Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)[OH:4].[Na+].[Na+].[Na+].[C:17]([OH:38])(=[O:37])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33]CCC>C(O)C>[OH:4][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][C:17]([OH:38])=[O:37]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)C=CC=CCC=CCCCC(=O)O
Reaction time: 0.17 h

Procedure:
Eight ml of blood was gathered from the abdominal aorta of a rat (JcI : Wistar, male, 12-15 weeks age) subjected to abdominal incision under anesthesia by the use of 3.2 % sodium citrate (1 volume of sodium citrate solution to 9 volume of whole blood). The blood was centrifuged at 800 rpm for 10 minutes at room temperature to gather PRP (platelet rich plasma), and the residual blood was further centrifuged at 3000 rpm for 10 minutes to gather PPP (platelet poor plasma). The platelet number in PRP was measured and the PRP was adjusted by diluting with PPP so that the concentration of platelet was one million/μl. To 0.25 ml of the PRP, 125 μg of arachidonic acid and the test compound (the final concentration of 100 μM, 10 μM, 1 μM and 0.1 μM) were added, and the mixture was incubated at 37° C. for 15 minutes. After the reaction, 1.1 ml of ethanol was added, well shaken and centrifuged at 2000 rpm for 10 minutes to separate the supernatant. To 1 ml of the supernatant 1 ml of water was added and subjected to high performance liquid chromatography to determine HHT. The absorption at 240 nm due to HHT was measured by an ultraviolet absorption monitor. The inhibition rate of HHT formation calculated from the peak area is shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
5 g (30.3 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml of pyridine and admixed dropwise at 0° C. with 4.1 ml (31.8 mmol) of benzenesulfonyl chloride. The mixture was stirred for 3 h. The mixture was then concentrated under reduced pressure and the residue was recrystallized from ethanol. 7.3 g (85%) of the product were obtained.
Reaction SMILES: CC([S@@]([NH:7][C@:8]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:25][CH:24]=1)([CH2:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@:8]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])=[CH:25][CH:24]=1)([C:9]([F:12])([F:11])[F:10])[CH2:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccc(C(=O)C[C@](N[S@@](=O)C(C)(C)C)(c2ccc(OCCCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of Intermediate 8D (482 mg, 0.852 mmol) in MeOH (4 mL) was added 4 M HCl (1 mL, 4.00 mmol) in dioxane. The resulting mixture was stirred at rt for 2 h and then concentrated. The residue was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated to afford Intermediate (386 mg, 58%) as a colorless oil, which was used for the subsequent reaction without further purification. LCMS Anal. Calc'd for C23H25F6NO2 461.18, found [M+H] 461.9.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C([O-])(O)=O.[Na+].[F:34][C:35]1[CH:36]=[C:37]([S:44](Cl)(=[O:46])=[O:45])[CH:38]=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42].CC(O)C>ClCCl>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:44]([C:37]2[CH:38]=[CH:39][C:40]([N+:41]([O-:43])=[O:42])=[C:35]([F:34])[CH:36]=2)(=[O:46])=[O:45])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]-furan-3-yl ester (6) (9.81 g, 25 mmol, 1 equiv) was dissolved in dichloromethane (100 mL), followed by the addition of saturated NaHCO3 solution (100 mL). A solution of 3-fluoro-4-nitro-benzenesulfonyl chloride (6.11 g, 25.50 mmol, 1.02 equiv) in dichloro-methane (100 mL) was added drop wise to the previous solution. The solution was vigorously stirred at 20° C. After stirring for 4 h, the organic layer was separated and washed with saturated NaHCO3 solution (100 mL), water (100 mL), 5% HCl solution (100 mL) and brine (100 mL). The organic layer was dried on MgSO4, filtered, and evaporated to dryness. The crude product was recrystallized from 2-propanol (550 mL) (9.58 g, 25 mmol, 64.30%). LRMS (ES+): m/z 596 [M+H]+; 1H-NMR (CDCl3) δ0.90 (d, 3H, CH3), 0.92 (d, 3H, CH3), 1.40-1.72 (m, 2H, CH2, H4), 1.80-1.92 (m, 1H, CH (isobutyl)), 2.79 (dd, 1H, CH2—N), 2.87-3.19 (m, 5H, CH2—N (isobutyl), CH, H3, CH2—N and CH of CH2C6H5), 3.19-3.29 (m, 1H, CH of CH2C6H5), 3.29-3.39 (brs, 1H, OH), 3.60-3.78 (m, 2H, CH2, H5 and H2), 3.78-3.90 (m, 3H, CH, H5, CH—OH and CH), 3.95 (dd, 1H, CH2, H2), 4.90 (d, 1H, NH), 4.98-5.10 (m, 1H, CH, H3), 5.66 (d, 1H, CH, H6a), 7.19-7.33 (m, 5H, C6H5), 7.68-7.74 (m, 2H, CH of C6H3FNO2), 8.15-8.20 (m, 1H, CH of C6H3FNO2).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CCO>[NH2:13][C:11]1[O:12][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1coc(N)n1
Yield: 85 %

Procedure:
A stirred solution of ethyl bromopyruvate (50.2 g, 257.2 mmol) in EtOH was treated with urea (23.2 g, 385.8 mmol) refluxed overnight and concentrated under reduced pressure. The resultant residue was dissolved in EtOAC and water. The layers were separated and the aqueous layer washed with EtOAC. The combined organic layers were washed successively with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 85% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 157.1 (MH+).
Reaction SMILES: C(O)(=O)C.C([O:9][C:10](=O)[CH2:11][CH2:12][CH:13]([OH:31])[C@@H:14]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15])(C)(C)C.C([O-])(O)=O.[Na+]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:17]([N:16]([C@H:14]([C@H:13]1[O:31][C:10](=[O:9])[CH2:11][CH2:12]1)[CH3:15])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](C(O)CCC(=O)OC(C)(C)C)N(Cc1ccccc1)Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C[C@@H]([C@@H]1CCC(=O)O1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Glacial acetic acid (0.4 mL) and one drop of methanesulfonic acid were added to a solution of (5S)-5-(N,N-dibenzylamino)-4-hydroxy-hexanoic acid-tert-butyl ester (0.6 g, 1.57 mmol) in dry toluene (15.0 mL) in a 50 mL round bottom flask fitted with a reflux condenser. The reaction mixture was heated at reflux for 12 hours and then cooled to ambient temperature. The pH of the solution was adjusted to 7 by slow addition of a saturated solution of NaHCO3. The organic layer was separated, and the aqueous layer was extracted with Et2O (10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue thus obtained was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to obtain 0.41 g (85% yield) of pure (5S)-5[(1S)-1-(N,N-dibenzylamino)-ethyl]-dihydrofuran-2(3H)-one (5a). White solid, mp. 61°-62° C., 1H NMR (300.15) δ1-11 (d, J=6.6 Hz, 3H), 1.83-2.15 (m, 2H), 2.44-2.50 (m, 2 2.86 (pentet, J=6.9 Hz, 1H), 3.71 (ABq, δA =3.87, δB =3.56, JAB=13.8 Hz, 4H), 4.49 (pentet, J=7.2 Hz, 1H), 7.10-7.41 (m, 10H); 13C NMR (75.8 MHz) 10.9, 25.6, 28.7, 54.3, 55.8, 83.1, 126.8, 128.2, 128.7, 139.9, 177.1; MS (10W res.) 310 (M+1, 20%), 224 (MeCHNBn2, 40%), 91 (NBn2, 100%); HRMS for C20H24NO2 : 310. 1807 (calc'd 310.1801); Anal calc'd for C20H23NO2 : C 77.64, H 7.49, N 4.53; Found: 77.54, H 7.55, N 4.49.
Reaction SMILES: C(OC([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([O:16][CH3:17])[O:14][CH3:15])=O)C1C=CC=CC=1.[ClH:24].O1CCOCC1>CO.[H][H].[Pd]>[ClH:24].[CH3:17][O:16][CH:13]([O:14][CH3:15])[CH:12]([NH2:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COC(OC)C(NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(OC)C(N)c1ccccc1
Yield: 91 %

Procedure:
1-Benzyloxycarbonylamino-2,2-dimethyloxy-1-phenylethane (1.21 g, 3.84 mmol) was dissolved in methanol (38.4ml), and 4 N hydrogen chloride/1,4-dioxane (0.96 ml, 3.84 mmol) and palladium black (121 mg) were added to it and hydrogenolyzed overnight at room temperature in hydrogen atmosphere. After the palladium black was removed by filtration, the filtrate was concentrated under reduced pressure, and methylene chloride and diethyl ether were added to the resulting residue. The precipitated solid was collected by filtration whereby the title compound (760.3 mg, 91% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][NH2:27].CC([O-])=O.[Na+]>CCO>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][N:27]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18]
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 65.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (3.21 mg, 10.17 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (3.16 mg, 10.68 mmol) and anhydrous NaOAc (876 mg, 10.68 mmol) in EtOH (120 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 2:3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2PE to give N-{2-[1-(2,4-bistrifluoromethylbenzyloxyimino)propyl]-4-chlorophenyl}trifluoromethanesulfonamide 76 (3.70 g, 65%), as a pale yellow oil. 1H n.m.r. (200 MHz, CDCl3) δ 10.96, br s, 1H; 7.96, s, 1H, 7.85+d, J=8.4 Hz, 1H, 7.72, d, J=8.4 Hz, 1H, 7.61, d, J=8.8 Hz, 1H, 7.49, d, J=2.4 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 5.45, s, 2H, 2.88, q, J=7.6 Hz, 2H, 1.21, t, J=7.6 Hz, 3H. HRMS (M+) 556.0254.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([OH:8])=[C:3]1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:22](I)[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([O:8][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)(C)CI
Reactant: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reaction time: 18 h

Procedure:
To a mixture of 5,5-dimethyl-3-hydroxy-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one (500 mg, 1.77 mmol, Example 109, Step 1) in DMF (6 mL) were added NaH (65 mg, 1.2 eq.), and neopentyl iodide (585 μL). After a period of 18 h at 70° C., the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and the organic phase separated, dried over MgSO4 and evaporated under reduced pressure. The resulting oil was purified by flash chromatography to provide the title compound (124 mg) as a white solid after precipitation with Et2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.COC1C=C(C=CC=1OC)C=[N:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]
Reactant: COc1ccc(C=NCC(OC)OC)cc1OC
Reactant: COc1ccc(C=O)c(OC)c1OC
Solvent: c1ccccc1
Product: COc1ccc(C=NCC(OC)OC)c(OC)c1OC
Yield: 100 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (10e, 11.48 g, 0.05851 mol) was dissolved in benzene (200 mL) and aminoacetaldehydedimethylacetal (10.0 mL, 9.75 g, 0.0927 mol) was added. The same procedure was applied as for 11a. The product was isolated as a clear light yellow oil (16.58 g, 100%), bp 153-155° C. (0.45 mm Hg). 1H NMR (300 MHz CDCl3) 8.49 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.61 (t, J=5.4 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.71 (d, J=5.4 Hz, 2H), 3.36 (s, 6H); low resolution ESIMS m/z (rel intensity) 284 (MH+, 100), 252 (45). Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C, 59.67; H, 7.55; N, 4.88.
Reaction SMILES: [Na+].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([CH3:37])[CH:8]=[CH:9][C:10]=1[S:11]([NH:14][C:15]1[C:24]2[C:23]([S:25]([O-:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([O-:32])(=[O:31])=[O:30])=[CH:20][C:19]=2[C:18]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:17][CH:16]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[N+:44]([C:47]1[CH:48]=[C:49]([S:53](Cl)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1)([O-:46])=[O:45].C(=O)([O-])[O-]>O>[N+:44]([C:47]1[CH:48]=[C:49]([S:53]([NH:4][C:5]2[CH:6]=[C:7]([CH3:37])[CH:8]=[CH:9][C:10]=2[S:11]([NH:14][C:15]2[C:24]3[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:20][C:19]=3[C:18]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:17][CH:16]=2)(=[O:13])=[O:12])(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1)([O-:46])=[O:45]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
To a stirred solution of 2.0 g of 8-(3-amino-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid trisodium salt and 342 mg of anhydrous sodium carbonate in 10 ml of water is added 1.5 g of m-nitrobenzenesulfonyl chloride. The mixture is stirred for 16 hours. An additional 170 mg of anhydrous sodum carbonate is added followed by 750 mg of m-nitrobenzenesulfonyl chloride and the mixture is stirred for an additional 16 hours. The reaction mixture is evaporated and the residue dissolved in hot water. A product is precipitated on the addition of absolute ethanol. The product is collected, washed with ethanol and ether and dried. Additional product is collected from the filtrate and is washed and dried as above. The above fractions of product are combined and dissolved in water, then 2.5 ml of 5 N sodium hydroxide is added and the mixture is stirred for 30 minutes. The mixture is acidified with glacial acetic acid and evaporated. The residue is dissolved in hot water and precipitated with ethanol. The product is collected and washed twice with ethanol and ether and dried to yield 700 mg of 8-(3-m-nitrobenzenesulfonamido-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:15]=[C:14]([C:25]([OH:27])=O)[C:13]=2[CH3:28])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:15]=[C:14]([C:25]([Cl:3])=[O:27])[C:13]=2[CH3:28])=[CH:10][CH:11]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.3 ml, 22.0 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2.09 g, 5.5 mmol) in toluene (50 ml) maintained at room temperature. The mixture was refluxed at 110° C. for 2 hours and then cooled to room temperature. The resulting solution was evaporated and dried under a vacuum to produce crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride, which are not further purified. 27% aqueous ammonia (2 ml) was added to the solution of crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride in methylene chloride (10 ml) at 0° C. After stirring 3 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride which was extracted twice with 50 ml portions of ethyl acetate. After concentrating the extract by evaporation, the crude residue was purified using a silica gel column (hexane/ethyl acetate=1/1), to obtain the title compound (2.07 g, 99%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:42][CH2:43][CH:44]([OH:56])[CH2:45][N:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1>C(Cl)Cl>[CH2:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:54][CH2:55][N:46]1[CH2:45][CH:44]([OH:56])[CH2:43][NH:42][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NCC(O)CN2CCc3ccccc3C2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-methyl-3-nitrobenzoic acid (1.0 g, 5.5 mmol) in DCM (20 mL) was added EDCI (1.58 g, 8.25 mmol), HOBt (1.11 g, 8.25 mmol), Et3N (1.11 g, 11.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (1.36 g, 6.6 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (1.6 g, 78.8%). LCMS (m/z): 370.2 (M+1).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(O)C>[CH3:13][C:11]1[NH:5][C:6]([NH2:8])=[N:7][C:9](=[O:14])[CH:10]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)O
Solvent: CCO
Product: Cc1cc(=O)nc(N)[nH]1
Reaction time: 8 h
Yield: 125.6 %

Procedure:
Dry ethanol (600 mL), 91.89 g of guanidine carbonate, and 146.1 g of ethyl acetoacetate were added to a 1 L flask. The reaction solution was gradually heated to reflux temperature and stirred overnight. Ethanol (300 mL) was evaporated, and the reaction mixture was heated under reflux for two hours. After the reaction mixture was cooled, 300 mL of hexane was added. The resulting precipitate was filtered, washed and dried. 119.3 g of 6-methyl-iso cytosine was obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19]/[C:20](=[CH:22]/CO)/[CH3:21])[CH3:16].CO>C1(C)C=CC=CC=1>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH:14]=[C:15]([CH3:16])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:9])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)=CCCC(C)=CCOC(=O)c1ccc(N)cc1
Yield: 12.2 %

Procedure:
Sodium hydride (600 mg, cat. 60% disp in oil) was added to a suspension of methyl 4-aminobenzoate (50 g, 330 mmol), geraniol (51 g, 330 mmol) in PhMe (100 mL). The suspension was heated under reflux for 8 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane:isopropanol (95:5) as eluant to give the crude ester (X) as a pale yellow oil. Recrystallization from methanol gave the ester (11 g, 12%) as needles.
Reaction SMILES: C([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:33])([CH3:32])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:32])([CH3:33])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C@@:36]([OH:41])([C:14]#[C:13][CH:10]2[CH2:12][CH2:11]2)[C:37]([F:38])([F:39])[F:40])[CH:17]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Ethylmagnesium bromide 3M in ether (5.98 mL, 17.95 mmol) was added slowly to a solution of cyclopropyl acetylene (1.19 g, 17.95 mmol) in tetrahydrofuran (18 mL) in an ice-bath under argon and the mixture was stirred at 40° C. for 3 hours. Then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9, 1.45 g, 3.59 mmol) was added in portions while the flask was in an ice-bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate and two layers were separated. The organic layer was evaporated to dryness to give 1.67 g of the compound as a crude oil. It was further crystallized with petroleum ether and ethyl acetate to furnish (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut 3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) as a white or off-white solid. This solid was shown to be 98.8% de by HPLC.