Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[OH-:14].[Na+]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=Cc1ccc(Br)c2cccnc12
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromoquinoline-8-carbaldehyde (10 g, 0.039 mol) in THF (300 ml) was added aqueous NaOH (30 g) and followed by silver nitrate (10.79 g, 0.0635 mol) lot wise at RT for 10 min and this reaction mixture was stirred at RT for 30 min. The reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was filtered. The black solid was wanded with THF, MeOH and DMF (50 ml each). (Note: Product was not soluble in any of these solvents!! The filtrate and washings were discarded). The black solid was dried to afford the title compound (crude −30 g). The crude product was as such taken for the next step. 1H NMR (DMSO-d6, 400 MHz): δ 8.92-8.91 (dd, J=4.12, 5.8 Hz, 1H), 8.49 (s, 1H), 8.46-8.44 (dd, J=8.56, 10.2 Hz, 1H), 7.83-7.81 (dd, J=7.6, Hz, 1H), 7.63-7.6 (dd, J=8.52, 12.68 Hz, 1H), 7.46-7.44 (d, J=7.6 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][N:6]=1.Cl.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)C.NCCCC1C(C)=CC(Br)=CN=1>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCN
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 197.5 %

Procedure:
2-(3-Aminopropyl)-5-bromo-3-methylpyridine (5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (4.45 g) and triethylamine (10 ml) were refluxed together in ethanol (200 ml) for 5.5 hr. A further addition of 2-(3-aminopropyl)-5-bromo-3-methylpyridine (0.5 g) was made and refluxing was continued for a further 2.5 hr. The reaction mixture was then concentrated to dryness giving a yellow oil (13.59 g). The oil was chromatographed on silica in first methanol/chloroform 1:19 increasing the polarity to 1:9. The product was recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (5.11 g), m.p. 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
A solution of 2-chloro-5-fluoro-4-methylbenzoic acid (Preparation 1b, 51.57 g) dissolved in conc sulfuric acid (143 mL) was treated with potassium nitrate (32.4 g) portionwise over 10 min at 0° C. under nitrogen. The resulting mixture was allowed to warm to room temperature before stirring at 50° C. for 1 h. The reaction mixture was quenched with ice water and the precipitate was collected and dried in vacuo to afford the subtitle compound (65.5 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C([O:14][C:15](=O)[C:16](=[CH:19]OCC)[C:17]#[N:18])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[CH:19][C:16]([C:17]#[N:18])=[C:15]2[OH:14])(=[O:3])[CH3:2]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CC(=O)Nc1ccc(N)cn1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2ncc(C#N)c(O)c2n1
Temperature: 257.5 °C

Procedure:
A solution of 2-acetamido-5-aminopyridine (1.6 g, 10.7 mmol) and ethyl(ethoxymethylene)cyanoacetate (3.6 g, 21.3 mmol) in toluene (50 ml) was heated at reflux for 10 hrs under argon. After cooling, the white solid was collected and dried. A solution of this solid in Dowtherm (250 ml) was heated at 255-260° C. for 6 hrs under nitrogen. During this process, ethanol was distilled off. The mixture was heated at 260° C. for an additional 5 hrs. After cooling, the mixture was poured in hexane. The solid was collected, dissolved in a 1:1 mixture of DMF and ethyl acetate, and ether was added to give the title compound as a solid. mass spectrum (electrospray, m/e): 228.7 (M+H); IR cm-1: 2228, 1682.; H-NMR δ (DMSO-d6): 2.182 (3H, s, CH3), 7.96 (1H, s, OH), 8.09 (1H, d, C7-H), 8.49 (1H, d, C8-H), 8.71 (1H, s, C2-H), 11.20 (1H, s, NH).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[C:14]1([C:24](Cl)=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:24]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:25])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 1-naphthoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.29-1.39 (m, 2 H) 1.59-1.69 (m, 2 H) 2.26 (s, 6H) 4.02-4.07 (m, 2 H) 6.30 (s, 1 H) 7.50-7.59 (m, 3 H) 7.68-7.71 (m, 1 H) 7.94-8.01 (m, 2 H) 8.30-8.34 (m, 1 H); MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:7]([NH:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:1]1([C@H:7]([N:11]([C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)[NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C1CCCCC1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H](C1CCCCC1)N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of (R)-3-methoxy-2-methyl-benzoic acid N′-(1-cyclohexyl-but-3-enyl)-hydrazide (1.3 g, 4.11 mmol) in CH2Cl2 (5 mL), was added K2CO3 (2.27 g, 16.44 mmol), H2O (5 mL), and finally 3,5-dimethylbenzoyl chloride (727 mg, 4.31 mmol). The reaction was stirred at room temperature for 24 h. Additional CH2Cl2 and H2O were added to aid manipulation, the CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The CH2Cl2 solutions were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to provide (R)-3,5-dimethyl-benzoic acid N-(1-cyclohexyl-but-3-enyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide as a white solid (1.45 g, 78% yield). Rf=0.21 (3:1 EtOAc:n-Hexane); 1H NMR (400 MHz, DMSO-d6) δ 10.47+10.39 (2s, 1H), 7.20-7.01 (m, 5H), 6.37 (d, J=7.2 Hz, 1H), 6.22-5.89 (m, 1H), 5.18 (dd, 1H), 5.02 (dd, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 2.44-2.34 (m, 2H), 2.29 (s, 3H), 2.02-1.53 (m, 8H), 1.26-1.02 (m, 3H); HRMS (ESI) m/z calcd for C28H37N2O3 [M+H]+ 449.2804. found 449.2793, calcd for C28H36N2NaO3 [M+Na]+ 471.2624. found 471.2615.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].N([O-])=O.[Na+].OS(O)(=O)=O>O.CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[C:7]1[N:10]=[N:11][NH:12][N:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc(I)c1C#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(I)c1-c1nn[nH]n1
Temperature: 100 °C
Yield: 90.2 %

Procedure:
A reaction vessel was charged with DMF (1.225 L), Preparation 21, 4-iodo-1-methyl-1H-pyrazole-5-carbonitrile (175 g, 751 mmol), sodium azide (147 g, 2.25 mol), and ammonium chloride (121 g, 2.25 mol). H2O (525 mL) was added slowly to minimize exotherm. The reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and poured into a mixture of H2O (2 L) and ice (1 kg). An aqueous solution of NaNO2 (600 mL, 120 g NaNO2, 20% by weight) was added followed by the slow addition of aqueous H2SO4 until the pH of the reaction mixture was 1. The precipitate was collected via filtration, washed with H2O and dried in vacuo to afford 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole as a colorless solid (187 g, 90%).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:13](Cl)[N:14]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:13]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccn2)ccc1=O
Yield: 28.1 %

Procedure:
A toluene solution of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (200 mg), 2-(tributylstannyl)pyridine (311 mg), and Pd(PPh3)4 (22.5 mg) was refluxed for 5 hours. Water (20 ml) and EtOAc (15 ml) were poured into the reaction mixture and the aqueous solution was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH (97:3). The eluent was evaporated and the residue was suspended with IPE and filtrated to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2-pyrazinecarboxamide (64 mg) as a yellow powder.
Reaction SMILES: O1CCOCC1.C([Si]([O:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([O:30][CH3:31])[CH:16]=1)(C)C)(C)(C)C.Cl[C:33]1[N:38]=[N:37][C:36]([N:39]([CH3:50])[CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:17]1[CH:16]=[C:15]([OH:14])[CH:20]=[CH:19][C:18]=1[C:33]1[N:38]=[N:37][C:36]([N:39]([CH3:50])[CH:40]2[CH2:45][C:44]([CH3:46])([CH3:47])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)=[CH:35][CH:34]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 72 °C
Yield: 53 %

Procedure:
A 20 L jacketed reactor fitted with a reflux condenser, N2 inlet, thermocouple and overhead stirrer was charged with 2.7 L of dioxane followed by tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (290 g, 557 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 113 g, 398 mmol), and sodium bicarbonate (100 g, 1194 mmol). 700 mL of water was added, followed by addition of Pd(PPh3)4 (27.6 g, 23.88 mmol). The reaction mixture was heated at 72° C. overnight. After cooling to RT, the layers were separated. The organic layer was concentrated, and the reside was purified by silica gel chromatography using 5% MeOH (containing 1% TEA) in DCM to provide the desired product, 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (83 g, 211 mmol, 53% yield). MS=371.4.
Reaction SMILES: [O:1]=[C:2]([C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31]([O:1]/[C:2](/[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[C:17]=1[CH3:23])=[C:3](\[C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=1)/[C:4]#[N:5])=[O:36]
Reactant: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(/C(OC(=O)C(C)(C)C)=C(\C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 7 °C
Reaction time: 20 h
Yield: 73.3 %

Procedure:
In a 10 L-reaction flask, 594 g (1.92 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile and 6000 g of tetrahydrofuran were added, 214 g (2.11 mol) of triethyl amine was added and then 255 g (2.11 mol) of pivaloyl chloride was added dropwise at 25 to 27° C. over 1 hour. After reacting for 20 hours, tetrahydrofuran was removed by concentrating under a reduced pressure, and then 1800 g of toluene and 1800 g of water were added to separate out toluene phase. After distilling out toluene, 794 g of hexane was added and dissolved, and crystallization was carried out by gradually cooling to 7° C. After filtering, the crystal was washed with 1000 g of hexane cooled at 5° C., dried to obtain 554 g (yield 73.4%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl) acrylonitrile.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(I)cc1
Product: COc1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert 4-iodoanisole and thiophenol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (416 mg, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.29 (dt, J=7.72, 2H; Ha, Ha′), 7.13–6.97 (m, 5H; Hc, Hc′, Hd, Hd′, He), 6.77 (d, J=7.54, 2H; Hb, Hb′), 3.67 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 159.74 (C4), 138.54 (C8), 135.29 (C2, C6), 128.85 (C9, C13), 128.08 (C10, C12), 125.66 (C11), 124.17 (C1), 114.90 (C3, C5), 55.23 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.34; H, 5.70; S, 14.81.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:42])[CH2:38][CH2:39][CH:40]=[CH2:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:42])[CH2:38][CH2:39][CH:40]=[CH2:41]
Reactant: C=CCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 100 mg (1 mmole) of 4-pentenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 155 mg (Yield: 42%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]1[O:16][C@@H:15]1[CH2:17][OH:18]>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:18][CH2:17][CH:15]2[CH2:14][O:16]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OC[C@@H]1CO1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Temperature: -20 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
m-Nitrobenzensulfonylchloride (12.6 g; 57 mmol) was added to a cold (−20° C.) solution of (R)-(+)-glycidol (5.5 g; 74 mmol) and TEA (10.3 mL; 74 mmol). The reaction mixture was stirred at −20° C. for 96 h. The solution was filtered and the filtrate washed with tartaric acid (10% w/w), brine, H2O and concentrated giving the title compound in a 97% yield.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=1O)#[N:7]>O1CCOCC1>[Cl:3][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:8]=1[C:6]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Solvent: C1COCCO1
Product: CSc1nc(Cl)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
POCl3 (100 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-hydroxy-pyrimidine (example 9(a), 25.0 g) in dry 1,4-dioxane (300 ml). After 3 h at 90° C., the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (100 ml) and the resulting solution was cooled to 0° C. Ice water was cautiously added. The resulting precipitate was filtered off and washed with water. Residual water in the precipitate was removed by coevaporation with 1,4-dioxane.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([N:23]([CH3:31])[C:24]([CH2:26][CH2:27][C:28]([OH:30])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38]>C1COCC1.O>[CH2:16]([N:23]([CH3:31])[C:24]([CH2:26][CH2:27][C:28]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38])=[O:30])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Triethylamine (4.0 ml) and isobutyl chloroformate (1.86 ml) were added dropwise to a solution of 3-(N-benzyl-N-methylcarbamoyl) propionic acid (2.5 g) in THF (30 ml) cooled to -20° C. The mixture was stirred for 30 mins at the same temperature. Triethylamine (4 ml) was added to a solution of (S)-2-pyrrolidinemethanol (1.45 g) in THF (30 ml). To the solution cooled to -25° C., the above solution was added dropwise. The mixture was stirred for 1 hr at the same temperature. After reaction, water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (2.59 g) having the following physical data:
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(N(CC)CC)C>C(Cl)Cl>[N:25]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:22][CH3:23])=[O:24])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccc(C(=O)NC)cc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1ccc(-c2ccc(C(=O)NC)cc2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(5-(4-(methylcarbamoyl)phenyl)pyridin-2-yl)propyl methanesulfonate (0.02 g, 0.057 mmol), 1H-imidazole (0.008 g, 0.114 mmol) and triethylamine (0.03 mL, 0.114 mmol) in DCM (10 mL) was stirred and refluxed at 50° C. for 3 h. The mixture was then cooled to room temperature, poured out into ice water (50 mL) and extracted with DCM (2×50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under vacuo. The resulting residue was purified by preparative TLC using 5% methanol in dichloromethane and the product isolated as off white solid (0.007 g, 39% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, 1H), 8.46 (d, 1H), 8.12 (d, 1H), 7.91 (d, 2H), 7.80 (d, 3H), 7.39 (d, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 5.37 (t, 1H), 2.78 (d, 3H), 2.27 (m, 2H), 0.89 (t, 3H). LC-MS: m/z 321.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(F)(F)F)cc2)SC[C@H]1OC(C)=O
Yield: 40 %

Procedure:
If the procedure described in Preparation I is followed starting from 5.58 g (32.10-3 mol) of 4-trifluoromethylbenzenethiol, 8.87 g (35.10-3 mol) of mercuric cyanide, Hg(CN)2, and 12.3 g (35.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 6.2 g (yield: 40%) of the expected product are obtained.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)C.[OH-].[Li+].Cl>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:11]2([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[CH2:10][CH2:9][CH:8]([CH2:7][S:6][CH2:5][C:4]([OH:32])=[O:3])[CH2:13][CH2:12]2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CSCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CSCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 772 %

Procedure:
The product from Example 69 (15 mg, 0.003 mmol) was dissolved in methanol (1 mL) and lithium hydroxide (1 mg, 0.015 mmol) added. The reaction was stirred at room temperature overnight, diluted with water, acidified with 2 M aqueous hydrochloric acid and extracted with ethyl acetate (x3). The organic extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with iso-hexane/ethyl acetate (1:1) to give a white solid (11 mg).