Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C[O-].[Na+].CO.Cl>CN(C=O)C.O>[CH3:1][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Yield: 85 %

Procedure:
To a mixture of 4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (prepared according to U.S. Pat. No. 7,928,120) (20 mg, 0.054 mmol) in DMF (0.5 mL) was added 0.5 M NaOMe/MeOH (0.32 mL, 0.16 mmol). The resultant mixture was microwaved at 80° C. for 1.5 h. Reaction mixture was diluted with water (70 mL) and acidified by 1 N HCl to pH=4. Precipitate was collected and dried in vacuo to provide the title compound 15 mg (0.046 mmol) in 85% yield. LC-MS ESI+: 326.10 (M+1)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Proprionyl chloride (190 μL, 2.17 mmol) was added drop-wise to a stirring solution of crude phenol 122 (880 mg, 1.67 mmol) and DMAP (2 mg, 0.016 mmol) in pyridine (5 mL). The reaction was continued for 3 hr at room temperature followed by the addition of ethyl acetate (100 mL). The organic layer was washed with cold aqueous HCl (0.5 N), H2O and saturated aqueous NaCl then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 to 20% methanol in ethyl acetate) using a Biotage Horizons™ system, resulting in 123 as a pale yellow liquid (644 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.0, 3H), 1.26 (t, J=7.5, 3H), 1.30 (t, J=7.0, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 2.50-2.63 (m, 4H), 2.82 (AB q, J=14.4, 2H), 3.93-4.16 (m, 6H), 4.93 (s, 2H), 7.12-7.18 (m, 3H), 7.26-7.32 (m, 3H), 7.70 (ddd, J=1.8, 8.4, 11.6, 1H), 7.86 (dd, J=1.8, 13.4, 1H): 31P (162 MHz, CDCl3) δ 20.21 (d, J=9.7, 1 P), 34.03 (d, J=9.7, 1 P).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH:20]1([C:26]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:35]([O:34][C:32]([C:26]1([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:30][CH2:31]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Reactant: BrCCC=C1c2ccccc2C=Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C2CCCCC2)CCN(CCC=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 39 %

Procedure:
A mixture of 5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene (4.45 g, 14.2 mmol), ethyl 4-cyclohexyl-4-piperidinecarboxylate (3.4 g, 14.2 mmol, prepared similarly as described in Brit. 1 124 661 (1967)), potassium carbonate (2.1 g, 15.2 mmol) and N,N-dimethylformamide (10 ml) was heated at 120° C. for 5 h. Benzene (50 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using mixtures of benzene and chloroform as eluents to give 2.6 g (39%) of 1-(3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-cyclohexyl4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](C(O)=O)[C:8]([CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C[N:49]([CH:51]=[O:52])C>>[CH3:1][C:2]1[CH:10]=[C:9]([C:51]([NH2:49])=[O:52])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: Cc1cc(C(=O)O)c(C)cc1C(=O)O
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(N)=O)c(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
2,5-Dimethylterephthalic acid (200 mg, 1.03 mmol) was dissolved in DMF (5 mL) and HATU (392 mg, 1.03 mmol) was added and the mixture was stirred at ambient for 15 minutes. N,N-Diisopropylethylamine (0.7 mL, 3.99 mmol) was added and after 5 minutes 1-[6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridine-3-yl]ethanone (prepared in Example 19 Step 3) (250 mg, 1.02 mmol) was added and the mixture was stirred at 50° C. for 15 h. The mixture was cooled to ambient temperature and HATU (392 mg, 1.03 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.14 mmol) were added and the mixture was stirred at ambient for 15 minutes. Ammonia gas was bubbled into the solution and a thick precipitate formed. The mixture was stirred at 50° C. for 0.5 h and then was cooled to ambient temperature and was concentrated. The residue was treated with 1N aqueous hydrochloric acid (2 mL) and DMSO. Water was added and the precipitate was collected by filtration then further purified by reverse phase HPLC. The pure fractions were combined and concentrated to an aqueous residue. The aqueous residue was basified with sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic portion was dried over magnesium sulfate then filtered and was concentrated to afford N-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2,5-dimethylbenzene-1,4-dicarboxamide (77 mg, 0.183 mmol, 18% yield). 1H NMR (400 MHz, d6-DMSO): δ 8.74 (d, 1H), 8.28 (d, 1H), 7.97 (dd, 1H), 7.71 (br s, 1H), 7.41 (br s, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 6.79 (d, 1H), 4.62 (br s, 2H), 3.87 (br s, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H), 2.27-2.18 (m, 2H), 2.15-1.94 (m, 4H), 1.89 (d, 2H); MS (EI) for C24H28N4O3: 421 (MH+).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13](B3[O:20][C:19]([CH3:22])(C)C(C)(C)O3)=[CH:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.[C:50](=[O:53])([O-])[O-:51].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([OH:51])(=[O:20])[CH3:22].[C:50]([OH:51])(=[O:53])[CH3:1].[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C@@H:39]2[CH2:38][CH2:37][C@H:36]([N:28]3[C:29]4=[N:30][CH:31]=[N:32][C:33]([NH2:35])=[C:34]4[C:26]([C:13]4[CH:12]=[CH:11][C:10]([NH:9][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH3:8])=[CH:15][CH:14]=4)=[N:27]3)[CH2:41][CH2:40]2)[CH2:43][CH2:44]1
Reactant: O=C([O-])[O-]
Reactant: CC(Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CC(Nc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(1-phenylethyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.070 g, 0.000235 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.000181 mol), tetrakis(triphenylphosphine)palladium (0.012 g, 0.000011 mol) and sodium carbonate monohydrate (0.056 g, 0.00045 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(1-phenylethyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.062 g, 0.0000984 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH3:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50]Br.[I-].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH3:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCOCCOCCOCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCCOC)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 73.7 %

Procedure:
A mixture of 2.0 g (3.83 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 4.15 g (15.3 mmol) of 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl bromide, 1.2 g (7.66 mmol) ofsodium iodide and 1.6 g (11.5 mmol) of potassium carbonate in 60 ml of acetone and 30 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residual oil was purified by HPLCusing 60% ethyl acetate-hexane to give 2.01 g (73% yield) of N-[3-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH3:28])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.CC1NC2C=CC=CC=2N=1.[CH3:65][C:66]([OH:70])([C:68]#[CH:69])[CH3:67]>>[OH:70][C:66]([CH3:67])([CH3:65])[C:68]#[C:69][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH3:28])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: Cc1nc2ccccc2[nH]1
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Product: Cc1nc2ccccc2n1Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 24 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-methylbenzimidazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (26 mg, 24%).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=[C:3]([CH2:15]O)[N:2]=1.ClCCCl.S(Br)([Br:23])=O>C(Cl)(Cl)Cl>[Br:23][CH2:15][C:3]1[N:2]=[N:1][C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:5]=2[CH:4]=1
Reactant: OCc1cc2c(nn1)Oc1ccccc1O2
Reactant: O=S(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: BrCc1cc2c(nn1)Oc1ccccc1O2
Yield: 76.5 %

Procedure:
To [1,4]benzodioxino[2,3-c]pyridazin-3-ylmethanol (8.1 g) was added 1,2-dichloroethane (80 ml) and the mixture was stirred. Thionyl bromide (38.9 g) was added, and the mixture was stirred with heating under reflux for 2 hr. The mixture was diluted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with diethyl ether to give 3-(bromomethyl)[1,4]benzodioxino[2,3-c]pyridazine (8.0 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:7][C:8]=1[CH:9]([CH3:12])[CH2:10][OH:11])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34].C1(C)C=CC=CC=1.C(P(CCCC)CCCC)CCC>CCOCC>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:11][CH2:10][CH:9]([C:8]2[O:7][C:6]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:12])=[CH:29][C:28]=1[CH3:34]
Reactant: COC(=O)Cc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 0 °C

Procedure:
A mixture of 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol, (0.18 g, 0.5745 mmol), (4-Hydroxy-2-methyl-phenyl)-acetic acid methyl ester (0.114 g) and toluene (10 mL) and azodicarboxylic dipiperidide (0.19 g, 0.747 mmol) is stirred at −20 deg C. Neat tri-n-butyl phosphine (0.19 mL, 0.747 mmol) is added dropwise and the resulting mixture is allowed to reach room temperature with stirring 18 hr. The mixture is diluted with ether (25 mL) and cooled in ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 95:5 hexanes:ethyl acetate to afford the title compound as a thick oil, 0.065 g, 24%. MS M++1 476. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
MeOH (240 mL) was added to a flask containing 4-[1-(cyclopentylmethyl-amino)-ethylidene]-pent-2-enedioic acid dimethyl ester (7.2 g, 25.6 mmol). NaOMe solution (5.9 mL, 25.6 mmol, 4.375 M in MeOH) and N-bromosuccinimide (5.5 g, 30.7 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 4.46 g of the title compound. MS: (+) m/z 350.22, 352.24 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32]>>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23]([NH:24][C:34]([NH:33][CH2:31][CH3:32])=[S:35])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCN=C=S
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OCC)OCCC2CNC(=O)N1CC(C)=C(CC)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-ethoxychroman ##STR55## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is synthesized analogously to Example 14, starting from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-ethoxychroman and ethyl isothiocyanate. Melting point: 178°-180° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 94.7 %

Procedure:
This reaction was repeated on a larger scale with the sodium salt of 2-chloro-6-(2-propylimidazol-1-yl)purine (1.54 g, 5.87 mmol) in dried CH3CN (100 mL) treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (3.74 g, 9.62 mmol) in CH2Cl2 (100 mL) by general method 2 for 5 h (reaction complete, TLC). Sampling at different reaction times showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated, and the residue was dissolved in CH2Cl2. The solution was washed (H2O) and dried (Na2SO4), and volatiles were evaporated in vacuo. The residue was chromatographed (EtOAc/hexanes, 1:1→7:3) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (3.42 g, 95%). Recrystallization from EtOAc gave the β-anomer (2.75 g, 76%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.O>CC(O)C>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([C:4]3[O:3][C:2]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:6][CH:5]=3)[CH:8]=[CH:9][CH:10]=2)[CH:19]=1
Reactant: NCc1ccncc1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Solvent: CC(C)O
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Yield: 55 %

Procedure:
A solution of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (50 mg, 0.174 mmol) in iPrOH (5 ml) was treated with 4-aminomethylpyridine (53 μl) and heated to reflux for 40 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on Al2O3 (Brockman grade III, 7% H2O), eluting with 2% EtOH in DCM. Precipitation from DCM with n-pentane afforded the title compound as pale yellow solid (34 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (d, J=4.6 Hz, 2H), 8.25 (t, J=5.8 Hz, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.36 (d, J=4.9 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.73 (d, J=5.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.29 (s, 3H). (ESI+) m/z 359 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][CH2:12][C@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=1>>[ClH:29].[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][O:11][CH2:12][C@H:13]([NH:20][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCC(COC[C@H](N)c2ccccc2)CC1
Product: COc1ccc(C(=O)N[C@@H](COCC2CCN(C(C)C)CC2)c2ccccc2)cc1
Product: Cl

Procedure:
Using coupling method B, (R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (150 mg, 0.54 mmol) and 4-methoxybenzoyl chloride (0.12 mL, 1.0 mmol) afforded, after purification (SiO2: 4:2:1 DCM:EtOAc:isopropyl-amine) and conversion to the HCl salt by general method A, 205 mg (91%) of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].[OH-].[Na+].[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([CH2:19][CH2:20][NH:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)(=[O:18])=[O:17]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: C=CS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-nitrobenzylamine hydrochloride (1.0 g, 5.3 mmol) in DCM was converted to the free base by treating with 2 N NaOH. The organic layer was separated and concentrated, and the residue was redissolved in MeOH. To this solution was added methylvinylsulfone (232 μL, 2.6 mmol), and the reaction was stirred at rt. After 5 h, the crude reaction mixture was adsorbed onto silica gel and purified by column chromatography to generate the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 3.93 (s, 2H), 3.16-3.24 (m, 4H), 3.01 (s, 3H). ES-LC/MS m/z=259 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:24]#[N:25])[C:15]([N:19]=[CH:20][N:21](C)C)=[CH:16]2)=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:35]=[C:34]([Cl:36])[C:33]([O:37][CH3:38])=[CH:32][C:30]=1N>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:26][CH3:27])=[CH:11][C:12]2[CH:13]=[C:14]3[C:15](=[CH:16][C:17]=2[CH:18]=1)[N:19]=[CH:20][N:21]=[C:24]3[NH:25][C:30]1[CH:32]=[C:33]([O:37][CH3:38])[C:34]([Cl:36])=[CH:35][C:29]=1[Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2cc(C#N)c(N=CN(C)C)cc2cc1OCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1Cl
Solvent: CC(=O)O
Product: COc1cc(Nc2ncnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidine and 0.092 g (0.48 mmol) of 2,4-dichloro-5-methoxyaniline in 4 mL of glacial acetic acid is heated under reflux for 7 hours, then cooled to room temperature and stirred overnight. The resulting solid is collected by filtration, washed with ether and dried to yield 0.05 g of (8-benzyloxy-7-methoxybenzo[g]quinazolin-4-yl)-(2,4-dichloro-5-methoxyphenyl)amine as a yellow solid, mp 275-280° C.