Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:24])([CH3:25])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([N:29]5[CH2:28][CH2:27][N:26]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]5)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCCOCCN1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(F)c1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(N2CCN(CCOCCO)CC2)c1
Temperature: 105 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:1][C:2]4[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=4)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 37.2 %

Procedure:
A mixture of N-(4-hydroxy-phenyl)-acetamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 35%) as a white solid. Mass spectrum MH+=453.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O)#[N:2].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][N:27]=[N+:28]=[N-:29])#[N:2]
Reactant: COc1ccc(C#N)c(CO)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-cyano-5-methoxybenzyl alcohol (1.8 g, 11 mmol) in THF (50 mL) was cooled to 0° C. and then treated sequentially with diphenylphosphoryl azide (2.8 mL, 13 mmol) and DBU 1.9 mL, 13 mmol), the former added in one portion and the latter dropwise. The reaction mixture was allowed to warm gradually to room temperature and to then stir there overnight. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute citric acid, then brine and dried (Na2SO4). The solvent was removed in vacuo and the residue purified by column chromatography eluting with 4:1:1 hexane/chloroform/ethyl acetate to give the product as a yellow oil: 1H NMR (CDCl3) δ7.62 (d, J=8.6 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.92 (dd, J=2.6, 8.6 Hz, 1H), 4.59 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (366 mg) in tetrahydrofuran (5 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 221.2 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cc(Cl)ccc12
Yield: 60.6 %

Procedure:
Ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-chloro-2-amino benzothiazole (9.2 g, 50 mmol) and ethyl bromopyruvate (11.6 g, 60 mmol), 8.5 g (60% Yield) of ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brown solid. (M+H) 281.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][OH:24])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[N:56]2[N:60]=[C:61]([CH:63]=O)[N:62]=[C:55]2[N:54]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][OH:24])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:63][C:61]3[N:62]=[C:55]4[N:54]=[C:53]([CH3:52])[CH:58]=[C:57]([CH3:59])[N:56]4[N:60]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(O)c(CO)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione (Example A(195)) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde from that example. 1H NMR (400 MHz, DMSO-d6): δ 1.34–2.09 (m, 11H) 2.0–2.21 (m, 2H), 2.47–2.74 (m, 10H), 3.74 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 4.44 (s, 2H), 6.65 (d, J=8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 9.06 (s, 1H). Anal. Calcd. For C27H32N4O5.H2O: C, 62.96; H, 6.75; N, 10.88. Found: C, 62.97; H, 6.57; N, 10.83. MS (ESI): 493.2 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][S:2]([C:5]2[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Solid 2-[4-(chlorosulfonyl)phenoxy]acetamide (Intermediate A91, 65.87 g, 0.264 mol) was added to a solution of 4-methoxy-2-nitroaniline (27.72 g, 0.165 mol) in pyridine (500 mL) at room temperature under argon. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added 0.5 M hydrochloric acid (1000 mL) and stirred for 30 min. The orange solid was collected and recrystallized from acetone to give 42.8 g (68%) of the title compound, nitro sulfonamide as yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]3[CH:25]=[CH:26][N:27]=[C:16]23)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]3[N:17]([CH:25]=[CH:26][N:27]=3)[C:18]=12
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 9-[4-(benzyloxy)phenyl]-5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridine (1.35 g), 10% palladium on carbon (containing water (50%), 0.675 g), THF (50 ml) and methanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from hexane/THF to give the title compound (0.950 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([C:36](O)=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:42]([O:41][C:39]([NH:30][C@@H:31]([C@@H:32]([CH3:33])[CH2:34][CH3:35])[C:36]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)=[O:37])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.1 %

Procedure:
A mixture of parent compound 89 (438 mg, 1.0 mmol), N-Boc-Ile (463 mg, 2.0 mmol), EDCI (384 mg, 2.0 mmol) and DMAP (162 mg, 1.3 mmol) in DMF (0.9 mL) was stirred at room temperature for 15 h. The reaction mixture was poured into 1.0 M HCl solution, and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled intermediate (157 mg, 24%). MH+651.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[NH:10][C:11](=[O:19])[C:12]2[CH2:18][O:17][CH2:16][CH2:15][C:13]=2[N:14]=1.[F:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:7]([CH2:8][C:9]3[NH:10][C:11](=[O:19])[C:12]4[CH2:18][O:17][CH2:16][CH2:15][C:13]=4[N:14]=3)[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:35])[CH2:31][CH2:32]2)=[O:26])=[CH:37][CH:38]=1
Reactant: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2cccs2)CC1
Yield: 24.5 %

Procedure:
The title compound (296 mg) was prepared following the general procedure of Example from 2-((thiophen-2-ylmethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (710 mg, 2.3 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (720 mg, 2.7 mmol). 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.00 (d, J=8.8, 575 Hz, 2H), 7.38 (d, J=4.4 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.95 (s, 1H), 4.85 (s, 2H), 4.47 (s, 2H), 4.38 (s, 2H), 3.85 (t, J=5.7 Hz, 2H), 3.18-3.45 (m, 2H), 2.80-3.12 (m, 3H), 2.53 (t, J=5.4 Hz, 2H), 2.29 (t, J=10.7 Hz, 2H), 1.67-1.87 (m, 2H), 1.42-1.63 (m, 2H). HRMS calculated for C27H29FN4O4S 525.1972. found (ESI, [M+H]+), 525.1968. MS m/z 525.2 (M+1), retention time=3.08 min.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)O
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
L-Proline (1.81 g, 15.6 mmol) was added to a stirring, heterogeneous mixture of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (13.5 g, 78.0 mmol, Intermediate 45, step a) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11.2 g, 78.0 mmol) in ethanol (520 mL) at 23° C. After 1.5 hours, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (19.7 g, 78.0 mmol) was added in one portion. After 16 hours, the ethanol was removed by rotary evaporation at 35° C. to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was stirred for 10 minutes at 23° C. The mixture was filtered and the filter cake was washed with isopropanol (150 mL). The solids were collected and dried under vacuum to provide the titled compound as a white solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH2:10])[CH2:3]2.CN1CCCN(C)P1.F[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([NH:27][CH3:28])=[O:26]>CS(C)=O>[CH3:28][NH:27][C:25](=[O:26])[C:24]1[CH:29]=[C:20]([NH:10][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[CH:21]=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: NC1CN2CCC1CC2
Agent: CN1CCCN(C)P1
Agent: Cl
Solvent: CS(C)=O
Product: CNC(=O)c1cc(NC2CN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 26.9 %

Procedure:
To a mixture of quinuclidin-3-amine hydrochloride (1.06 g, 5.30 mmol) and polymer supported dimethylperhydro-1,3,2-diazaphosphorine (7.0 g, 15.4 mmol) in DMSO (50 mL) was added 5-fluoro-N-methyl-2-nitrobenzamide (Intermediate 3A) (1 g, 5.05 mmol) and reaction heated at 60° C. for 72 hours. The resin was removed by filtration and washed thoroughly with methanol and dichloromethane. The filtrate was purified using a 20 g SCX cartridge followed by trituration with dichloromethane/methanol/diethyl ether to afford N-methyl-2-nitro-5-(quinuclidin-3-ylamino)benzamide (0.41 g, 1.36 mmol).
Reaction SMILES: [H-].[Na+].[C:3]1(=[N:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.C(O)(=O)/C=C/C([O-])=O>>[CH3:17][N:18]([CH2:19][CH2:20][O:16][N:15]=[C:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:22]
Reactant: CN(C)CCCl
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCON=C1CCCCCCCCCCC1

Procedure:
Starting from 2.4 g. (0.1 moles) of sodium hydride, 19.73 g. (0.1 moles) of cyclododecanone oxime and 11.8 g. (0.11 moles) of 1-dimethylamino-2-chloroethane the title compound is prepared as in Example 1. Yield: 19.5 g. (72.65%). Hydrogen fumarate, m.p.: 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:78])[C@H:4]([CH2:76]O)[NH:5][C:6](=[O:75])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:74])[C@H:13]([CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)[NH:14][C:15](=[O:67])[C@H:16]([C@H:63]([CH2:65][CH3:66])[CH3:64])[NH:17][C:18](=[O:62])[C@H:19]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[NH:20][C:21](=[O:53])[C@H:22]([CH:50]([CH3:52])[CH3:51])[NH:23][C:24](=[O:49])[C@H:25]([CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:48])[NH2:47])[N:26]([C:30](=[O:41])[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[N+:27]([O-:29])=[O:28].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:78])[C:4](=[CH2:76])[NH:5][C:6](=[O:75])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:74])[C@H:13]([CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)[NH:14][C:15](=[O:67])[C@H:16]([C@H:63]([CH2:65][CH3:66])[CH3:64])[NH:17][C:18](=[O:62])[C@H:19]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([OH:61])=[CH:59][CH:60]=1)[NH:20][C:21](=[O:53])[C@H:22]([CH:50]([CH3:51])[CH3:52])[NH:23][C:24](=[O:49])[C@H:25]([CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:47])[NH2:48])[N:26]([C:30](=[O:41])[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[N+:27]([O-:29])=[O:28]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C=C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)[C@@H](C)CC)C(=O)OC
Reaction time: 2 h

Procedure:
3.0 g of t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolylserine methyl ester is dissolved in 20 ml of pyridine and 10 ml of triethylamine. The solution is cooled in an ice bath. 0.51 g of tosyl chloride is added to the solution. At ten minute intervals, three additional 0.51 g batches of tosyl chloride are added. After standing for two hours, the reaction mixture is filtered. 200 ml of methylene chloride is added to the reaction. The solution is extracted three times with 5% ammonium hydroxide in water. The solution is then dried over sodium sulfate and stripped under vacuum. The residue istaken up in 2% methanol/methylene chloride and passed through a silica gel column to remove the colored impurities and afford the pure product t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolyldehydroalanine methyl ester.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 22.5 h
Yield: 52.7 %

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 11.5 mmol) in dimethylformamide (50 mL) was treated with cesium carbonate (5.62 g, 17.25 mmol) and triphenylmethyl chloride (3.85 g, 13.8 mmol). The reaction mixture was stirred at 70° C. for 22.5 h under a nitrogen atmosphere. Cesium carbonate (3.75 g, 11.5 mmol) and triphenylmethyl chloride (3.2 g, 11.5 mmol) were added to the reaction mixture and was stirred for 6.5 h. The reaction mixture was added to ice water. The precipitate was filtered and washed with water. The product, 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was dried over night on the lyophilizer. The resulting solid was triturated with ethyl acetate to give 3.05 g (53%) of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.3190-7.1106 (m, 16H); TLC (Baker Pre-coated Hard Layer Silica Gel TLC plates, Si250F254, 30% Ethyl acetate in heptane) Rf=0.33.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[N:41]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH2:55])=[N+:42]=[N-:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:41]=[N+:42]=[N-:43])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCOCCOCCOCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
518 mg (0.92 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.92 mmol) 2-{2-[2-(2-Azidoethoxy)ethoxy]ethoxy}ethanamine, 160 μl (0.92 mmol) N,N-diisopropylethylamine and 348 mg (0.92 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 276 mg (0.34 mmol, 37% of theory) of the desired product.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH:5]1[C:10]2[C:11]3[C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[O:13][C:14](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[O:13]=[C:14]1[C:9]2[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:22](=[O:23])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: CCCN
Solvent: ClC(Cl)Cl
Product: CCCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Yield: 56 %

Procedure:
Propylamine (0.3 mL, 3 mmol) was added to a stirred solution of benz[d]indeno[1,2-b]pyran-5,11-dione (2) (0.49 g mmol) in CHCl3 (10 mL). The red solution stirred overnight before CHCl3 (75 mL) was added and the mixture washed with H2O (3×20 mL) and brine (1×20 mL), dried (MgSO4), and concentrated under reduced pressure to give a yellow-orange solid (0.32 g, 55%): mp 166-167° C.; IR (neat) 2967, 1660, 1502, 1427, 1317, 1193, 959 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.69 (d, 1H, J=8.0 Hz), 8.33 (d, 1H, J=9.0 Hz), 7.70 (td, 1H, J=9.0, 3.0 Hz), 7.62 (d, 1H, J=6.2 Hz), 7.40 (m, 4H), 4.46 (t, 2H, J=8.0 Hz), 1.92 (m, 2H), 1.12 (t, 3H, J=7.4 Hz); CIMS m/z (relative intensity) 290 (MH+, 100). Anal. Calcd for C19H15NO2: C, H, N.