Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23]C)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br>C(O)(=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: Br
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Temperature: 80 °C
Yield: 385.9 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-methoxy-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (1.0 g, 2.97 mmol) in acetic acid (40 mL) was treated with 48% aqueous HBr (37.7 mL) and heated at 80° C. for 5 h before being concentrated in vacuo. The resultant residue was suspended in water (60 mL) and pH adjusted to ˜6 using 5N aqueous NaOH. The precipitate formed was filtered off, washed with water then dried in vacuo. The resultant solid was triturated in acetone to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol as a beige solid (3.58 g, 69%). LCMS RT=2.04 min, [M+H]+=313. 1H NMR 400 MHz (DMSO-d) δ: 8.42 (1 H, s), 7.90 (1 H, s), 7.83 (1 H, s), 5.84 (1 H, s), 5.78 (1 H, m), 4.71-4.30 (4 H, m), 1.45 (6 H, d, J=6.60 Hz).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4].[ClH:43].[H][H]>[C].[Pd].CO>[ClH:43].[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(O)c1ccc(O)c(O)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To 130 ml of a methanol solution containing 1.75 g of 1-[3-hydroxy-3-(3,4-dibenzyloxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine is added 1 ml of a methanol solution containing 120 mg of hydrogen chloride, and, 0.2 g of palladium carbon is added thereto. The mixture is vigorously shaked in a hydrogen stream at room temperature. After stirring overnight, the catalyst is removed by filtration and the mother liquor is concentrated under reduced pressure. The resultant oily material is crystallized by adding a small amount of n-butanol. The crystals are collected by filtration, and dried to obtain 1.06 g of the crude crystals. Recrystallization thereof from n-butanol yields 0.8 g of 1-[3-hydroxy-3-(3,4-dihydroxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride having m.p. 187°-189° C.
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]>C(OCC)C>[CH:4]([C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:2]#[N:1])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1ccc(N)cc1
Reactant: N#CBr
Solvent: CCOCC
Product: CC(C)c1ccc(NC#N)cc1
Yield: 83.2 %

Procedure:
A solution of cyanogen bromide (1.59 g, 15 mmol) in diethylether (20) was added dropwise to a solution of 4-isopropylaniline (3.24 g) in diethylether (50 mL) at 4° C. with stirring. After the addition, the reaction mixture was kept stirring at room temperature for 18 h. Then a solution with white precipitates formed and the precipitates were removed by filtration. The etherate solution was washed with aqueous HCl (1N, 30 mL, two times) as well as brine, dried over MgSO4, filtered, concentrated, and dried under vacuum to yield 4-isopropylphenyl cyanamide (2.0 g, 84%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].NN>[Ni].C(O)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CCN(CC)Cc1ccc(N)cc1
Yield: 91.3 %

Procedure:
To a suspension of N-ethyl-N-(4-nitrobenzyl)ethanamine (335 mg, 1.61 mmol) and Raney Ni (50 mg) in refluxing ethanol (10 mL) was added drop-wise anhydrous hydrazine (0.5 mL). After the addition was complete, the mixture was refluxed for an additional 20 minutes and then filtered through a pad of Celite. The Celite bed was washed with ethanol (100 mL) and the combined solution was evaporated under reduced pressure to provide pure 4-((diethylamino)methyl)aniline (262 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=O.N#N>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]1[O:10][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:13]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2F)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.17 h

Procedure:
5-Nitroanthranilic acid (0.6 g) was dissolved in triethyl amine/toluene (1/1) (18 mL) and stirred for 10 min. 2,6-Difluorobenzoylchloride (1.3 g) was slowly added under stirring which resulted in the formation of a precipitate. The reaction was performed in an N2-atmosphere. After stirring at RT for 24 h the mixture was extracted with sat.NaHCO3 and ethyl acetate (20 mL), the organic layer was separated and evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C:16]([CH3:23])([CH3:22])[CH2:15]1.[O:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1.O1C=CC(B(O)O)=C1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:22][C:16]1([CH3:23])[CH2:15][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:26]4[CH:28]=[CH:29][O:24][CH:25]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccoc4)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 26 %

Procedure:
5-Bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (80 mg, 0.20 mmol) was placed in a microwave vial and dissolved with 1,4-dioxane (2 mL) and water (1 ml). 3-Furanylboronic acid (44.8 mg, 0.401 mmol) and K2CO3 (83 mg, 0.60 mmol) were added. Argon was bubbled in the mixture for 10 min with stirring. PdCl2(dppf) (4.83 mg, 0.01 mmol) was added, and argon was bubbled another 10 min. The vial is sealed and heated in a microwave for 5 min at 100° C. on high absorption. The reaction was evaporated to remove most of the dioxane. The residue was partitioned between ethyl acetate and water. The layers were separated, the organic layer was dried (MgSO4), and the solvent was removed under vacuum. The residue was dissolved in the minimum amount of MeOH and EtOAc, and was run through a thiol-SPE cartridge eluting with 2 mL of MeOH. The solvent was removed under vacuum, and the residue was dissolved in 1-2 mL of DMSO, and purified on a Gilson HPLC. The desired fractions were concentrated, giving 22 mg (26%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=O)=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([N:24]2[C:5](=[O:7])[CH2:4][NH:1][C:2]2=[O:3])=[C:22]([CH3:28])[CH:21]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CCOC(=O)CN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C)c1N1C(=O)CNC1=O
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Ethyl isocyanatoacetate (581 mg, 4.50 mmol) and N,N-diisopropylethylamine (426 mg, 1.65 mmol) were added to a solution of 4-bromo-2,6-dimethylaniline (600 mg, 3.00 mmol) in toluene (6 ml) with stirring in a nitrogen stream, and the mixture was heated with stirring at 120° C. After 30 minutes, the reaction solution was brought to room temperature, and the precipitate was collected by filtration, washed with toluene and then dried under reduced pressure. The resulting solid was suspended in toluene (6 ml). DBU (68.4 mg, 2.25 mmol) was added and the mixture was heated with stirring at 120° C. After 30 minutes, the reaction solution was brought to room temperature and diluted with ethyl acetate, and the organic layer was washed with a 1 N aqueous hydrochloric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the magnesium sulfate was then removed by filtration. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane-ethyl acetate) to give 3-(4-bromo-2,6-dimethyl-phenyl)-imidazolidine-2,4-dione (570 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc([N+](=O)[O-])cc4s3)c2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The crude (6,7-dimethoxyquinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine (383 mg, 1 mmol) was dissolved in dimethylformamide (100 mL). Palladium on charcoal (106 mg, 10% Pd, 0.1 mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was vigorously stirred for 5 h at 80° C. and then filtered through Celite. After removal of the solvent in vacuo and subsequent drying, pure N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine was obtained as a tawny powder (202 mg, 0.57 mmol, 57%). LC/ESI-MS: m/z=354 [M+H]+; m/z=352 [M−H]−; Rt=2.15 mm.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=C)=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=[O:35])=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (Preparation 62G, 0.060 g, 0.146 mmol) and a 50% aqueous solution of NMO (0.030 mL, 0.146 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.046 mL, 5.85 μmol). The reaction mixture was stirred at room temperature for 5 h. The intermediate diol had an HPLC ret. time=3.09 min and an LCMS M+1=445.0. Sodium periodate (0.047 g, 0.219 mmol) was added to the homogeneous mixture followed by water (0.10 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole-7-carbaldehyde (0.057 g, 0.138 mmol, 95% yield) as a pale yellow solid. The product had an HPLC ret. time=3.49 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[NH2:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1>[Cu].O>[CH3:23][N:22]1[C:18]([NH:17][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1

Procedure:
To a solution of 4.84 grams of potassium carbonate in 18 ml. of water were added in succession 8.0 grams of o-iodobenzoic acid, 3.88 grams of 5-amino-1,3-dimethyl pyrazole and 0.8 gram of the copper catalyst. The mixture was stirred at reflux for 5 hours. There was then added an additional 50 milliliters of water, the mixture being refluxed an additional 30 minutes and then filtered through diatomaceous earth. The filtrate was digested with decolorizing carbon, heated to reflux and filtered. The filtrate was cooled and acidified with 3N aqueous hydrochloric acid to produce N-(1,3-dimethyl-5-pyrazolyl)anthanilic acid, mp 175°-189° C., recrystallized from ethanol to give needles, mp 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-chloro-4-ethynyl-benzene (240 mg, 1.76 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (106 mg, 0.207 mmol, example 6), Pd(PPh3)4 (23 mg, 0.021 mmol), CuI (11 mg, 0.058 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 120 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 63 mg (54%) yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:32][C:33]1[S:34][C:35]([CH3:38])=[N:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH2:30][S:32][C:33]2[S:34][C:35]([CH3:38])=[N:36][N:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(CBr)nc12
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(CSc3nnc(C)s3)nc12
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of the product from Step A (137 mg, 0.28 mmol), 2-mercapto-5-methyl-1,3,4-thiadiazole (37 mg, 0.28 mmol), and potassium carbonate (77 mg, 0.56 mmol) in DMF (15 mL) was stirred at 50° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was purified using SiO2-gel chromatography using 50% EtOAc/hexanes to yield the desired product as a yellow solid. API-MS: 546 (M+1). 1H NMR (300 MHz, CDCl3): d 7.8 (d, 1 H), 7.4 (t, 1 H), 7.2 (d, 1 H), 4.95 (s, 2 H), 4.1 (t, 2 H), 4.0 (s, 3 H), 2.75 (s, 3 H), 2.8 (t, 3 H), 1.8-1.0 (m), 1.45 (s, 9 H).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[C:21]([CH3:23])[C:8]([CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=[C:7]([CH3:24])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:22]=[C:21]([CH3:23])[C:8]([CH2:9][CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])=[C:7]([CH3:24])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1c(C)cc(C(C)(C)C)c(O)c1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(C(=O)O)C(=O)O

Procedure:
35 grams of the compound of Example 14 was dissolved in 125 ml of methanol together with 12.3 grams of sodium hydroxide dissolved in 50 ml of water and heated at reflux for 6 hours. After removal of most of the methanol by distillation at reduced pressure, 300 ml of water was added and stirred to yield a turbid solution which was clarified by filtration. The clear filtrate was extracted with ether, and the ether extract washed with water and dried over anhydrous sodium sulfate. After removal of the ether by distillation at reduced pressure, the glassy residue was crystallized from 1,2-dichloroethane yielding white crystals melting at 174°.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1([S:9][CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O)C>O.ClCCl>[CH2:10]([S:9][C:6]1([C:3]([CH:4]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[Cl:13])=[O:5])[CH2:8][CH2:7]1)[CH2:11][CH3:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCCSC1(C(C)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.6 %

Procedure:
5 pellets of solid sodium hydroxide are added at room temperature to a mixture of 41.7 g (0.26 mol) of 1-acetyl-1-propylmercapto-cyclopropane, 46 g (0.26 mol) of 2,4-dichlorobenzaldehyde, 130 ml of ethanol and 30 ml of dichloromethane. The mixture is stirred for 14 hours at room temperature. 50 ml of water are added, and the oil phase is separated off and taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated by removing the solvent under reduced pressure. In this manner, 80 g (97% of theory) of 2,4-dichlorophenylethenyl 1-propylmercaptocyclopropyl ketone (cis/trans isomers) are obtained in the form of an oily product.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[S:18](Cl)([C:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:26]([N:27]([CH3:29])[CH3:28])[C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:18]([C:21]1[C:33]2[C:25](=[C:26]([N:27]([CH3:29])[CH3:28])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: C=CC(=O)OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)OCCOS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 56.5 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (25.8 mg, 0.2 mmol) in 2 ml of freshly distilled CH2Cl2 was added diisopropylethylamine (DIPEA, 0.35 ml, 0.2 mmol) dropwise at 0° C. Dansyl chloride (50.0 mg, 0.19 mmol) was then added dropwise, and the resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and extracted (3×20 ml) with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 37.5 mg (56%) of 2-(5-dimethylamino-naphthalene-1-sulfonyloxy)-ethyl acrylate as a yellow semi solid. 1H NMR (250 MHz) δ 8.61 (d, J=8.6 Hz, 1H), 8.26 (t, J=6.3 Hz, 2H), 7.56 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 6.19 (dd, J=16.5, 2.5 Hz, 1H), 5.80 (dd, J=16.5, 10.3 Hz, 1H), 5.71 (dd, J=16.5, 10.3 Hz, 1H), 4.25 (m, 4H), 2.88 (s, 6H). 13C NMR (63 MHz) δ 158.0, 151.7, 131.8, 131.5, 130.9, 130.6, 129.8, 128.8, 127.3, 123.0, 119.4, 115.6, 67.8, 61.5, 45.4.
Reaction SMILES: [N:1]([C@@:4]1(O)[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].Cl.[Cl:21]C1C=CC=C(C(OO)=O)C=1.O>CC(N(C)C)=O>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Cl:21])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [N-]=[N+]=N[C@]1(O)C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 2 h

Procedure:
3'-Azido-2'-deoxyuridine (0.25 g; 1 mMol) was dissolved in 2 mL dry dimethylacetamide (DMAC), cooled to 0° and 2 mL of 0.5M HCl in DMAC was added. m-Chloroperbenzoic acid (0.277 g; 1.6 mMol) was added in two portions over ten minutes and the mixture was allowed to come to ambient temperature. After two hours, 4 mL H2O was added and the solution filtered. The aqueous DMAC solution was extracted with Et2O (3×3 mL) and the Et2O was evaporated in vacuo to an oil which was applied to a silica gel column. Elution with CHCl3 /MeoH (15:1 v/v), combination of appropriate fractions and evaporation in vacuo yielded an oil which was crystallized from Et2O to give 58.5 mg (0.2 mMol, 20%): mp=169°-170° C.; UV (nm): at pH 1 max=276 (=7400), min=239 (=500); at pH 13 max=274 (=6400), min=249 (=3800); H1NMR (DMSO-d6) 8.29 (s, 1H, H6), 6.05 (t,1H,H1', J=5.5 Hz), 5.49-5.29 (m,1H,5'-OH), 4.44-4.20 (m,1H,H3'), 3.88-3.71 (m,1H,H4'), 3.71-3.53 (m,2H,H5'), 2.63-2.31 (m,2H,H2'); analysis calculated for C9H10N5O4Cl:ε37.58, H 3.50, N 24.35, Cl 12.32.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][SH:25].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][S:25][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CN(C)CCS
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CN(C)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
The title compound of Step 10 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromotography on silica gel, eluting with 20:1 CH2Cl2:MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98.