Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 1-amino-1,4-dihydro-2,3-quinoxalinedione (53 mg, 0.30 mMol) and pyridine (1 mL, fresh distilled from KOH before use) and acetic anhydride (1 mL, Aldrich) was stirred under nitrogen at 60° C. for 4 hrs. The reaction mixture became a clear solution. All of solvent and reagent were then evaporated under reduced pressure and washed with benzene:cyclohexane=1:1(2×2 mL); ether (2×2 mL), dried at 60° C. with rotavapor for 2 h, affording 57 mg (86%) of pure 1-acetamido-1,4-dihydro-2,3-quinoxalinedione as a white powder; mp: 211°-213° C. IR (KBr, cm-1): 3430; 3127; 1741; 1717; 1668. NMR (1H, DMSO-d6) δ 2.326 (s, 3H); 7.121-7.287 (m, 4H); 12.345 (s, 1H). Mass:calcd for C10H9N3O3 (M+) m/z:219.0641; found: 219.0651.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3].[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: CC(C)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaBH3CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCO3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5% MeOH in DCM as eluent to collect tert-butyl 2-isopropylhydrazinecarboxylate 3 (0.4 g, 77% yield): mp=47-49° C.; Rf=0.44 (5% MeOH in DCM); 1H NMR 300 MHz (CDCl3) d 6.03 (s, N—H, 1H), 3.92 (s, N—H, 1H), 3.14 (m, 1H), 1.46 (s, 9H), 1.02 (d, 6H, J=6 Hz); 13C NMR 300 MHz (CDCl3) d 157.2, 80.8, 51.2, 28.7, 21.0.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][C:9]([CH3:21])=[C:8]([CH3:22])[C:7]=3[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][CH2:31][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][C:9]([CH3:21])=[C:8]([CH3:22])[C:7]=4[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cc(C)c(C)c2c1Cc1sc(S)nc1-2
Product: Cc1cc(OCC(=O)O)c2c(c1C)-c1nc(SCCC(c3ccccc3)c3ccccc3)sc1C2
Yield: 53 %

Procedure:
Using ethyl [(2-mercapto-4,5-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 53%.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17]>>[CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:14]([CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:16][OH:17])[CH2:13][CH3:12]
Reactant: CCCCC=O
Solvent: CCCCCCCCCCO
Product: CCCCCC(CO)CCC

Procedure:
The C5 aldehyde mixture thus obtained can be converted, for example by aldol condensation and subsequent hydrogenation of the aldol condensate, to a decanol mixture. In the case of C5 aldehyde mixtures in which the proportion of n-valeraldehyde is less than 95%, it is advisable to remove a proportion of the 2-methylbutanal by distillation in order to obtain a high-quality decanol mixture with a content of 2-propylheptanol of more than 90%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:8][C:9]([N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
Cbz-Cl (0.393 ml, 2.8 mol, 1.2 eq.) was added to a mixture of tert-butyl 4-(methylamino)-piperidine-1-carboxylate (500 mg, 2.336 mmol, 1.0 eq.) and K2CO3 (616 mg, 4.67 mmol, 2.0 eq.) in DCM (6 ml), and the mixture was stirred for 14 hours at RT. The reaction mixture was diluted with DCM (100 ml), washed with water and sat. NaCl solution (in each case 40 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 15% ethyl acetate in hexane). Yield: 49% (400 mg, 1.149 mmol)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH2:27][CH2:28][O:29]C)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH2:27][CH2:28][OH:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCCO)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To stirred solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 44, 90 mg, 0.21 mmol) in dry dichloromethane (10 mL) was added a solution of boron tribromide (0.67 mL, 6.95 mmol) in dry dichloromethane (5 mL) at −78° C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was poured into ice-water, neutralized with a 2.5 M aqueous sodium hydroxide solution (pH ˜6) and then extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propan-1-ol (20 mg, 23%) as a white solid: LC/MS m/e calcd for C24H30N2O3S [M+H]+ 427.58, observed 427.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.35 (s, 1H), 8.14 (br. s., 1H), 7.90-7.95 (m, J=8.1 Hz, 2H), 7.60-7.65 (m, J=8.3 Hz, 2H), 6.67-6.72 (m, 1H), 4.37-4.46 (m, 1H), 3.62 (t, J=6.2 Hz, 2H), 3.11 (s, 3H), 2.92 (t, J=7.7 Hz, 2H), 2.26-2.35 (m, 1H), 2.14-2.23 (m, 1H), 1.83-1.96 (m, 3H), 1.64-1.81 (m, 4H), 1.47-1.58 (m, 2H), 1.20-1.33 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[CH2:13]([O:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCCc2ccc3occc3c2)cc1

Procedure:
The title compound is prepared by benzylation of 5-(2-hydroxyethyl)benzo[b]furan with benzyl bromide in the presence of sodium hydride.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].[CH3:9][C:10]([CH3:12])=O>CO.[Pd]>[CH:10]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7])([CH3:12])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCC[C@H]1C(=O)O
Reaction time: 9 h
Yield: 101.8 %

Procedure:
A suspension of (S)-pyrrolidine-2-carboxylic acid (5 g, 50 mmol), acetone (5.52 mL, 50 mmol) and 10% Pd/C (2.5 g) in methanol (100 mL) was stirred under hydrogen atmosphere for 6 to 12 hours. The reaction mixture was filtered on a pad of celite and the filtrate was concentrated. The residue obtained was filtered through a column of silica gel to afford (S)-1-isopropylpyrrolidine-2-carboxylic acid (8.0 g, 94%) as a colorless solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>ClC(Cl)C>[CH3:5][CH:6]([CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:12][CH:13]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Under ice cooling, 24.86 g of anhydrous aluminum chloride was added to a dichloroethane suspension (250 ml) containing 12.83 g of [2-methyl-4-phthalimidobutyl]benzene and 9.29 g of succinic anhydride, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate-hexane to obtain 16.11 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:23])[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].I[CH2:25][CH3:26]>O1CCCC1>[C:3]([O:7][C:8](=[O:23])[N:9]([CH2:25][CH3:26])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a suspension of sodium hydride (477 mg, 18.88 mmol) (Aldrich, 95%) in tetrahydrofuran (25 mL) was added a solution of [3-(4-nitrophenoxy)propyl]-carbamic acid tert-butyl ester (3.0 g, 10.13 mmol) (from Example 64, Step A) in tetrahydrofuran (15 mL) at 0° C. Upon addition, the mixture was allowed to stir at room temperature for 30 minute, treated with iodoethane (3.76 g, 24.25 mmol) (Aldrich), and heated at 55° C. for one hour before it was quenched with aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL) and the combined organic extracts were washed with brine and dried (Na2SO4) and evaporated in vacuo. The residue was purified on silica gel with 75:25 hexane/ethyl acetate to give ethyl-[3-(4-nitrophenoxy) propyl]carbamic acid tert-butyl ester (3.15 g, 96%). MS (ES) MH+=325.
Reaction SMILES: [CH:1]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[C:13]([F:31])[CH:12]=2)[CH:7]=[N:6]1)([CH2:3][CH3:4])[CH3:2].Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH:1]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[C:13]([F:31])[CH:12]=2)[CH:7]=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(F)c2)c1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)c(F)c2)c1=O
Temperature: 120 °C
Yield: 84.5 %

Procedure:
Triazolone 8 (0.1 g, 0.23 mmol) was added to aqueous HBr (48%, 1.9 mL). The reaction was heated to 120° C. and refluxed overnight. The reaction mixture was cooled to room temperature and the solution was neutralized with saturated Na2CO3 and extracted with dichloromethane (DCM). The combined organic layer was dried (Na2SO4), filtered, and concentrated to yield the product, which was purified by column chromatography to obtain compound 9 (0.08 g, 83%). 1H NMR (400 MHz, CDCl3, δH): 7.57 (s, 1H), 7.24 (dd, J=10.2, 2.0 Hz, 1H), 7.15 (dd, J=6.8, 1.6 Hz, 1H), 6.92 (t, J=7.0 Hz, 1H), 6.79 (d, J=6.8 Hz, 2H), 6.67 (d, J=7.2 Hz, 2H), 4.24-4.20 (m, 1H), 3.17-3.16 (m, 8H), 1.82-1.77 (m, 1H), 1.66-1.63 (m, 1H), 1.32 (d, J=5.6 Hz, 3H), 0.82 (t, J=5.8 Hz, 3H). 13C NMR (100 MHz, CDCl3, δC): 156.3, 154.3, 150.8, 144.9, 139.7, 133.6, 127.8, 119.4, 118.9, 116.0, 111.4, 53.1, 51.2, 50.5, 28.4, 19.3, 10.8.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]2[NH:1][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=N[C@@H]1Cc1ccccc1
Reaction time: 120 h

Procedure:
The procedure of Example 1 was carried out using 2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol), Boc-D-Phenylalanine (2.65 gm, 0.01 mol), and DCC (10 ml of 1.0M solution in CH2Cl2) in CH2Cl2 (10 ml). After filtration and evaporation, the crude solid was deprotected and cyclized by the procedure of Example 2. After stirring 5 days, the mixture was evaporated in vacuo, treated with H2O (50 ml), and extracted with EtoAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo. Chromatography on silica gel eluted with 7.5% (v/v) Et2O in CH2Cl2 gave a white foam which was crystallized from Et2O. The solid was dried in vacuo at 65° C.: (m.p. 154°-7° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[NH:12]C(=O)C.[N:17](OC(C)(C)C)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[C:6](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[NH:12][N:17]=1)=[O:16]
Reactant: COC(=O)Cc1ccc(Cl)cc1NC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2cc(Cl)ccc12
Yield: 77 %

Procedure:
To a solution of (2-Acetylamino-4-chloro-phenyl)-acetic acid methyl ester )32.0 g, 133 mmol) in acetic acid (200 mL) stirred at 90 degree Celsius was added tert-butyl nitrite (20.5 mL, 172.3 mmol) over 1 hour. The reaction was poured into water (1.4 L) and the solids were recovered by filtration. The yellow precipitate was dissolved in EtOAc, then washed with saturated NaCl. The organic was dried over MgSO4, filtered, and concentrated to a solid. The solids were triturated with hexanes and filtered to afford the desired material (21.63 g, 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C(C)CCN.[IH:12].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:22]=1[N:21]=[C:20](SC)[C:19]=3[CH:25]=[CH:26][CH:27]=2>C(O)C>[IH:12].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:22]=1[N:21]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:5]1[CH:6]=[N:1][CH:2]=[CH:3][CH:4]=1)[C:19]=3[CH:25]=[CH:26][CH:27]=2
Reactant: CSC1=Nc2c(C)ccc3cccc1c23
Reactant: CC(CCN)c1ccccn1
Agent: I
Solvent: CCO
Product: Cc1ccc2cccc3c2c1N=C3NCCCCc1cccnc1
Temperature: -10 °C

Procedure:
To a solution of 2.6 grams of 4-(3-pryidinyl butylamine in 75 ml of ethanol, 5.1 grams of 8-methyl-2-methylthiobenz(cd)indole hydriodide was added. The mixture was then stirred and heated under reflux for 16 hours. The hot reaction mixture was clarified and the filtrate cooled at -10° C., yielding 4.75 grams of 8-methyl-N-(4-(3-pyridinyl)butyl)benz(cd)indol-2-amine hydriodide, m.p. 175°-176° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:34]=[C:35]([NH2:45])[C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([OH:43])=[C:38]([CH3:44])[CH:37]=1>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[C:9]2[O:11][N:45]=[C:35]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([OH:43])=[C:38]([CH3:44])[CH:37]=3)[N:34]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(N)=NO)cc(C)c1O
Reactant: Cc1ccc(SC(C(=O)O)c2cccc(Cl)c2)cc1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: Cc1ccc(SC(c2cccc(Cl)c2)c2nc(-c3cc(C)c(O)c(C)c3)no2)cc1C
Reaction time: 0.17 h

Procedure:
2-(3-Chlorophenyl)-2-((3,4-dimethylphenyl)thio)acetic acid (3.00 g, 9.78 mmol) was dissolved in dichloroethane, then carbonyldiimidazole (2.00 g, 12.35 mmol) was added, the resulting reaction mixture was stirred for 10 minutes, N′,4-dihydroxy-3,5-dimethylbenzimidamide crude (prepared according to Diana, Guy D et al. Journal of Medicinal Chemistry, 1994, vol. 37 (15) p. 2421-2436) (1.80 g, 9.99 mmol) was added. The reaction mixture was stirred for 30 minutes, then concentrated. Flash chromatography (40% EtOAc/Hex) gave the desired adduct which was dissolved in xylene (10 mL) and heated to 125° C. for 30 minutes, then cooled. Flash chromatography (20% EtAc/Hex) gave Intermediate 4.
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)C1.[Si]([O:36][CH2:37][C@H:38]1[O:42][C@@H:41]([N:43]2[C:52]3[N:51]=[CH:50][N:49]=[C:47]([NH2:48])[C:46]=3[N:45]=[CH:44]2)[CH2:40][C@@H:39]1[CH:53]=[CH:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:53]([C@@H:39]1[C@@H:38]([CH2:37][OH:36])[O:42][C@@H:41]([N:43]2[C:52]3[N:51]=[CH:50][N:49]=[C:47]([NH2:48])[C:46]=3[N:45]=[CH:44]2)[CH2:40]1)=[CH:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)C[C@@H]1C=Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](C=Cc2ccccc2)[C@@H](CO)O1
Yield: 91 %

Procedure:
2'-Deoxyadenosine was conveniently transformed into 5'-O-tert-butyldiphenylsilyl-2',3'-dideoxy-3'-C-styryladenosine in 60% yield utilizing the radical reaction described in Example 82 of application Ser. No. 08/040,903. The 5'-O-TBDPS group of the latter compound was deblocked to provide 2',3'-dideoxy-3'-C-styryladenosine in 91% yield, mp 215°-217° C. Anal.: C18H19N5O2.1/4 H2O Calcd.: C% 63.23; H% 5.74; N% 20.48; Found: C% 63.31; H% 5.68; N% 20.69.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][C:26]#[C:27][Si](C)(C)C)[N:22]=[N:21]4)[O:16][C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4][CH2:3]1.[OH-].[K+].Cl>CO>[O:34]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][C:26]#[CH:27])[N:22]=[N:21]4)[O:16][C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)C#CCc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(3-(trimethylsilyl)-2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (251 mg, 0.5 mmol) (Intermediate 5) was dissolved in methanol (10 ml). Potassium hydroxide (1 M, 0.75 ml) was added and the mixture was stirred at room temperature for 4 hours. Aqueous HCl (2M, 0.5 ml) was added, the excess of methanol was evaporated and the residue was extracted with dichloromethane, dried over magnesium sulfate and concentrated to give the title product (220 mg).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[N:28]1[C:37](=[O:38])[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=[C:29]1[CH3:39].C(=O)=O.[C:43](OCC)(=[O:45])[CH3:44]>C1COCC1.[Al].O>[CH2:39]([C:29]1[N:28]([C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:21])[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[C:43]([CH3:44])=[O:45]
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1-n1c(C)nc2ccccc2c1=O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Al]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1nc2ccccc2c(=O)n1-c1ccccc1C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a magnetically stirred solution of 5 mmol of LDA, prepared by mixing 2.1 ml (5 mmol) of n-butyllithium (2.4 M) and 0.71 g (7 mmol) of diisopropylamine in 25 ml of dy THF at 0° under nitrogen, was added 1.25 g (5 mmol) of methaqualone. After 30 minutes, the entire solution of lithio salt was transferred via syringe (50 ml) to an addition funnel which was attached to a three-necked 100 ml flask. The bottom half of the additional funnel was loosely enclosed in aluminum foil which formed a cup that held several small pieces of dry ice. To a solution of 4.40 g (50 mmol) of ethyl acetate in 60 ml of dry THF at 0°, was added dropwise the 5 mmol solution of lithio salt over a 65 minute period. After addition was complete, the clear yellow solution was poured into 100 ml of water containing 10 ml of 1 N NCl. The resulting solution was extracted twice with 200 ml portions of ether, which were combined, dried and concentrated. TLC analysis (ether-acetone, 98:2) revealed two spots, with methaqualone as the major component. Column chromatography afforded, on elution with hexane-ether (9:1), 0.14 g (8%) of 2-acetonyl-3-o-tolyl-4(3H)-quinazolinone (III n) as white crystals, mp 164°-165.6°. The 1H NMR spectrum was identical with samples prepared by the general sodium hydride acylation procedure described subsequently.