J=5.5 Hz, 2H), 4.24 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[O:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([OH:8])=[C:6]([C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(O)c(C(C)=O)cc1Cl
Temperature: 0 °C

Procedure:
Chloro-2,4-dimethoxybenzene (4.94 g, 28.6 mmol) and AlCl3 (4.58 g, 1.2 eq.) were dissolved in 280 ml of CH2Cl2 and cooled down to 0° C. Acetyl chloride (2.03 mL, 1.0 eq.) was slowly added via syringe and the mixture allowed to react for another 3 h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by short flash chromatography (SiO2, hexane/AcOEt=95/5), yielded 4.22 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH:14]=[O:15])=[C:11]([CH3:16])[C:10]=2[CH:17]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:14]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:18])=[CH:17][C:10]=3[C:11]=2[CH3:16])[OH:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COCCN(C)c1ccc2oc(C=O)c(C)c2c1
Solvent: C1CCOC1
Product: COCCN(C)c1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 5-[(2-methoxyethyl)(methyl)amino]-3-methyl-1-benzofuran-2-carbaldehyde (0.09 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (2 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.11 g, quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.CS(C)=[O:22]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[O:22])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: CS(C)=O
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1,2-bis(4-methoxyphenyl)ethan-1-one (1 g, 3.90 mmol) in DMSO (20 mL) was added SeO2 (1.76 g, 15.86 mmol) in several batches at 100° C. over 30 min, and then stirred for 3 hr at this temperature. The reaction was quenched by the addition of water (200 mL) and extracted with dichloromethane (3×50 mL), dried over magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1%˜10% ethyl acetate in petroleum ether) to afford 1,2-bis(4-methoxyphenyl)ethane-1,2-dione as a brown solid (600 mg, 76%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[N:18][C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]5[N:34]([CH3:35])[C:33]([CH3:36])=[N:32][CH:31]=5)=[CH:26][C:25]=3[O:37][CH3:38])=[CH:16]4)[CH:10]=[N:9]2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:35][N:34]1[C:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:17]3[N:18]=[CH:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][CH:5]([OH:6])[CH2:4][OH:3])[CH:12]=3)=[CH:22][CH:21]=4)=[C:25]([O:37][CH3:38])[CH:26]=2)=[CH:31][N:32]=[C:33]1[CH3:36]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(CC4COC(C)(C)O4)c3)ccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(CC(O)CO)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)isoquinolin-3-amine (Example 40, 20 mg, 0.038 mmol) in THF (8 mL) at 0° C. was added TFA (1 mL). the reaction was stirred at room temperature for 16 hours before concentrating in vacuo. The residue was purified by elution through an SCX-2 column using 2M NH3/MeOH to afford the title compound (18 mg, 97%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC(OC(C)C)=O.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3=[N:37][CH:38]=[N:39][C:40]([O:41][CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[C:35]3[CH:34]=[N:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:45]2[CH2:46][CH2:47][CH:42]([O:41][C:40]3[N:39]=[CH:38][N:37]=[C:36]4[N:32]([C:29]5[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:24])=[O:25])=[CH:31][CH:30]=5)[N:33]=[CH:34][C:35]=34)[CH2:43][CH2:44]2)=[O:13])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CCCCc1ccc(C(=O)O)nc1
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.3 %

Procedure:
5-Butyl-pyridine-2-carboxylic acid (92 mg, 0.51 mmol) and isopropyl chloroformate (70 μL, 0.51 mmol) were dissolved in DMF and stirred at room temperature for 40 min. 1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (70 mg, 0.17 mmol) and triethylamine (72 μL, 0.51 mmol) were added next and continued to stir for 24 hours. Progress of the reaction was monitored by TLC and LCMS. Removal of organic solvents in vacuo and purification by HPLC afforded Compound A125 as a white solid (13 mg, 13%). Exact mass calculated for C27H30N6O4S 534.63, found 535.20 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[C:11]([NH:14][C:15]1[NH:16][C:17](=O)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[C:11]([NH:14][C:15]1[N:16]=[C:17]([C:5]2[N:4]=[CH:3][NH:2][N:1]=2)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1OC
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A suspension of 1,2,4-triazole (8.28 g, 120 mmol) and phosphorus oxychloride (3.2 ml, 36 mmol) in dry acetonitrile (150 ml) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (4.08 g, 12 mmol) and triethylamine (5.2 ml, 36 mmol) in dry acetonitrile (150 ml). The mixture was stirred at room temperature under nitrogen for 3 days and the yellow precipitate was filtered off, then successively washed with ethanol and ether, and dried over P2O5 in a vacuum dessicator resulting in the pure title compound (4.3 g, yield 90%) which was characterized by its mass spectrum as follows: MS (m/z): 392 ([M+H]+, 100), 414 ([M+Na]+; 804 [2M+Na]+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH2:29][CH2:28][N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCN4CCOCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (60 mg, 0.21 mmol) was reacted with 2-morpholinoethanamine (CAS 2038-03-1) (55 mg, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-morpholinoethyl)benzamide 11. LC/MS (ESI+): m/z 397 (M+H). 1H NMR (400 MHz, DMSO) δ 8.70 (t, J=5.6 Hz, 1H), 8.62 (d, J=10.2 Hz, 1H), 8.54 (dd, J=17.5, 8.6 Hz, 2H), 8.44 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=9.3 Hz, 1H), 3.67-3.52 (m, 4H), 3.46 (dd, J=13.1, 6.6 Hz, 2H), 2.55-2.51 (m, 2H), 2.47-2.41 (m, 4H).
Reaction SMILES: C(N[CH:4]([OH:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)C.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19]N=C1)=[O:15]>O1CCCC1>[CH2:20]([N:16]1[CH:5]([CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH2:4][O:13][C:14]1=[O:15])[CH3:19]
Reactant: CCNC(O)CCc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1C(=O)OCC1Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
Crude α-(ethylamino)-4-pyridinepropanol (2.07 g, 0.0122 mol) is stirred in dry tetrahydrofuran (20 mL) with activated 3Å sieves for about 10 minutes. Carbonyldiimidazole (2.26 g, 0.0139 mol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and Kugelrohr distilled at 80-100° C. and 2 mm Hg to remove excess imidazole. The residue is chromatographed on silica gel eluting with 10:1 chloroform:methanol to afford 1.7 g of the title compound as an amber oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:29]([O:31][CH3:32])=[O:30])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:23](Cl)=[O:24])[C@@H:10]([CH:26]2[CH2:28][CH2:27]2)[CH2:9]1.[CH:42]([OH:45])([CH3:44])[CH3:43]>>[CH:42]([O:45][C:23]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[Br:22])[C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:9][C@@H:10]1[CH:26]1[CH2:28][CH2:27]1)=[O:24])([CH3:44])[CH3:43]
Reactant: CC(C)O
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2c(Br)cc(C(F)(F)F)cc21
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2c(Br)cc(C(F)(F)F)cc21

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl chloride (Example 100D) (1.5 g) in isopropanol was heated to reflux for 48 h. The reaction was cooled and concentrated, and the residue was chromatographed (5-10% EtOAc/hexane) to afford the title product (1.0 g). MS m/z 705.4 (M+); 1H NMR (CDCl3) δ 3.8 (s, 3H), 7.1 (s, 1 H), 7.8 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([O:10][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:13]=[N+]=[N-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(OCC)(OCC)OCC>C1CCCCC1>[CH:1]1([CH2:6][CH2:7][C:8]2[O:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NC=C(OC(=O)CCC1CCCC1)c1ccccc1
Agent: CCOP(OCC)OCC
Solvent: C1CCCCC1
Product: c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a stirred solution of 2-azido-1-phenylvinyl 3-cyclopentylpropionate from Step A (4.0 g, 14 mmol) in dry cyclohexane (10 mL) was added triethyl phosphite (12 g, 74 mmol) dropwise. After stirring at room temperature for 1 h, the mixture was heated at 90° C. in an oil bath under nitrogen for 6 h. The mixture was cooled and chromatographed on a silica gel column (eluent: 1:5 ethyl acetate:hexanes) to give 1.57 g (46.6%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ7.59 (dt, 2H, J=2.0,8.2 Hz), 7.38 (dr, 2H, J=1.4, 8.0 Hz), 7.29 (tt, 1H, J=2.0, 8.0 Hz), 7.19 (s, 1H), 2.82 (t, 2H, 7.5 Hz), 1.89-1.75 (m, 5H), 1.61-1.47 (m, 4H), 1.11 (m, 2H).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15].[C:24]1([P:30]([N:38]=[N+:39]=[N-:40])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[NH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:24]1([P:30]([N:38]=[N+:39]=[N-:40])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: NCC(=O)O

Procedure:
Coupling of the tosylate salt of benzyl glycinate with acid 9 proceeded smoothly to give the protected acyclic precursor 12, Scheme 5. Simultaneous hydrogenolysis of the Cbz and Bn protecting groups followed by cyclization with diphenylphosphoryl azide (DPPA) in dilute DMF solution afforded cyclic tripeptide methyl ester 13 in high yield.40In anticipation of future incorporation of amino acids beside Gly into the mimic, DPPA was chosen for cyclization because of the low propensity of acyl azides to racemize.41This cyclization has also been performed with Ala in the central position in 80% yield. ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccc(Cl)cc1Cl
Yield: 36.9 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 2,4-dichlorobenzenesulfonyl chloride (103 mg, 0.42 mmol) gave the title compound (40 mg, 40%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>CC(N(C)C)=O.CS(C)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:32]([NH:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.96 g, 2.47 mmol) in 10 mL of DMA was added 2,4-difluoro phenyl isocyanate (0.42 g, 2.71 mmol), and the mixture was stirred at ambient temperature overnight The reaction mixture was diluted with DMSO and was purified by RP-HPLC. The fractions containing the product were pooled and evaporated to a small volume. The aqueous solution was neutralized with 1N NaOH to a pH of 9.0 and the product was extracted with ethyl acetate (2×, 50 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea as a colorless solid in 59% yield. LCMS m/z (%)=520 (M+H 79Br, 100), 522 (M+H 81Br, 98). 1H NMR (400 MHz. DMSO-d6) δ: 9.03 (bs, 1H), 8.49 (bs, 1H), 8.01-8.1 (m, 1H), 7.61 (s, 1H), 7.51 (dd, J=8.96 and 2.73 Hz, 1H), 7.35 (d, J=2.72 Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, J=9.04 Hz, 1H), 7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, 3H), 2.51-2.73 (m, 2H), 2.34-2.38 (bs, 4H), 1.59-1.63 (bs, 4H).
Reaction SMILES: [C:1]1([NH2:10])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([NH:10][C:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of phenetylamine was dissolved in 50 ml of methylene chloride, and 7.0 ml of triethylamine and 3.6 ml of acetyl chloride were added to the solution at 0° C. The solution was stirred at room temperature for 2 hours, washed with water, aqueous solution of citric acid, and saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. After separating the desiccant by filtration, the solution was purified by silica gel column chromatography to obtain 5.52 g of N-acetylphenetylamine, which was white crystal (yield: 82%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([NH2:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>COCCOC.[O-2].[O-2].[Mn+4]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[NH:28][C:24]([CH:25]([CH3:27])[CH3:26])=[N:23][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(N)cc3c12
Reactant: CC(C)CN
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4nc(C(C)C)[nH]c4c3c12

Procedure:
627 mg of 6-amino-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is stirred in 10 ml of ethylene glycol dimethyl ether with 1.6 g of manganese dioxide and 0.98 ml of isobutylamine for 16 hours at room temperature. The reaction mixture is filtered on Celite, the filtrate is concentrated by evaporation and chromatographed on silica gel with methylene chloride and ethanol=10+1. 499 mg of 2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester (oily) is obtained from the desired fractions.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4](Br)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:15][O-:16].[Na+]>CO>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[CH:4]([O:16][CH3:15])[C:3]([OH:2])=[O:14]
Reactant: C[O-]
Reactant: COC(=O)C(Br)c1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(C(=O)O)c1c(Cl)cccc1Cl

Procedure:
10 g (0.033 mols) 2 bromo-2(2,6-dichlorophenyl)-acetic acid methyl ester (Example 8) are heated with sodium methylate in methanol (1.6 g Na in 100 ml MeOH) in an autoclave for 5 hours at 150 degrees C. After evaporation of the solvent, the residue is taken up in a water-chloroform mixture. By acidification of the aqueous phase, 3.9 g 2-(2,6-dichlorophenyl)-2-methoxy-acetic acid is obtained. It melts at 119-122 degrees C. after recrystallization from diisopropyl ether.