Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([NH:13][C@@H:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:12])=[CH:9][CH:8]=1.FC1(F)C[C@H]1COC1C=CC(C(N[C@@H](CC2C=CC(OC(F)(F)F)=CC=2)C(NCCO)=O)=O)=CC=1.OCCNC(=O)[C@H](NC(=O)C1C=CC=CC=1)CC1C=CC(OC(F)(F)F)=CC=1>>[F:1][C:2]1([F:35])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C@@H:14]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=2)[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:12])=[CH:33][CH:34]=1
Reactant: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OC[C@H]2CC2(F)F)cc1
Agent: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OC[C@@H]2CC2(F)F)cc1
Agent: O=C(N[C@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccccc1
Product: O=C(N[C@@H](Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCC2CC2(F)F)cc1

Procedure:
4-[(2,2-Difluorocyclopropyl)methoxy]-N-{2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide prepared in Example 40 was separated into three stereoisomers A, B, and C by HPLC under conditions as in Example 10 to give the title compound (referred to as Isomer A). Isomer A was estimated to be a mixture of 4-{[(1R)-2,2-difluorocyclopropyl]methoxy}-N-{(1S)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide and 4-{[(1S)-2,2-difluorocyclopropyl]methoxy}-N-{(1S)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide. Isomer B and Isomer C were estimated to be 4-{[(1R or S)-2,2-difluorocyclopropyl]methoxy}-N-{(1R)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide and 4-{[(1S or R)-2,2-difluorocyclopropyl]methoxy}-N-{(1R)-2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide, respectively.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[C:21]([O:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:34]Br)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:22]1([C:21]([O:29][CH2:30][C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=2[CH2:39][O:40][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])[CH2:34][O:1][C:2]2[C:3]([CH3:20])=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH3:19])[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C)c(-c2cccc(O)c2C)c(C)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(C)c(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2C)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 980 mg (3.6 mmol) of methyl 3′-hydroxy-2,6,2′-trimethylbiphenyl-4-carboxylate with 1.75 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 570 mg (4.1 mmol) of potassium carbonate, the desired product is obtained in the form of white crystals (m.p.=131-132° C.; m=2.16 g; Y=95%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[C:13]([F:19])[CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2F)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1onc(-c2ccc(Cl)cc2F)c1CO
Yield: 43.5 %

Procedure:
As described for example 84d, 3-(4-chloro-2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (6.3 g, 20 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (2.1 g, 43%) which was obtained as an orange solid. MS: m/e=242.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.C1([SiH3])C=CC=CC=1.CO>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 3,4-dimethoxy-phenylamine (786 mg; 5.13 mmol) and dibutyltridichloride (219 mg; 0.72 mmol) in ethyleneglycol dimethylether (7 mL), 4-formyl-benzoic acid (748 mg; 4.98 mmol) was added. The suspension was stirred at room temperature for 10 min, treated with phenylsilane (1.0 mL; 7.9 mmol) and the mixture stirred at the same temperature for 12 h. Methanol and a few drops of water were added, stirred for 5 h, concentrated under vacuum, suspended in dichloromethane and stirred for one day at room temperature. After filtration, pure acid 4 (1.13 g; 79% yield) was obtained as a beige solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([CH:29](O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)OC(Cc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Oxalyl dichloride (141 μl, 1.67 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (300 mg, 1.67 mmol) in DCM (20 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (20 ml). 1,2-Diphenylethanol (331 mg, 1.67 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=97/3 to 94/6) to obtain 1,2-diphenylethyl 1-methylpiperidine-4-carboxylate (200 mg).
Reaction SMILES: B.[Na].C([O:5][C:6]([C:8]1[N:9]2[CH:16]=[N:15][CH:14]=[C:10]2[S:11][C:12]=1[CH3:13])=O)C>CO>[OH:5][CH2:6][C:8]1[N:9]2[CH:16]=[N:15][CH:14]=[C:10]2[S:11][C:12]=1[CH3:13]
Reactant: CCOC(=O)c1c(C)sc2cncn12
Agent: B
Agent: [Na]
Solvent: CO
Product: Cc1sc2cncn2c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A 1.91 g portion of sodium boron hydride was added to 30 ml of a methanol solution containing 2.10 g of 3-ethoxycarbonyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue and the solution was then extracted five times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 1.4 g of the title compound as a yellow crystal.
Reaction SMILES: I.[CH3:2][CH:3]([CH3:17])[CH2:4][CH2:5][N:6]1[C:10]([NH:11][C:12](=[NH:15])SC)=[CH:9][C:8]([CH3:16])=[N:7]1.[CH2:18](N)[CH2:19][NH2:20]>C(O)CC>[CH3:2][CH:3]([CH3:17])[CH2:4][CH2:5][N:6]1[C:10]([NH:11][C:12]2[NH:20][CH2:19][CH2:18][N:15]=2)=[CH:9][C:8]([CH3:16])=[N:7]1
Reactant: CSC(=N)Nc1cc(C)nn1CCC(C)C
Reactant: NCCN
Agent: I
Solvent: CCCO
Product: Cc1cc(NC2=NCCN2)n(CCC(C)C)n1

Procedure:
N[1-(3-methylbutyl)-3-methyl-5-pyrazolyl]-S-methyl isothiourea hydroiodide (29.0 g.) was suspended in 160 ml. n-propyl alcohol. Ethylene diamine (10.2 g.) was added and the solution was refluxed 18 hrs. The solvent was concentrated in vacuum and the residue was treated with KHCO3 in water. The resulting solid was recrystallized from CHCl3 -ether mixtures to obtain 14.3 g. product, mp 104°-106° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]CC)[N:30]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:31]3[N:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:27][CH2:28]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)Nc1cccnn1
Reactant: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Temperature: 180 °C
Yield: 36 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (1 mmol, from Step 5), in acetonitrile (3 mL) was treated with ethyl pyridazin-3-ylcarbamate (184 mg, 1.10 mmol) and diisopropylethylamine (0.52 mL, 3.00 mmol) and was heated to 180° C. in a microwave for 40 min. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (0-6% ethanol (containing 11% aq NH4OH):dichloromethane) to afford a light yellow foam (168 mg, 36% yield). MS (APCI) M+1=466.0; 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=5.46 Hz, 2H) 2.58-2.65 (m, 2H) 3.60 (t, J=5.75 Hz, 2H) 3.65-3.74 (m, 2H) 6.42 (s, 1H) 6.86 (dd, J=8.67, 0.49 Hz, 1H) 6.96-7.03 (m, 2H) 7.07 (d, J=7.60 Hz, 1H) 7.38 (t, J=7.80 Hz, 1H) 7.44 (dd, J=9.16, 4.48 Hz, 1H) 7.79 (dd, J=8.77, 2.53 Hz, 1H) 8.24 (dd, J=2.53, 0.39 Hz, 1H) 8.26-8.37 (m, 1H) 8.79 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=[O:12])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>[Cl-].[Na+].O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=[O:12])[NH:18][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)cc(F)c21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1NCCc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer, was charged with 5,7-difluoro-2,3-dihydro-1H-indene-1-one (10 g, 59.4 mmol) followed by dry dichloromethane (100 ml) and methanesulfonic acid (71.3 ml, 1.1 mol). The reaction was cooled to 0° C. (ice bath) and to this was added sodium azide (5.41 g; 83.2 mmol) in 4 equal portions over 20 minutes. The reaction was stirred at 0° C. for 2 hours and then a 20% aqueous solution of sodium hydroxide (175 ml) was added over 30 minutes with vigorous stirring. After complete addition the mixture was transferred to a separatory funnel and the methylene chloride phase was isolated. This was shaken with an equal volume of 50% diluted brine solution. The organic phase was collected and the aqueous phases were back extracted with dichloromethane (2×80 ml). The organic phases were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified via HPLC on silica gel, eluting with 40% to 95% ethyl acetate/hexanes to provide the desired product as a white solid (8.364 g). (M+H)+=184 m/e.
Reaction SMILES: [BrH:1].C(=O)=O.[CH3:5]COCC.N[C@H](C(N[C:22]1[CH:30]=[CH:29][C:25]([N+]([O-])=O)=[CH:24][CH:23]=1)=O)CCCNC(=N)N>C(O)(=O)C>[CH2:5]([Br:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:29][CH:30]=1.[BrH:1]
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOCC
Agent: Br
Agent: O=C=O
Solvent: CC(=O)O
Product: BrCc1ccccc1

Procedure:
4.65 g (10 mM) of compound 1a were treated, while stirring, with 40 ml of 2 N HBr in glacial acetic acid for 45 min. at 20° in the absence of moisture. The amino acid derivative dissolved with CO2 evolution. The reaction solution was added dropwise with vigorous stirring to 250 ml of absolute ether which resulted in the precipitation of 2HBr.H-Arg-pNA. The ethereal phase was sucked off, whereupon the solid phase was washed 4 times with portions of 100 ml of abs. ether in order to substantially remove benzyl bromide which had formed as a by-product as well as excess HBr and AcOH. The residue was dissolved in 50 ml of MeOH, the pH was adjusted to 4.5 by the addition of Et3N, and the solution was concentrated to dryness in vacuo at 30°. The resulting product was dissolved in 75 ml of MeOH and passed through a column of "Sephadex" LH-20 (cross-linked dextran gel) equilibrated with MeOH. From a fraction of the eluate there were obtained 4.18 g (91.6% of the theory) of amorphous compound 1b which was homogeneous in the SS as shown by TLC. Elementary analysis and calculation from the empirical formula C12H20N6O3Br2 gave the following values: C=31.15% (31.60%), H=4.35% (4.42%), N=18.84% (18.43%) and Br=34.81% (35.03%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[N:22][CH:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(Cl)n3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cncc(Cl)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(6-chloro-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.11 g, 0.30 mmol) in THF (3 mL) was added a solution of LiOH (0.036 g, 1.5 mmol) in water (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-chloro-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as an off white solid (0.05 g, 50%). mp 187.2-188° C. 1H NMR (400 MHz, DMSO-d δ 12.34 (s, 1H), 9.26 (s, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 5.55 (m, 1H), 3.10 (dd, J=15.60, 2.80 Hz, 1H), 2.32 (s, 3H), 2.16 (m, 1H). MS (ESI) m/z: 333 (M−1)−. HPLC purity: 98.97% (Maxplot), 99.14% (220 nm).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 23.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 3-Trifluoromethylbenzoyl chloride (156.4 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (50.0 mg). Yield 23.4%.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl-].[Cl-].[Cl-].[Cl-].[Hf+4:23]>>[N+:1]([O-:4])([O-:3])=[O:2].[Hf+4:23].[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: [Hf+4]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Product: O=[N+]([O-])[O-]
Temperature: 30 °C

Procedure:
Nitrogen is produced as a result of the reaction between phosphorus pentoxide (P2O5) and fuming nitric acid (HNO3). P2O5is placed in flask 12. Fuming nitric acid is placed in dropping funnel 14 and is slowly dropped into the P2O5 in flask 12. Hafnium tetrachloride is placed in flask 20, with stirring bar 22, and is cooled using liquid nitrogen bath 26. When fuming nitric acid is dropped into flask 12 and quickly reacted with P2O5, N2O5 is produced, and condensed into flask 20. When sufficient N2O5 is generated, flask 20 is disconnected from flask 12, and warmed up to about 30° C. After refluxing in N2O5 for a while, e.g., about 30 minutes, hafnium nitrate is produced in high yield. P2O5+2HNO3→N2O5+2HPO3  (5) 4N2O5+HfCl4→Hf(HNO3)4+4NO2Cl  (6)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[CH3:13][C:14]([CH3:16])=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][CH3:16])[C:7]2=[O:12]
Reactant: CC(C)=O
Reactant: O=c1[nH]ccc2c(Cl)cccc12
Product: CCCn1ccc2c(Cl)cccc2c1=O
Yield: 40 %

Procedure:
According to Scheme 28 Step 3: The title compound was prepared from 5-chloroisoquinolin-1(2H)-one (1 eq, 2.66 mmol, 0.48 g) and 1-bromopropyl (1.1 eq, 2.93 mmol, 0.27 mL) according to the procedure described for Example 1 Step 2. Reaction conditions: microwaved at 150° C. for 60 min. in acetone. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using pure CH2Cl2 to afford 5-chloro-2-propylisoquinolin-1(2H)-one (1.06 mmol, 0.24 g, 40%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15](C)([O-])[CH3:16].[K+].IC(C)C>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:15]([CH3:16])[CH3:14])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CCOC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-bromophenylacetate (3.0 g, 12.3 mmol) and potassium tert-butoxide (1.38 g, 12.3 mmol) were combined in DMF (35 mL). 2-Iodo-propane (2.09 g, 12.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH2:16][CH2:17][CH2:18][Br:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:6]([C:13]1[CH:14]=[CH:15][C:10]([CH2:16][CH2:17][CH2:18][Br:19])=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: BrCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CCCBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Concentrated sulfuric acid (18.3 g) was gradually added dropwise to 13.94 g of concentrated nitric acid and the mixture was vigorously shaken for 10 minutes. To the mixed solution, 10 g of 3 phenylpropyl bromide was gradually added dropwise at -20° C. and the mixture was stirred at -20° C. for 1 hour. The reaction mixture was poured into 500 ml of ice water and extracted with ether. The extract was washed and dried, and the solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 4.5 g of 3-(4-nitrophenyl)propyl bromide as a colorless, oily substance.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C@H:18]3[C@H:22]([C:23]4[C:33]5=[C:34]6[C:29](=[CH:30][CH:31]=[CH:32]5)[CH2:28][CH2:27][CH2:26][N:25]6[CH:24]=4)[C:21](=[O:35])[NH:20][C:19]3=[O:36])=[CH:14][NH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:23]1([C@H:22]2[C@H:18]([C:13]3[C:12]4[C:16](=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=4)[NH:15][CH:14]=3)[C:19](=[O:36])[NH:20][C:21]2=[O:35])[C:33]2=[C:34]3[C:29](=[CH:30][CH:31]=[CH:32]2)[CH2:28][CH2:27][CH2:26][N:25]3[CH:24]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2cc(O)ccc12
Yield: 28.9 %

Procedure:
The (rac)-trans-3-[6-(benzyloxy)-1H-indol-3-yl]-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrolidine-2,5-dione (500 mg, 1.05 mmol) and 10% Pd/C (10 mg) were stirred under 1 atmosphere of hydrogen in methanol (200 mL) at room temperature for 24 hours. The reaction mixture was filtered through a bed of Celite and the filtrate evaporated to dryness. The residue was purified by silica gel chromatography, eluting with 1-7% methanol in dichloromethane to afford to yield (rac)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(6-hydroxy-1H-indol-3-yl)pyrrolidine-2,5-dione (117 mg, 28%) as an off-white solid. Mp: 167-170° C.; 1H NMR (DMSO-d6) 400 MHz δ: 11.50 (bs, 1H), 10.62 (s, 1H), 7.32 (s, 1H), 7.13-7.17 (m, 3H), 6.83-6.89 (m, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.48-6.52 (m, 1H), 4.46 (d, J=6.6 Hz, 1H), 4.37 (d, J=6.6 Hz, 1H), 4.01 (s, 2H), 2.89 (s, 2H), 2.09 (s, 2H); LCMS [M+H]: 386.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.[ClH:41].C(OCC)(=O)C>>[ClH:41].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:40])([F:39])[F:27])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(C(F)(F)F)cc3)cn2)cs1)C(=O)O

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyridin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 100-1 and 4-(trifluoromethyl)phenylboric acid as starting materials by operations similar to those of Example 100-2 and Example 100-3 was reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4](Cl)[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH:19]([NH2:21])=[S:20]>CO>[CH3:1][O:2][C:3]([C:4]1[S:20][CH:19]=[N:21][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:18]
Reactant: COC(=O)CCCCCCC(=O)C(Cl)C(=O)OC
Reactant: NC=S
Solvent: CO
Product: COC(=O)CCCCCCc1ncsc1C(=O)OC

Procedure:
16.8 g of 9-carbomethoxy-2-chloro-3ketonononoic acid methylester (VI) and 4.5 of thioformamide (VII, R1 = H) were refluxed in 90 ml of methanol for 1 hour, then methanol was evaporated in vacuo, and the distillation residue was dissolved in 150 ml of 2 N hydrochloric acid. The obtained solution was neutralized with a 5 % solution of sodium carbonate, saturated with ammonium sulphate and extracted with 3 × 150 ml of diethyl ether. The ethereal extract was dried over sodium sulphate, then ether was evaporated. Thus 16 g of crude 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, R1 = H) were obtained which could be used without any further purification for the preparation of 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = H) according to point (e).