Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:19])[CH2:16][CH2:17]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reaction time: 3.5 h

Procedure:
To a solution of compound 7c in CH2Cl2 (100 mL) was added TFA (30 mL). The reaction was stirred for 3.5 h and the solvent was evaporated in vacuo. The residue was purified by reverse phase preparative HPLC to give compound 5e (5.15 g). MS m/z (M+H+) 253.1.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10]1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH2:18]([N:11]1[CH2:12][C@H:13]([CH2:16][OH:17])[C@@H:14]([OH:15])[C@H:9]([OH:8])[CH2:10]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN1C[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCN1C[C@H](CO)[C@@H](O)[C@H](O)C1
Yield: 65.2 %

Procedure:
(3R,4R,5R)-3-Benzyloxy-1-(n-butyl)-5-hydroxymethyl-4-piperidinol (105 mg, 0.4 mmol) was dissolved in ethanol (20ml) containing aqueous hydrochloric acid (4N, 0.3 ml), and palladium on carbon (10%, 30mg) was added. The mixture was hydrogenated at 1 atm. H2 -pressure for 3h, filtered through celite and concentrated in vacuo. Purification on a silica gel column (Eluent: ethyl acetate/methanol/25% ammonium hydroxide (4/1/1%)) gave the free base of (3R,4R,5R)-1-butyl-5-hydroxymethyl-3,4-piperidinediol (Yield: 53 mg, 74%) as a semicrystalline compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1)[CH2:15][O:16][Si:26]([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOc1cc(CO)cc(OCOC)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COCOc1cc(CO[Si](C)(C)C(C)(C)C)cc(OCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of (3,5-bis-methoxymethoxy-phenyl)-methanol (220b) (290 g, 1.27 mol) and imidazole (129 g, 1.9 mol) in CH2Cl2 (1.5 L) was added TBSCl (286 g, 1.9 mol) at 5° C. in several portion was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) showed that the reaction was complete. The mixture was filtered and the filtrate was washed with water, dried over Na2SO4 and concentrated under high vacuum to give the title compound (320 g, 97%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.68 (d, 2H), 6.57(t, 1H), 5.14 (s, 4H), 4.66 (s, 2H), 3.48 (s, 6H), 0.94 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: N1C=CN=C1.[C@@H:6]1([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:12][CH2:11][C@H:10]1[O:13][C@@H:6]([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:7][C@@H:8]1[OH:9])([CH3:24])[CH3:23]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (0.183 g, 2.69 mmol) was added to a solution of 2′-deoxyuridine (0.272 g, 1.19 mmol) in dry DMF (5 mL) under nitrogen. The mixture was cooled in an ice-salt bath before drop-wise addition of triisopropylsilyl chloride (0.28 mL, 1.31 mmol) via a syringe. The reaction mixture was kept at 0° C. for 3 h, allowed to warm up to room temperature and then stirred at room temperature for 22 h. After addition of water (5 mL), the crude mixture was extracted with CHCl3 (2×10 mL). The organic layers were combined and dried over MgSO4. Removal of the solvent under reduced pressure afforded a crude transparent oil which was further purified by flash chromatography eluting the column (ISOLUTE SI) a gradient of 0→10% CH3OH in CHCl3. The title compound was obtained from the fractions with Rf=0.25 (10% CH3OH in CHCl3) as a crystalline white solid (0.366 g, 74%). M.p. 152-153° C.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:25][C@@H:24]([N:26]2[C:38]3[C:37]4[NH:39][C:40]5[CH:41]=[C:42]([F:47])[C:43]([F:46])=[CH:44][C:45]=5[C:36]=4[C:35]4[C:48](=[O:52])[NH:49][C:50](=[O:51])[C:34]=4[C:33]=3[C:32]3[C:27]2=[CH:28][C:29]([F:54])=[C:30]([F:53])[CH:31]=3)[C@H:23]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@:22]([CH3:64])([OH:63])[CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Si](OC[C@H]1O[C@@H](N2C3C4NC5C=C(F)C(F)=CC=5C=4C4C(=O)NC(=O)C=4C=3C3C2=CC(F)=C(F)C=3)[C@H](OCC2C=CC=CC=2)[C@](C)(O)C1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>CC#N.C(OCC)(=O)C>[CH2:56]([O:55][C@@H:23]1[C@:22]([CH3:64])([OH:63])[CH2:21][C@@H:20]([CH2:19][OH:18])[O:25][C@H:24]1[N:26]1[C:38]2[C:37]3[NH:39][C:40]4[CH:41]=[C:42]([F:47])[C:43]([F:46])=[CH:44][C:45]=4[C:36]=3[C:35]3[C:48](=[O:52])[NH:49][C:50](=[O:51])[C:34]=3[C:33]=2[C:32]2[C:27]1=[CH:28][C:29]([F:54])=[C:30]([F:53])[CH:31]=2)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@](C)(O)[C@@H](OCc2ccccc2)[C@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)O1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](OC[C@@H]1C[C@@](C)(O)[C@@H](OCc2ccccc2)[C@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)O1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@]1(O)C[C@@H](CO)O[C@@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 127 %

Procedure:
To a solution of this material ( ) in 5 mL of dry THF, at −78° C. under Ar, was added MeMgBr (1.4M solution in THF-toluene, 0.49 mL, 0.69 mmol) dropwise. The resulting mixture was stirred at −78 C. for 2 h and then it was allowed to warm to −20° C. over 2 h. The mixture was then quenched with 1 mL of 1 M NaHCO3, and then it was patitioned with ethyl acetate (20 mL) and 1 M NaHCO3 (5 mL). The organic phase was separated, washed (H2O brine), dried (MgSO4) and evaporated. Flash chromatography (SiO2/2-28% ethyl acetate-hexane) of the residue afforded 12-[4-deoxy -6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-methyl-β-D-allopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.052 g, 43%) and then 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-methyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.028 g, 23%); MS (ESI−) m/e 884 (M−H)−. To a cold (5° C.) solution of 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-methyl -β-D-allopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (0.050 g, 0.056 mmol) in 5 mL of MeCN under Ar was added Et3N.3HF (0.091 mL, 0.56 mmol) and the mixture was stirred at room temperature for 2 days. The resulting mixture was diluted with ethyl acetate, washed (1M NaHCO3, H2O, brine) dried (MgSO4) and evaporated. The residue was purified by prep tlc (SiO2/ethyl acetate-hexane, 3:2) to give 12-[4-deoxy-2-O-benzyl-3-methyl-β-D-allopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.026 g, 72%) as a yellow solid; MS (ESI−) m/e 646 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc([N+](=O)[O-])cn1
Yield: 37 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was converted using 2-hydroxy-5-nitro-pyridine instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=80:0:20 to 50:30:20, 122 mg, 37%) which was obtained as a white solid. MS: m/e=312.2 [M+H]+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:15])([C:7]([F:14])([F:13])[C:8]([F:12])([F:11])[CH2:9][OH:10])[CH2:5][OH:6].[CH2:16](I)[CH3:17]>O>[F:3][C:4]([F:15])([C:7]([F:13])([F:14])[C:8]([F:12])([F:11])[CH2:9][O:10][CH2:16][CH3:17])[CH2:5][OH:6]
Reactant: CCI
Reactant: OCC(F)(F)C(F)(F)C(F)(F)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOCC(F)(F)C(F)(F)C(F)(F)CO
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
30.8 g potassium hydroxide was dissolved in 400 ml of water, 100 g (0.4715 moles) of 2,2,3,3,4,4-hexafluoropentane-1,5-diol (prepared essentially as described supra) was added, and the resulting mixture was heated to 90° C. Over a period of one hour, 74.9 g (0.480 moles) of ethyl iodide was added to the flask via an addition funnel with rapid stirring. The reaction flask was then heated to reflux for two hours. The reaction mixture was cooled to room temperature, and the bottom product phase (87.1 g) was split away from the aqueous layer. The crude product was distilled at 6.0 mm Hg (6.0 torr) to give 58.8 g of 2,2,3,3,4,4-hexafluoro-5-ethoxypentanol distilling at 85°-91° C. (conversion=68%; yield based on converted material=76%).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1>>[F:1][C:2]1[C:20]([N:35]2[CH2:34][CH2:33][NH:32][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][O:23][CH3:22])=[CH:30][CH:29]=3)[CH2:36]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COCc1ccc(C2CNCCN2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Product: COCc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CCN2)cc1
Yield: 89.3 %

Procedure:
Using the procedure described in Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.16 g) and (RS)-2-[4-(methoxymethyl)phenyl]piperazine (1.82 g), (RS)-7-fluoro-8-{3-[4-(methoxymethyl)phenyl]-1-piperazinyl}-1-methyl-4-oxo -1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.70 g) is obtained in the form of a yellow solid, decomposing at 284° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCOCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 32.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.065 mmol), (2-amino-ethoxy)-acetic acid (39 mg, 0.32 mmol), and NaOMe (14 mg, 0.26 mmol) in MeOH (2 mL) was heated at 140° C. in a microwave reactor for 6 h. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 1, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (0-2% MeOH/EtOAc+1% AcOH) to give a yellow solid. The solid was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 8.3 mg of the title compound as an off-white solid. MS: (+) m/z 398.29 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([C:22]#[N:23])=[C:9]([S:20][CH3:21])[S:10][C:11]=2[C:12](=O)[C:13]([CH3:18])=[CH:14]N(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(OC)OC)C.[N+:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH2:44])=[NH:43])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.CCOC(C)=O.CN(C=O)C>[N+:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]2[N:44]=[C:12]([C:11]3[S:10][C:9]([S:20][CH3:21])=[C:8]([C:22]#[N:23])[C:7]=3[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]([CH3:18])=[CH:14][N:43]=2)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: CSc1sc(C(=O)C(C)=CN(C)C)c(C2CCCCC2)c1C#N
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1sc(-c2nc(Nc3cccc([N+](=O)[O-])c3)ncc2C)c(C2CCCCC2)c1C#N
Temperature: 90 °C
Yield: 42 %

Procedure:
To a solution of 4-cyclohexyl-5-(3-dimethylamino-2-methyl-acryloyl)-2-methylsulfanyl-thiophene-3-carbonitrile (0.5 g, 1.7 mmol) in toluene (3 ml) was added DMF-DMA and the reaction was heated at 90° C. overnight resulting in conversion to product as determined by TLC (40% EtOAc:hexanes). The crude product was combined with DMF (10 ml) and 3-Nitrophenylguanidine (0.5 g, 2.78 mmol) in a sealed tube and heated at 120° C. overnight resulting in conversion to product as determined by TLC (40% EtOAc:hexanes). The reaction was partitioned between EtOAc and water, the organics were dried over sodium sulfate then concentrated in vacuo. The crude product was purified by chromatography (silica gel, 10% EtOAC:hexanes) to afford 0.334 g (3.05 umol) of V-7 in 42% yield for 2 steps. 1H NMR (CDCl3) δ1.0-2.0 (m, 10H), 2.1 (s, 3H), 2.6(s, 3H), 7.4(m, 1H), 7.7 (d, 1H), 7.8 (d, 1H), 8.3 (s, 1H), 8.7 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4](Cl)[N:3]=1.CC(C)([O-])C.[K+].[OH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Reactant: OCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(N)nc(OCc2cccnc2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
102 mg (0.4 mmol) of 2-amino-6-chloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] and 54 mg (0.48 mmol) of potassium tert-butoxide are dissolved together in 1.696 g (=1.5 ml, 15.55 mmol) of 3-hydroxymethylpyridine, and the mixture is stirred at 60° C. for about 16 h. The resulting suspension is acidified with two drops of glacial acetic acid. The product which crystallizes out is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1cn2c(=O)[nH]nc2c2cc(Cl)ccc12

Procedure:
To a solution of tert-butyl[(2E)-3-(9-chloro-3-oxo-2,3-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (3-10)(14 mg, 0.037 mmol, 1.0 equiv.) in EtOH (4 mL), was added Pd(OH)2/C (20% Pd, 1.3 mg, 0.002 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature for 1.5 hours under atmospheric pressure of hydrogen. The catalyst was then filtered off, and the filtrate was concentrated to dryness. The resulting crude product was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) to afford the titled product (3-12). LRMS m/z (M+H) 377.1 found, 377.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([NH:1][C:18]2[CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
Aniline (3 g, 10.75 mmol), m-terphenyl (3.34 g, 10.85 mmol), Pd2(dba)3 (3 mol %), and t-BuONa (1.45 g, 15.05 mmol) is dissolved in toluene in a round flask, and a solution thereof is stirred at 100° C. Upon finishing reaction thereof, the toluene is removed from the solution, and a compound is extracted from the solution by using water and dichloromethane. The compound extracted thus is separated by using silica gel. The separated substance is re-crystallized by using dichloromethane and petroleum ether, and filtered, to obtain N-Phenyl-3,5-diphenylaniline (2.9 g, 84%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:16]=1)(=[NH:4])[NH2:3].[OH-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:16]=1)=[NH:3])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N=C(N)c1ccc2oc(C(=O)O)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Tetrahydrofuran (200 ml) was added to hydrochloride (7.55 g, 31.4 mmol) of 5-amidino-2-benzofurancarboxylic acid, and the mixture was ice-cooled. The mixture was maintained at pH 10 with a 1N aqueous sodium hydroxide solution while dropwise addition of benzyloxycarbonyl chloride (6.74 ml, 47.0 mmol) over about 15 minutes. The mixture was stirred for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was collected by filtration, and washed with water and an equivalent mixture of n-hexane and ethyl acetate to give 7.94 g of 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid as a pale-yellow solid (75%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[I:12]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:9]([I:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-fluoro-2-methoxybenzonitrile (3.00 g, 20 mmol) and N-iodosuccinimide (NIS) (4.7 g, 21 mmol) under nitrogen was added TFA (35 mL) and the reaction was stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was taken up in 1:1 ethyl acetate:ether and was washed with aqueous sodium bicarbonate and then brine containing enough sodium sulfite to remove the iodine color. The aqueous layers were back extracted with more 1:1 ethyl acetate:ether and the combined organic layers were dried over sodium sulfate and evaporated. The residue was treated with ether/hexanes to afford clean iodo title product as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.930 (s, 3H), 6.730 (d, J=9.4 Hz, 1H), 7.900 (d, J=6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:22])[CH2:20][Br:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: O=C1NC(Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CBr)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-benzyl-2-oxazolidinone in dry THF (300 ml) was stirred at −78° C. under nitrogen during the dropwise addition of 1.6 M n-butyl lithium in hexanes, (60 ml, 97 mmol) followed by bromo-acetyl bromide. The pale yellow solution was stirred for a further 10 minutes at −78° C. and allowed to warm to room temperature over 30 minutes. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution. After dilution with ethyl acetate and brine, the two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 4-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one (26.2 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I:22]I.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 85.7 %

Procedure:
To acetic acid (263.7 L, 6.8 rel vol) was charged 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (38.6 kg, 1 mol eq, limiting reagent), iodine (17.4 kg, 0.53 mol eq) and concentrated sulfuric acid (3.7 L, 0.1 rel vol). The temperature was adjusted to 50° C.-55° C. and 90% nitric acid (4.1 kg, 0.6 mol eq) charged over 15 minutes. The reaction was stirred until deemed to be complete as judged by HPLC analysis. The reaction was cooled, stirred and the product collected by filtration. The solid was washed twice with water (2×77.0 L, 2×2 rel vol) and acetone (2×38.6 kg, 2×1 rel vol). The solid was dried under vacuum to constant weight to yield the title compound (47.0 kg, 111.0 mol, 85.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:34])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([I:34])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2cc(Br)ccc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (1.0 g, 3.37 mmol) was dissolved in dry dichloromethane (30 mL) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (3.5 g, 6.754 mmol) was added in one portion as a solid. The solution was protected from light and permitted to stir overnight at room temperature. Upon completion, the reaction was quenched by addition of aqueous sodium thiosulfate (2.0 g in 50 mL of water. The layers were separated and the organic phase washed with 1M hydrochloric acid, brine and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (3-15% ethyl acetate in hexanes) to provide the iodo-isoquinoline in 77% yield which was used immediately in the next step.