Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:26])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)[CH:9]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[N:11]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Yield: 93.7 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate hydrochloride (0.250 g, 0.5 mmol), cyclopropane carbonyl chloride (0.108 g, 1.0 mmol), DIPEA (2.0 mL), THF (10 mL) to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 2H), 1.60 (m, 2H), 3.14 (m, 1H), 3.87 (s, 3H), 4.33 (d, J=5.7 Hz, 2H), 7.41-7.61 (m, 4H), 8.11-8.17 (m, 3H), 8.69 (m, 1H), 12.65 (br s, 1H); MS (m/z): 427.14 (M+H)+.
Reaction SMILES: [Mg].[C:2]([CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])(=[O:4])[CH3:3].[N+:11]([C:14]1C=[CH:21][CH:20]=[CH:19][C:15]=1C(Cl)=O)([O-:13])=[O:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(O)C>[N+:11]([C:14]1[CH:15]=[CH:19][CH:20]=[CH:21][C:3]=1[C:2]([CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])=[O:4])([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)C1CCOC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCCC1C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 16.2 g of magnesium turnings, 67.5 g of anhydrous ethanol and 5 ml of carbon tetrachloride was allowed to react on standing for several minutes. After the exothermic reaction had subsided, 500 ml of anhydrous toluene was slowly added under stirring, and the resulting mixture was stirred at 35°-40° C for an additional 2 hours. To the resulting mixture, a solution of α-acetyl-γ-butyro lactone (170.8 g) in anhydrous toluene (200 ml) was added thereto dropwise under cooling below 10° C, and the resultant mixture was stirred at room temperature for 1 hour. A solution of o-nitrobenzoyl chloride, prepared from 100 g of the corresponding acid, in anhydrous toluene (200 ml) was added thereto dropwise at 20°-25° C, and stirring was carried out for an additional 2 hours. Under cooling, 1.4 liters of 5% sulfuric acid was slowly added to the resulting mixture, and the whole was extracted with ethyl acetate (900 ml). The aqueous layer was extracted with two portions of toluene-ethyl acetate (1:1), and the combined extracts were washed with water and aqueous saturated sodium chloride solution and extracted with three portions of cold 5% aqueous ammonium hydroxide solution (840 g × 3). The combined aqueous layer was washed with toluene and acidified with 25% sulfuric acid under cooling. The precipitated crystals were collected by filtration, washed with water and dried to give 120 g (85%) of α-(2-nitrobenzoyl)-γ-butyrolactone. M.P. 75°-76° C.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]>ClCCl>[CH2:5]([C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:14][CH2:15]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OC)cc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 2.6 g of boron tribromide in 50 ml of absolute dichloromethane was treated dropwise at 0° C. with a solution of 2.0 g of 2-(trans-4-pentylcyclohexyl)-1-(4-methoxyphenyl)ethane in 50 ml of absolute dichloromethane. The mixture was stirred for 1 hour and then poured into ice-water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from hexane at 0° C. gave 1.8 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol of m.p. 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[CH:14][C:13]([OH:19])=[CH:12][C:11]=3[OH:10])=[N:21][NH:22][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)ccc12
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2n[nH]cc2-c2ccc(Br)cc2)c(O)c1

Procedure:
This compounds was synthesised in the same manner as described in the preceding experiment. 3-(4-Bromo-phenyl)-7-hydroxy-chromen-4-one (0.1 g, 0.3 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was washed in hot ether to give 4-[4-(4-Bromo-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.069, 60.6%); Rf 0.44 Cf SM 0.79 ethyl acetate/hexane (75/25).
Reaction SMILES: [N:1]([CH:4]1[C:11](=[O:12])[N:10]2[CH:5]1[CH2:6][CH2:7]OC2(C)C)=[N+:2]=[N-:3].O=C1N2C(CCOC2(C)C)C1.[Si:26](N1C(C=C)CC1=O)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[Si:26]([N:10]1[CH:5]([CH:6]=[CH2:7])[CH:4]([N:1]=[N+:2]=[N-:3])[C:11]1=[O:12])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Reactant: C=CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC1(C)OCCC2CC(=O)N21
Product: C=CC1C(N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Following the procedure described for the preparation of 7-azido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 5, Step A) and using 1-(t-butyldimethylsilyl)-4-vinyl-2-azetidinone there is obtained 1-(t-butyldimethylsilyl)-3-azido-4-vinyl-2-azetidinone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.[CH3:12][C:13]1(C)[O:20]C(=O)[CH2:17][C:15](=O)[O:14]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:11]=[C:9]([CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:12][C:13]([O:14][CH2:15][CH3:17])=[O:20]
Reactant: O=C(O)CCc1cccnc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCc1cccnc1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a mixture of 3-(3-pyridyl)propionic acid (13.6 g, 0.09 mol), Meldrum's acid (13.0 g, 0.09 mol) and dimethylaminopyridine (11 g, 0.09 mol) was added 1,3-dicyclohexylcarbodiimide (18.54 g, 0.09 mol) and DCM (140 ml). The reaction was stirred for 4 h, filtered, concentrated, diluted with 200 ml ethanol and 25 ml 4M HCl/dioxane. The mixture was warmed to reflux 2 h, concentrated, combined with excess sodium carbonate, followed by 50% sodium hydroxide, then triturated with ethyl acetate, filtered, dried (Na2SO4), filtered, then concentrated to give A as an amber oil (19.8 g, 100%). LCMS m/z 222 (MH+)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:28][C:26]1[O:27][C:23]2[CH:22]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:30]=[CH:29][C:24]=2[N:25]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ccc(N)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)oc3c2)cc1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (163 mg, 0.744 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (105 mg, 0.709 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (164 mg, 70%), single spot at Rf 0.49 (60:40 hexane:ethyl acetate). mp 101.7-102.3° C., HPLC purity 99% (tR 2.02 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.61 (2H, m), 7.43 (1H, d, J=8.4 Hz), 7.37 (1H, d, J=1.8 Hz), 7.19 (2H, m), 6.83 (2H, m), 2.57 (5H, m), 1.58 (2H, sextet, J=7.3 Hz), 0.88 (3H, t, J=7.3 Hz). LCMS: 329.21 (M−). FAB-MS (MH+, C17H18N2O3S): calcd 331.1116, found 331.1107.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH3:29])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Yield: 45.6 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to give the title compound as a white solid (0.055 g); mass spectrum (m/e): 365.07 (M+H)
Reaction SMILES: C(S)[C@@H:2]([OH:7])[C@H:3](O)[CH2:4]S.[CH2:9]([C:17]1[C:18]([NH:20][C:21](=O)[CH:22]=1)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13]CCC>CS(C)=O>[CH2:21]([N:20]1[C:18](=[O:19])[CH:4]=[CH:3][C:2]1=[O:7])[CH2:22][CH2:17][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC1=CC(=O)NC1=O
Reactant: O[C@H](CS)[C@H](O)CS
Solvent: CS(C)=O
Product: CCCCCCCCN1C(=O)C=CC1=O

Procedure:
For a vehicle control, combine a solution of vehicle (5 mM NaPO4 pH 5.5, 150 mM NaCl, 0.5 mM DTT) with PBS (Gibco product #20012-027, pH 7.2) in a 1:10 ratio. Add 1/400 vol. of 20 mM Octylmaleimide in DMSO and a 1/400 vol. of DMSO to give a final concentration of 50 μM N-octylmaleimide and 0.5% DMSO. Finally, add 1:1000 vol. of 0.35 M DTT.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[C:10]([C:12]3[S:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[C:14](=[O:22])[N:13]=3)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-n2cccn2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-n3cccn3)n2)sc2ccccc12
Yield: 66.9 %

Procedure:
6-(Pyrazol-1-yl)-2-pyridinecarbonitrile (0.68 g, 4.0 mmol) and methyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (5 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.82 g, 67%) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C(O)(=O)C(O)=[O:21]>O1CCOCC1>[OH:21][C:11]1([CH:12]=[CH:13][CH:14]=[CH:15][CH2:16]1)[CH2:10][C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1
Reactant: O=Cc1ccccc1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC1=C(O)C(=O)C(C)(CC2(O)C=CC=CC2)O1
Yield: 205.8 %

Procedure:
A mixture of 5 g of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone and 10.6 g of benzaldehyde was added to a mixture of 20 ml of water, 20 ml of dioxan and 0.5 g of oxalic acid. The mixture was then refluxed for 4 hours, cooled and extracted with chloroform. The chloroform extract was evaporated and the residue purified by column chromatography over polyamide using ether - light petroleum 50/50 as the eluent; 2.7 g (30% yield) of the title compound was obtained which was recrystallized from chloroform, m.p. = 122°-124°C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[C@@H:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 62.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b obtained from step 2 of Example 8 as starting materials to obtain (S,Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 38 (49 mg, yield 62.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[NH:18][N:17]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1nccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2nccs2)[nH]n1
Yield: 33.2 %

Procedure:
A mixture of 2,4-diketo-4-(thiazol-2-yl)butyric acid ethyl ester (9.88 g), hydrazine hydrate (1.74 g), and ethanol (25 ml) was refluxed for one hour, concentrated and the residue chromatographed (silica gel, EtOAc/Hex 1/2) to afford 2.58 g of 5-(thiazol-2-yl)pyrazole-3-carboxylic acid ethyl ester. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 7.37 (s, 1H, 4-pyrazolyl H), 7.40, 7.75 (2d, 2H, thiazolyl H's).
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14](N)[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].C[N:40](C=O)C>>[NH2:40][C:15]1[N:16]=[CH:17][N:18]=[C:19]2[C:14]=1[N:13]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:20]2[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)NCCCBr
Reactant: Nc1nc(Sc2cc3c(cc2I)OCO3)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)C(=O)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio-9H-purin-6-amine (74 mg, 0.18 mmol) in DMF (2 mL) was added N-(3-bromopropyl)pivalamide (80 mg, 0.36 mmol) and Cs2CO3 (117 mg, 0.36 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS45 as a white solid (18 mg, 18%). 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.45 (br s, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 5.93 (s, 2H), 5.69 (br s, 2H), 4.20 (t, J=6.1 Hz, 2H), 3.00 (m, 2H), 1.80 (m, 2H), 1.21 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C20H24IN6O3S, 555.0675. found 555.0681.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:8]2[OH:20].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[C:8]2[O:20][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: COc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Reactant: ClCCN1CCOCC1
Product: COc1cccc2c(OCCN3CCOCC3)c(-c3ccccc3)c(=O)oc12
Yield: 76 %

Procedure:
As in Example 8, 45.6 g. (0.17 mol) of 8-methoxy-4-hydroxy-3-phenyl-coumarin are treated with 30.5 g. (0.20 mol) of 2-morpholino-1-chlorethane. After evaporation of the chloroform and recrystallisation from isopropanol, 48 g. of a beige-coloured solid are obtained. M.P. 90°-91° C.; yield 76% (theoretical yield 63 g.).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=3)[CH:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[CH2:23]([O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1)[CH:21]=[CH:20]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
4-(6-Benzyloxy-2-naphthyloxy)benzoic acid ethyl ester (10.6 g, 26.2 mmol) was dissolved in a 2:1 mixture of THF and methanol (150 ml), added with 4N lithium hydroxide (33 ml) and stirred at room temperature. After completing the reaction, the reaction liquid was adjusted to pH 2 or thereabout with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated to obtain the subject compound (8.70 g, 23.4 mmol). The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2[C:29]([O:31]C(C)(C)C)=[O:30])[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][C:15]=2[C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
Trifluoroacetic acid (2.63 mL, 34.29 mmol) was added to tert-butyl 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate #94) (1.38 g, 3.43 mmol) in CH2Cl2 (25 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (1.180 g, 99%) as a white to crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][NH:3]1.C(O[CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)(C)(C)C>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[N:3]1[C:2](=[O:1])[N:7]([CH:16]2[CH2:17][CH2:18][CH2:14][O:15]2)[C:6](=[O:8])[CH:5]=[N:4]1
Reactant: CC(C)(C)OC1CCCO1
Reactant: O=c1cn[nH]c(=O)[nH]1
Solvent: CN(C)C=O
Product: O=c1cnn(C2CCCO2)c(=O)n1C1CCCO1
Reaction time: 5 h
Yield: 12 %

Procedure:
3,5-Dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (1 g) and 2-t-butoxytetrahydrofuran (1.9 g) are dissolved in dimethylformamide (3 ml), and the mixture is stirred at 160°-165° C. for 5 hours. The dimethylformamide is removed in vacuo from the reaction mixture to give the residue. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 2,4-bis(tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 85) (yield, 0.2 g; 12%), the second gives 3,5-dioxo-4-(tetrahydro-2-furanyl)-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 86) (yield, 0.6 g; 36%) and the third gives 2-(tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 101) (yield, 0.4 g; 24%). Compound Nos. 85 and 86 melt at 67°-68° C. and 87° C., respectively.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:16])[C:12]=1[CH:13]1[CH2:15][CH2:14]1>CN(C)C=O>[CH:13]1([C:12]2[C:7]([C:4]#[N:5])=[CH:8][N:9]=[CH:10][C:11]=2[F:16])[CH2:15][CH2:14]1
Reactant: N#C[Cu]C#N
Reactant: Fc1cncc(Br)c1C1CC1
Solvent: CN(C)C=O
Product: N#Cc1cncc(F)c1C1CC1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
Copper cyanide (0.829 g, 0.00925 mol) was added at RT to a sealed tube containing 3-bromo-4-cyclopropyl-5-fluoro-pyridine (B; 1 g, 0.00462 mol) in dimethylformamide (20 mL). The reaction mixture was heated to 150° C. for 18 hr, then cooled to RT, quenched with 20% aqueous ammonia (20 mL) solution, and stirred for 5 min. It was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulphate to afford 4-cyclopropyl-5-fluoronicotinonitrile. MS (M+1): 163.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5](Cl)[N:6]=[C:7]2[O:12][CH3:13].[CH3:15][O-:16].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:16][CH3:15])[N:6]=[C:7]2[O:12][CH3:13]
Reactant: C[O-]
Reactant: COc1nc(Cl)cc2c(Br)cccc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Br)cccc2c(OC)n1
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-3-chloro-1-methoxyisoquinoline (420 mg, 1.54 mmol) in DMSO (4.0 mL) was added NaOMe (0.5 M in MeOH, 4.0 mL, 2.0 mmol). The solution was heated at 90° C. for 1.5 hours in a microwave reactor. The mixture was poured into water then extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 15% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H); 7.18 (t, J=8.0 Hz, 1H), 6.85 (s, 11-1), 4.18 (s, 3H), 4.05 (s, 3H). LC6: 3.67 min, (M+H): 268.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Cl:9].[H][H]>CO>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: [H][H]
Reactant: COC(=O)CC(=O)CCCCl
Solvent: CO
Product: COC(=O)CC(O)CCCCl
Yield: 44 %

Procedure:
A 214.9 g portion of the above-mentioned crude 6-chloro-3-oxo-hexanoic acid methyl ester (1), Ru2Cl4-[(S)-Segphos]2(NEt)3 (60.7 mg, 0.0725×10−3 mol) and methanol (130 ml) were put into a 500 ml capacity autoclave and stirred with hydrogen (3 MPa) at 65 to 70° C. for 6 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure using an evaporator, and then the residue was distilled under a reduced pressure (75 to 85° C./0.1 ton) to obtain 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 178.2 g {GC purity; 80.1%, pure amount; 142.7 g (0.790 mol, yield 44%/4-chlorobutanoic acid chloride)}.