Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:17][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1>O>[O:1]=[C:2]1[NH:17][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1
Reactant: COC(=O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Solvent: O
Product: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1

Procedure:
The title compound is prepared from methyl 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylate according to the method described in Example 1/b. Mp.: 288-290° C. (water).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1
Reactant: O=S(=O)(c1ccc(CO)cc1)N1CCc2occc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.27 g (33.6 mmol) of oxalyl chloride in 100 ml of dichloromethane, 4.78 ml (67.3 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To this solution, a solution of 6.580 g (22.431 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)benzyl alcohol in 50 ml of dichloromethane was added at -78° C., followed by stirring for 15 minutes. To this mixture, 18.8 ml (135 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1 to 2/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([C@@H:30]2[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]2[O:32][C:33](=[O:35])[CH3:34])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Cl:11])[C:4]=2[N:3]=1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2[nH]c(Br)nc2c(Cl)c1Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2c(Cl)c(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
2-Bromo4,5,6-trichloro-1H-benzimidazole (0.3 g, 1 mmol), acetonitrile (10 mL), and N,O-bis(trimethylsilyl)acetamide were stirred at 70° C. for 15 min., giving a homogeneous solution. To the solution was then added 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The resulting mixture was allowed to stir at 70° C. for 20 min. The mixture was then allowed to cool to RT and was diluted with ethyl acetate and was washed with a saturated aqueous NaHCO3 solution, dried over NaSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using chloroform as eluent and then recrystallization from methanol afforded 0.29 g (58%) of the title compound as white crystals; m.p. 160-162° C.; 1H NMR (DMSO-d6) δ: 8.14 (s, 1H), 6.16 (d, 1H), 5.63 (t, 1H), 5.27 (dd, 1H), 4.26 (m, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][C@H:14]2[C:18]([O:20][C@H:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH:33]=2)[CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N+:26]([O-:30])=[CH:25][C:24]=2[Cl:31])=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[NH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:53]([O:52][C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][C@H:14]2[C:18]([O:20][C@H:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH:33]=2)[CH2:22][C:23]2[C:24]([Cl:31])=[CH:25][N+:26]([O-:30])=[CH:27][C:28]=2[Cl:29])=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3])=[O:57])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
4-((S)-2-((S)-3-(3-Carboxyphenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (200 mg, 0.278 mmol), tert-butyl 2-aminoethylcarbamate (89 mg, 0.556 mmol), DMAP (40.7 mg, 0.334 mmol) and EDC (160 mg, 0.834 mmol) were dissolved in DMF. The reaction was stirred at room temperature overnight to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in ethyl acetate and extracted with HCl 1N, NaHCO3 5% and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 4-((S)-2-((S)-3-(3-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (211 mg, 0.245 mmol, 88% yield).
Reaction SMILES: O=[C:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].C(C1C=C(N)[O:17][N:16]=1)(C)C>>[O:9]1[CH2:10][CH2:11][CH:6]([C:2]2[CH:3]=[C:4]([NH2:5])[O:17][N:16]=2)[CH2:7][CH2:8]1
Reactant: CC(C)c1cc(N)on1
Reactant: N#CCC(=O)C1CCOCC1
Product: Nc1cc(C2CCOCC2)no1
Yield: 44 %

Procedure:
Prepared from 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (350 mg, 2.29 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine as a colorless solid (170 mg, 44%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.01 (s, 1H), 4.40 (brs, 2H), 4.02-4.05 (m, 2H), 3.46-3.55 (m, 2H), 2.87 (m, 1H), 1.71-1.84 (m, 4H); LC-MS (ESI) m/z 169 (M+H)+.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH2:34]>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[NH:34][C:21]([C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: COc1ccc(-c2cccc(C(=O)Cl)c2)c(OC)c1OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C(=O)Nc3cc([N+](=O)[O-])ccc3Br)c2)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Add a solution of 2′,3′,4′-trimethoxy-biphenyl-3-carbonyl chloride (35) (345 mg, 1.13 mmol) in dichloromethane (5 mL) to an ice cooled solution of 2-bromo-5-nitro-phenylamine (88) (232 mg, 1.07 mmol) in anhydrous dichloromethane (12 mL) and anhydrous pyridine (2.9 mL). Stir the reaction mixture for 15 min at 0° C. and additional 17 h at rt. Pour the reaction mixture into ice cooled 1M aqu. HCl (to get pH ca. 3), extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4 to afford crude 2′,3′,4′-trimethoxy-biphenyl-3-carboxylic acid (2-bromo-5-nitro-phenyl)-amide (89) as a beige solid (542 mg, quant.). 1H NMR (400 MHz, CDCl3): 3.72 (s, 3H); 3.91 (s, 3H); 3.93 (s, 3H); 6.77 (d, 1H, J=8.6 Hz); 7.08 (d, 1H, J=8.6 Hz); 7.56 (t, 1H, J=8.8 Hz); 7.75 (d, 2H, J=8.8 Hz); 7.86 (d, 1H, J=8.8 Hz), 7.87 (d, 1H, J=8.8 Hz); 8.09 (t, 1H, J=1.7 Hz); 8.61 (br. s, 1H); 9.59 (d, 1H, J=2.5 Hz).
Reaction SMILES: [NH:1]([CH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4]1)[NH2:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>O1CCOCC1>[CH:14](=[N:2][NH:1][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C=O
Reactant: NNC1NS(=O)(=O)c2ccccc21
Solvent: C1COCCO1
Product: CC(C)C=NNC1=NS(=O)(=O)c2ccccc21
Yield: 87.9 %

Procedure:
19.7 g (0.1 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide are dissolved in 200 ml of dioxane at 40°-50° C., and 8 g (0.11 mol) of isobutyraldehyde are added dropwise to the thoroughly stirred mixture. The product is precipitated directly during this procedure. When the addition is complete, the mixture is heated to 80°-90° C. for about 20 minutes and then cooled, and the crystals are filtered off under suction. 22.1 g (88.1% of theory) of 3-isobutylidenehydrazino-1,2-benzisothiazole 1,1-dioxide of melting point 225° C. are obtained in this manner.
Reaction SMILES: [P:1](Cl)([O:5][CH3:6])([O:3][CH3:4])=[S:2].[OH:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][CH3:16])[S:11][N:10]=1>>[CH3:4][O:3][P:1]([O:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][CH3:16])[S:11][N:10]=1)([O:5][CH3:6])=[S:2]
Reactant: COP(=S)(Cl)OC
Reactant: CCSc1nc(O)ns1
Product: CCSc1nc(OP(=S)(OC)OC)ns1

Procedure:
Using the procedure of Example 3, dimethyl chlorothiophosphate and 3-hydroxy-5-ethylthio-1,2,4-thiadiazole were reacted to obtain 3-(dimethoxythiophosphoryloxy)-5-ethylthio-1,2,4-thiadiazole with a refractive index of nD20 = 1.559 and Rf=0.5.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[CH:5]=1)(=[O:3])C.C(O)(=[O:17])C.O=O>[Cr].[Co].C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C:1]([OH:3])=[O:17])[CH:13]=[CH:12]2
Reactant: CC(=O)c1ccc2cc(C)ccc2c1
Reactant: CC(=O)O
Agent: [Co]
Agent: [Cr]
Agent: [Mn+2]
Solvent: O
Product: Cc1ccc2cc(C(=O)O)ccc2c1
Temperature: 140 °C
Yield: 69.6 %

Procedure:
A Hastelloy C autoclave equipped with heater, stirrer, gas introduction tube, temperature sensor, pressure gauge and pressurized reflux condenser was charged with 100 g of 2-acetyl-6-methylnaphthalene, 380 g of acetic acid, 20 g of water and 15 g of manganese(II) acetate. Compressed air was passed, with stirring, through the solution at 140° C. and a pressure of 25 bar, with a gas escape rate of 3 liters per minute. The reaction was observed by continuously measuring the oxygen content in the exhaust gas. When this oxygen content returned to the initial level of 21% after a reaction time of 105 minutes, the air feed was shut off, the reaction mixture was cooled, with stirring, to room temperature, filtered, and the filter cake washed with 300 g of a 95 wt.-% solution of acetic acid. 70.3 g of 6-methyl-2-naphthoic acid (69.3% of the theory) was obtained, in a purity of 99.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:35][C:36]1[O:40][NH:39][CH:38]([C:41](Cl)=[O:42])[CH:37]=1.O1CCCC1>O.N1C=CC=CC=1>[F:27][C:14]1[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:22])=[O:23])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:1][C:41]([CH:38]3[CH:37]=[C:36]([CH3:35])[O:40][NH:39]3)=[O:42])[CH:3]=2)[NH:8][CH:9]=1)=[O:12]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(N)cc23)c1F
Reactant: CC1=CC(C(=O)Cl)NO1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(NC(=O)C4C=C(C)ON4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a reaction vial, propane-1-sulfonic acid [3-(5-amino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (39, crude material e.g. from Scheme 5, step 2) is mixed with triethylamine (0.0363 mL, 0.26 mmol), 5-methyl-2,3-dihydro-isoxazole-3-carbonyl chloride (40, 45.4 mg, 0.312 mmol), 1 mL of tetrahydrofuran, and 1 mL of pyridine. The reaction is stirred at room temperature for 16 hours, then diluted with water, and extracted 3× with ethyl acetate. The combined organic layers are washed 2× with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is further purified by reverse phase chromatography and the resulting material confirmed by LC-MS.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:19][CH2:20][C:21]([F:22])([F:23])[F:24]
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCC1
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900 mg), in dry MeOH (50 mL), Pd(OH)2 (400 mg) was added and the mixture reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH, the combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (800 mg) as a thick liquid.
Reaction SMILES: [CH:1](=[N:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc2cnc3ccccc3c2n1NCc1ccccc1
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A solution of N-benzylidene(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (575 mg, 1.75 mmol) in 40 mL of MeOH was treated with NaBH4 (250 mg, 6.58 mmol). After stirring for 4 h, the reaction was quenched with saturated NaHCO3 solution and extracted into CHCl3. The organic portion was washed with H2O and brine and dried over Na2SO4. Chromatography (SiO2, 50–67% EtOAc/hexanes) gave N-benzyl(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (427 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[C:4]([CH3:27])[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(F)ccc1-c1nc2ccc(C(=O)O)cc2nc1N(C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of methyl 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (45 mg, 0.12 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 4 with aqueous HCl (3N). The solids were collected by filtration to afford 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (36 mg, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](O)=[O:38]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]=2[OH:26])=[O:38])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: N[C@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1
Product: O=C(N[C@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-2-benzooxazol-2-yl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C30H26N3O5[(M+H)+] 508, obsd. 508.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)C.[N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:19]=1[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=O)[C:31]=2[CH:30]=[CH:29][CH:28]=1.[Na].P([O-])(O)(O)=O.[K+]>C(O)C>[N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:19]=1[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]([NH:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Reactant: NCCc1ccccc1
Agent: CCN(CC)C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: c1ccc(CCNC2c3ccccc3-c3c(-c4nc5ccncc5[nH]4)cccc32)cc1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
In a microwave reactor, add 81 μL of 2-phenyl-ethylamine, 18 μL of diethylisopropylamine and 182 μL of titanium tetra-isopropylate to a solution of 84 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 0.5 ml of ethanol. Then heat successively at 60° C. for 5 minutes, at 70° C. for 20 minutes, at 100° C. for 15 minutes and finally at 130° C. for 30 minutes. After cooling to room temperature, add 25 mg of sodium cyanohydroborate and stir for 16 hours at room temperature. Pour the reaction mixture into 5 ml of a saturated aqueous solution of potassium dihydrogen phosphate, then extract 3 times with 10 ml of dichloromethane. After purification on silica gel, eluting with mixtures of dichloromethane and methanol (98-2, then 96-4 by volume), we obtain 4.8 mg of N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-phenethyl-amine, in the form of a white solid with the following characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>C(COC)OC.O.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:26]2[CH:27]=[CH:28][O:24][CH:25]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccoc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=C1CN(c2ccc(-c3ccoc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (163 mg, 0.37 mmol), furan-3-boronic acid (62 mg, 0.550 mmol), potassium phosphate (235 mg, 1.1 mmol), and palladium dppf (9 mg, 0.011 mmol) in 6 mL of glyme/water (9:1) is heated in a microwave apparatus at 120° C. for 25 min. The mixture is poured into EtOAc and extracted with 1N HCl and saturated NaCl. The organic phase is dried and the solvent removed is under reduced pressure to leave a crude semi-solid that is chromatographed on a C18 column using a gradient of 0-60% water/acetonitrile as eluent. The aqueous is lyophilized to afford the title compound as a hygroscopic solid: 1H NMR (DMSOd6) δ 8.1 (s, 1H), 7.7 (s, 1H), 7.5 (d, J=8.3 Hz, 1H), 7.4 (m, 6H), 7.1 (dd, J=8.3, 1.8 Hz, 1H), 6.9 (s, 1H), 5.2 (s, 2H), 4.0 (s, 2H); (M−1)−=383.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrCCCBr
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1OCCCBr
Temperature: 90 °C

Procedure:
A stirred mixture of 2-methoxy-5-nitrophenol (5.0 g. 29.6 mmol) and powdered potassium carbonate (6.5 g, 47.4 mmol) in dimethylformamide (50 mL) was treated with 1,3-dibromopropane (80.8 g, 0.4 mol), heated to 90° C. for 2 h, cooled, diluted with dichloromethane (250 mL), and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from methanol. The resulting solid was triturated with 30% ethyl acetate/hexane and then with boiling 30% ethyl acetate/hexane. The combined organic phases were concentrated in vacuo to give the title compound: 1H NMR (300 MHz, CDCl3) δ7.92 (dd, 1H), 7.75 (d, 1H), 6.92 (dd, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.62 (t, 2H), 2.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[CH2:41][CH2:40]1)=O)CC(C)C.N1C=CC=CC=1N1CCNCC1>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Agent: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@@H]1OC(C)(C)OC1=O

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 792.6 mg; 2.0 mmol; 1.0 eq.) in DMF (15 mL) was added 1-(2-pyridyl)piperazine (326.5 mg; 2.0 mmol; 1.0 eq.). After 14 h of reaction at RT, the solvent was evaporated to give an oil. Purification by chromatography (SiO2) gave the title compound as a colorless oil (as a mixture of 2 diastereoisomers 50/50). This product was dissolved on iPrOH (10 mL) at kept at −20° C. for 48 h. The supernatant was collected and evaporated to give a colorless oil (301 mg, 40%, single diastereoisomer). M+(ESI): 376.3. HPLC (Condition A): Rt: 5.0 min (HPLC purity: 77.1%). 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=4.2 Hz, 1H), 7.58-7.47 (m, 1H), 6.74-6.63 (m, 2H), 4.54 (d, J=6.0 Hz, 1H), 3.88-3.41 (m, 8H), 3.33-3.22 (m, 1H), 1.89-1.62 (m, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 0.99-0.88 (m, 6H).