Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[Cl:29][C:15]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:24])[N:7]1[CH2:6][C:5]1[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Yield: 100 %

Procedure:
2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolinone (150 mg, 0.390 mmol.) was reacted with thionyl chloride (0.031 mL, 0.429 mmol.) and a catalytic amount of DMF as for general procedure B, and the solvent removed to give a colourless oil of the crude 3-chloro-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one (157 mg, 0.390 mmol., 100%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1.[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCC(C)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
5.49 g of (+)-2-methylbutanoic acid,8.50 g of 4-hydroxy biphenyl and 20 ml of toluene were charged into a flask and then 4.0 ml (55 mmol) of thionyl chloride was added thereto with stirring. The resulting mixture was maintained at a temperature of 70°~80° C. and reacted for 8 hours. After the completion of the reaction, the resulting product was cooled to room temperature, added with water to decompose the excess amount of thionyl chloride, washed with water and dried on anhydrous magnesium sulfate. After the removal of solvent, it was purified by a column chromatography of silica gel to obtain 12.69 g of (+)-2-methylbutanoic acid biphenyl having an oily specific rotation [α]25 (16.46 wt% in chloroform) of +15.1°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH:21]=1
Reactant: Nc1cccnc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cncc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 90 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.565 g (6 mmol) 3-aminopyridine is heated for 3 h at 90° C. The residue is then distributed between acetate and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (49:1 to 4:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV (6 h, 80° C.); m.p. 137-139° C.; ESI-MS: (M+H)+=314.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[NH:8][C:7](=[O:9])[CH2:6][C:5]1=[O:10].Br[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>Cl[Pd]Cl.C(Cl)Cl.CN1CCCC1=O.O>[CH3:3][C:4]1([CH3:11])[NH:8][C:7](=[O:9])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:5]1=[O:10]
Reactant: CC1(C)NC(=O)CC1=O
Reactant: Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C2C(=O)NC(C)(C)C2=O)c1
Temperature: 125 °C
Yield: 84 %

Procedure:
Under argon, in a heat-dried apparatus, 1.0 g of solid sodium hydroxide (in the form of so-called “Micropills”) and 15 ml of water- and air-free N-methylpyrrolidone (NMP) are introduced as initial charge. With stirring, 1.907 g of 5,5-dimethylpyrrolidine-2,4-dione are then added and the mixture is stirred for 20 minutes at room temperature. 1.71 g of 3-bromotoluene are then added and the reaction mixture is heated to 125° C. At this temperature, 0.328 g of triphenylphosphine and 89 mg of PdCl2 are then added. The mixture is stirred for 4 hours at 125° C., left to cool to room temperature, stirred into 20 ml of ice-water and adjusted to pH 2 using dilute hydrochloric acid. 20 ml of methylene chloride are added, the mixture is stirred, the phases are separated and the aqueous phase is extracted by shaking two more times with 10 ml of methylene chloride in each case. The combined organic phases are dried and then concentrated on a rotary evaporator. This gives 1.82 g of target product (corresponding to a yield of 84% of theory).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCCC2)cc1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (15 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 1.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 4-methoxybenzenesulphonyl chloride (2.95 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the organic phase was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (2.771 g, 79%) as an oil. H1-NMR (chloroform-D3): 1.61 (m, 8H), 3.87 (s, 3H), 4.57 (m, 1H), 6.67 (s, 1H), 6.99 (m, 2H), 7.83 (m, 2H). MS(ESI): 294 (M+Na).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][Br:16])=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc2ccc(C)cc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Yield: 64.1 %

Procedure:
Compound 20 (0.265 g, 1.32 mmol) was diluted in anhydrous benzene (10 mL). N-Bromosuccinimide (0.247 g, 1.39 mmol) and a catalytic amount (0.020 g) of benzoyl peroxide were added, and the mixture was heated to reflux under argon until an orange tint was no longer visible in the solution refluxing in the condenser (typically 4 h). The mixture was cooled, concentrated, and purified by flash column chromatography (SiO2), eluting with a gradient of 7% to 14% EtOAc in CH2Cl2, to yield the product (0.236 g, 64%) as a flocculent yellow solid. 1H NMR chemical shifts for this compound are consistent with those reported in the literature for the 7-isomer. 1H-NMR (500 MHz; CDCl3): δ 8.43-8.41 (m, 2 H), 8.16 (d, J=8.9 Hz, 1 H), 7.79-7.77 (m, 2 H), 7.49 (dd, J=8.4, 1.7 Hz, 1 H), 4.65 (s, 2 H), 2.27 (s, 3 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20](Br)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(Br)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (5.95 g, 58.9 mmol) was added to a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate (Step D, 2.47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for 4 hours at room temperature, the reaction mixture was filtered through a pad of silica gel few times, and concentrated to give the title compound.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:13](OC)([CH3:15])[CH3:14]>CC(C)=O.[Cu](Cl)Cl>[CH3:14][C:13]1([CH3:15])[O:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: C[C@H](C(=O)O)[C@@H](O)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of (2R,3S)-2-hydroxy-3-methylsuccinic acid (2.48 g; 16.8 mmol; 1.0 eq.) in acetone (80.0 mL) was added 2,2-dimethoxypropane (4.13 g; 33.6 mmol; 2.0 eq.) and copper(II) chloride (226 mg; 1.68 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (mixture of diatereoisomers) as a greenish oil (1.85 g, 59%) used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Brc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c(Br)cccc32)nc(N2CCOCC2)cc1=O
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 352 mg of 4-bromoindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 201 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 161 mg of 2-[2-(4-bromo-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-acetylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 26.9, 28.9, 32.0, 42.6, 60.5, 127.0, 127.3, 127.9, 128.9, 136.4, 140.2, 142.5, 142.9 and 197.6.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N-:15]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[NH4+].[OH-]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[NH:15][C:7]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1coc2c1C(=O)CCC2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1coc2c1NC(=O)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a mixture of 1.0 g of methyl 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylate and 502 mg of sodium azide in 5 ml of chloroform is added dropwise at 32°-36° C. under argon 1.4 ml of sulfuric acid. The reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with 14 ml of water and rendered alkaline with NH4OH and extracted with chloroform. The separated organic layer is washed with water, brine and dried with Na2SO4 and concentrated in vacuo to give 1.0 g of the desired product as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (58 mg, 0.13 mmol; see step (e)) in dioxane (2.0 mL) was added imidazole (22 mg, 0.33 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound in 68% yield as a colourless syrup (38.4 mg, 0.088 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[O:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(OCCCCl)cc1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1ccc(OCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure G and Scheme B1 using 4-(3-chloropropoxy)-1,2-dimethylbenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[CH2:47]([S:54](Cl)(=[O:56])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][S:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:56])=[O:55])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cc1ccccc1)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (80 mg, 0.153 mmol) in dichloromethane (4 mL) was added pyridine (24 μL, 0.307 mmol) followed by benzylsulfonyl chloride (32 mg, 0.169 mmol). The mixture was stirred at room temperature for 16 h and concentrated. The solvent was removed under reduced pressure and the crude was dissolved in methanol (4 mL) and acetic acid (1 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 5% MeOH/dichloromethane as an eluent at afford the desired product as a yellowish solid (52 mg, 0.120 mmol, 79%). 1H NMR: 3.16 (t, 2H, J=63.4 Hz), 4.28 (t, 2H, J=6.4 Hz), 4.36 (s, 2H), 6.92 (t, 1H, J=6.8 Hz), 7.02 (s, 1H), 7.11 (d, 3H, J=7.2 Hz), 7.19 (s, 2H), 7.28-7.31 (m, 5H), 7.41 (s, 1H), 7.62 (s, 1H), 8.04 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12.2 g (74%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ=12.35 (br.s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH+].
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:12]1
Reactant: O=C1CCC(=O)O1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Succinic anhydride (2.27 g, 22.7 mmol) was added in portions to a hot solution of tryptamine (3.30 g, 20.6 mmol) and potassium acetate (2.23 g, 22.7 mmol) in acetic acid (10 ml). The reaction solution was heated at the boiling point for 3 h and subsequently stirred at RT overnight and the precipitate which had precipitated out was filtered off and washed with acetic acid and EtOH. Yield: 3.00 g (Ind-61, 60%)
Reaction SMILES: COC([S:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][NH:11][C:10]1=[O:20])=O.O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26]>CO>[O:20]=[C:10]1[N:9]([CH2:8][CH2:7][CH2:6][S:5][S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH2:23])[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][NH:11]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: COC(=O)SCCCN1C(=O)NCC1c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@@H](CSSCCCN1C(=O)NCC1c1ccccc1)C(=O)O

Procedure:
A solution of 3.3 g of methyl-[3-(2-oxo-4-phenyl-3-imidazolidinyl)propylthio]formate and 1.8 g of L-cysteine hydrochloride hydrate in 80 ml of methanol is refluxed under nitrogen for three hours. The solvent is removed in vacuo and the residue triturated with ether yielding a hygroscopic solid. The product is further purified by conversion to its 4-methyl benzene sulfonic acid salt, m.p. 172°-178° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[C:12]([C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[N+]([O-])=O)(=[O:14])[CH3:13].Cl>C1COCC1.C(OCC)(=O)C>[C:12]([C:15]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]([CH2:27][CH3:28])[C:17](=[O:29])[C:16]=1[NH:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2c(Cl)cncc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a stirred suspension of 50 mg (1.25 mmol) of sodium hydride in 5 ml of THF, 100 mg (0.62 mmol) of 4-amino-3,5-dichloropyridine in 5 ml of THF was added. The mixture was allowed stirring 30 minutes at room temperature and then cooled to 0° C. 150 mg (0.52 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 10 ml of THF was added. The reaction was allowed to warm to room temperature and to continue stirring for 12 hours. The mixture was acidified with 2N HCl to pH 2. Ethyl acetate was added and the organic layer was washed with water, brine, dried over Na2SO4 anhydride and evaporated. The residue obtained (210 mg) was purified by column chromatography (silica gel, hexane/ethyl acetate 1:1) to yield the title compound (35 mg, 16.7% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]([OH:48])CO)[C@@H:21]1[OH:49])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]=[O:48])[C@@H:21]1[OH:49])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC(O)CO)[C@@H]1O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC=O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
5′-O-tert-butyldiphenylsilyl-N6-benzoyl-2′-O-(2,3-dihydroxypropyl)-adenosine (5.59 g, 8.17 mmol) was dissolved in dry CH2Cl2 (40.42 mL). To this NaIO4 adsorbed on silica gel (Ref. J. Org. Chem. 1997, 62, 2622-2624) (16.34 g, 2 g/mmol) was added and stirred at ambient temperature for 30 minutes. Reaction monitored by TLC (5% MeOH in CH2Cl2). Reaction mixture was filtered and the filtrate washed thoroughly with CH2Cl2. Dichloromethane layer evaporated to get the title compound (5.60 g) that was used in the next step without purification. Rf 0.3 (5% MeOH in CH2Cl2).