Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 2-methyl-5-nitrophenol (765 mg, 5.00 mmol), 4-(trifluoromethoxy)benzeneboronic acid (1.24 g, 6.00 mmol), copper(II) acetate (999 mg, 5.50 mmol), triethylamine (3.48 ml, 25.0 mmol), molecular sieves 4A and dichloromethane (20.0 ml) was stirred at room temperature overnight under argon atmosphere. The reaction mixture was filtered through celite. The residue obtained by evaporation of the solvent of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=20:1) to give the title compound (323 mg, 20.6%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH2:10]1[C:9]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH2:13][CH2:12][CH2:11]1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Yield: 87 %

Procedure:
Aniline was reacted with cyclohexanone in the same way as in Example 3. Tetrahydrocarbazole was formed in a yield of 87% of the theoretical yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[SH:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>>[CH3:8][C:6]1[N:7]=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: OCCS
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 6-chloro-2-methyl-3-nitropyridine (2.17 g, 13 mmol) in 2-mercaptoethanol (5 mL, 71 mmol), potassium hydroxide (1.52 g, 27 mmol) was added. Mixture was stirred at room temperature for 2 h and then extracted with NaOH solution and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated to give 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as a brown oil (60% pure, 3.25 g, 72%). 1HNMR (CDCl3, 400 MHz) δ 2.87-2.90 (m, 6H), 3.43-3.46 (t, J=5.6 Hz, 2H), 7.22-7.24 (d, J=8.7 Hz, 1H), 8.15-8.17 (d, J=8.7 Hz, 1H). Exact mass calculated for C8H10N2O3S 214.04 found 215.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[F:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](I)[CH:17]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[N:14][CH:13]=1
Reactant: C#Cc1nc(C)ccc1N
Reactant: Fc1cncc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cncc(F)c2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
To a solution of Cul (11 mg, 0.06 mmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (40 mg, 0.30 mmol, described in Example 7), (PPh3)2PdCl2 (21 mg, 0.06 mmol), and 3-fluoro-5-iodopyridine (111 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 14 h. The solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to yield 15 mg (66 μmol, 22%) of (2-(5-fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: [CH2:1]([O:3]C1C=CC2C(=CC=CC=2)N1C(OCC)=O)[CH3:2].C(O)(=O)C.[NH:23]([C:25]([C:27]1[C:28]([N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:26])[NH2:24]>C1COCC1.C(#N)C>[C:1]([NH:24][NH:23][C:25]([C:27]1[C:28]([N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:26])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C(=O)NN)cnc3[nH]ccc23)CC1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Ethyl 2-ethoxyquinoline-1(2H)-carboxylate (226 mg, 0.916 mmol) was added to acetic acid (50.0 mg, 0.832 mmol) in THF/ACN (5 mL), and the reaction was stirred at room temperature for 1 hour. tert-Butyl 4-(5-(hydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (300 mg, 0.832 mmol, Example 18) was added, and the reaction was heated to 70° C. for 1 hour. The reaction was then concentrated to dryness. The resulting residue was crystallized from DCM to yield tert-butyl 4-(5-(2-acetylhydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (241 mg, 71.9% yield) as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(OC)ccc2cccc(Cc3ccccc3)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
79.5 g of 8-benzyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 300 ml of acetone to give a solution. 120 ml of 6N hydrochloric acid was added to the solution at room temperature. The obtained mixture was stirred for 1.5 hours, followed by the addition of 400 ml of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The obtained solid was washed with hexane/ diisopropyl ether (1:1) to give 51 g of the title compound as a colorless crystal.
Reaction SMILES: Cl.[CH2:2]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][C:21]([OH:23])=O)[C:16]([CH3:19])=[CH:17][N:18]=1)[CH:3]([CH3:5])[CH3:4].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:36])[CH:33]=2)[NH:28][CH:27]=1>>[CH2:2]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][C:21]([NH:36][CH2:35][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[C:26]3[CH3:25])=[O:23])[C:16]([CH3:19])=[CH:17][N:18]=1)[CH:3]([CH3:4])[CH3:5].[NH3:6]
Reactant: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@H]4CCCN4CC(C)C)c3=O)cc12
Product: N

Procedure:
The title compound was prepared by a similar method to preparation 49 from 2-[3-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid hydrochloride [see preparation 62] and (3-methyl-1H-indol-5-yl)methylamine (72 mg, 0.45 mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as the eluant, to afford the product as a foam. This was dissolved in methanol (5 ml) and hydrochloric acid (1M, 0.58 ml, 0.58 mmol), to afford the product, (56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:23])[CH3:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (10.30 g, 36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid (10 drops) and the mixture was stirred and heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into ice water (300 mL). 2N Aqueous sodium hydroxide solution was added to raise the pH of the solution to about 10 and the resulting orange precipitate was collected by filtration. The solid was washed with water, air-dried, and then dried under vacuum to afford the title compound as an orange solid, 11.87 g (quant.). 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.41 (d, 1H, J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s, 3H). MS (ES) 323 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1.Br[CH:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([CH:34]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)C1
Reactant: BrC1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)[C@@H](c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)C1
Reaction time: 4 h

Procedure:
1.3 kg of the compound from Example 6 are stirred with exclusion of moisture at -5° C. to +5° C. with 580 g of bromocycloheptane in 2.4 l of DMF. During the course of about 2 hours, a solution of 400 g of potassium tert-butoxide in 1.6 l of DMF is added. The mixture is stirred for a further 4 hours between -20° C. and -10° C. and 7.5 l of water are then added, during the course of which the title compound precipitates as a crude product. The crude product is centrifuged off, dried at 50° C. in vacuo and recrystallised twice using 6 l of ligroin; the solution is filtered hot in the first recrystallisation.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[Cl:28]CCl>>[ClH:28].[Br:19][C:15]1[N:14]=[C:13]([N:10]2[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2cccc(Br)n2)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCN(c2cccc(Br)n2)C1
Yield: 88 %

Procedure:
Combine (3S)-[1-(6-bromopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (260 mg, 0.76 mmol) and dichloromethane (10 mL). Add trifluoroacetic acid (2 mL) and stir at room temperature for 4 hours. Concentrate and dissolve in methanol. Load onto Dowex® 1×2-200 column and elute with methanol. Concentrate and add acetone to give a solid. Filter the solid to give (3S)-1-(6-bromopyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride (187 mg, 88%). 1H NMR (400 MHz, MeOH-d4) δ 7.39 (t, 1H, J=7.6 Hz), 6.77 (d, 1H, J=7.6 Hz), 6.47 (d, 1H, J=7.6 Hz), 4.04-3.99 (m, 1H), 3.80-3.75 (m, 1H), 3.66-3.59 (m, 2H), 3.56-3.50 (m, 1H), 2.52-2.43 (m, 1H), 2.21-2.13 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl [(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-[(2,4-dinitrophenyl)amino]hexanamide (20, 121 mg, 0.124 mmol) and K2CO3 (137 mg, 0.991 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (4 mL) was added thiophenol (100 μL, 0.971 mmol). After stirring at 23° C. for 18 h, the mixture was filtered and solvent removed in vacuo. Flash column chromatography (MeOH/triethylamine /CH2Cl2, 3:5:100) afforded 3 (50 mg, 51%) mp 157-158° C.; 1H NMR (360 MHz, CDCl3) δ 9.12 (d, J=2.6 Hz, 1H), 8.55 (t, J=5.0 Hz, 1H), 8.26 (dd, J=2.6 Hz, J=9.5 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 6.62 (t, J=5.5 Hz, 1H), 5.30 (d, J=4.7 Hz, 1H), 3.51 (dt, J=5.8 Hz, J=5.7 Hz, 2H), 3.41 (dt, J=7.0 Hz, J=5.5 Hz, 2H), 3.33 (dt, J=5.9 Hz, J=5.7 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.38-2.31 (m, 3H), 2.21-2.14 (m, 3H), 2.01-1.00 (m, 37H), 0.97 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.86 (d, J=1.4 Hz, 3H), 0.84 (d, J=1.4 Hz, 3H), 0.66 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 172.6, 171.8, 148.5, 141.6, 136.2, 130.6, 130.5, 124.6, 121.2, 114.1, 58.4, 57.0, 56.3, 50.5, 45.7, 43.5, 42.5, 40.4, 40.0, 39.7, 39.5, 38.2, 37.2, 36.5, 36.4, 36.0, 35.7, 35.5, 32.1 (×2), 29.9, 29.1, 28.6, 28.4, 28.2, 26.7, 25.2, 24.5, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0; IR (film) νmax 3354, 3299, 2933, 2868, 1647, 1620, 1335 cm−1; CI m/z 793.5584 (MH+, C45H73N6O6 requires 793.5592).
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([Cl:44])[CH3:43])=[O:40]>C(Cl)Cl>[Cl:44][CH:42]([O:41][C:39](=[O:40])[O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][P:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:43]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=P(OCCOCCOCCOCCO)(OCc1ccccc1)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCOCCOCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of dibenzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl phosphate (500 mg, 1.1 mmol) and pyridine (200 mg, 205 μl, 2.53 mmol) in methylene chloride (6 mL) at −78° C. was added slowly 1-chloroethyl chloroformate (178 mg, 134 μl, 1.24 mmol) in methylene chloride (2 mL). After addition, the reaction mixture was allowed to stir at −78° C. for 1.5 h. Then the cold bath was removed and the reaction mixture was warmed up to room temperature. 1H-NMR showed the completion of the reaction. The reaction mixture was concentrated in vacuo. The residue was reconstituted with diethyl ether. The solids in the ethereal solution were filtered off and washed thoroughly with diethyl ether. The filtrate and washing solutions were combined and concentrated to give carbonic acid 2-(2-{2-[2-(bis-benzyloxy-phosphoryloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester 1-chloro-ethyl ester as clear light-yellow thick oil. The crude product was used without further purification.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]([OH:20])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]([NH2:3])=[O:20]
Reactant: O=C(O)c1cnccn1
Reactant: CCN(CC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cnccn1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 425.5 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Pyrazinecarboxylic acid (0.31 mg, 2.5 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 mg, 2.5 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.31 mg, 2.3 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 17 h 40 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (80% ethyl acetate-hexanes) to give the pyrazine-2-carboxylic acid amide derivative (1.1 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]=[O:14])[C:3]1=[O:15].C([O:20][C:21](=[O:24])[CH2:22][CH3:23])(=O)CC>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:5](=[O:12])[CH2:6][CH3:7])=[C:4]([CH:13]([O:20][C:21](=[O:24])[CH2:22][CH3:23])[O:14][C:13](=[O:14])[CH2:4][CH3:3])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C=O)c(O)c2ccccc21
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)Oc1c(C(OC(=O)CC)OC(=O)CC)c(=O)n(C)c2ccccc12

Procedure:
Following the procedure of Example 5, 1-methyl-3-formyl-4-hydroxy-2(1H)-quinolinone (from Preparation B) was acylated with propanoic anhydride to give 1-methyl-3-[di-(1-oxopropoxy)]methyl-4-(1-oxopropoxy)-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS (CI): m/e 390 (M.+ +1); NMR (CDCl3): δ1.14 (t, 6H, 2 x CH3CH2), 1.38 (t, 3H, CH3CH2), 2.39 (m, 4H, 2 x CH2CO), 2.83 (q, 2H, CH3CH2CO), 3.74 (s, 3H, NCH3), 8.10 (s, 1 H, (CH3CH2COO)2CH) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.[Cl:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17].Cl>C(OCC)(=O)C>[ClH:15].[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:16]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:17])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: OCc1cncs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: -1 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
Distilled 5-(hydroxymethyl)thiazole (14.1 g, 123 mmol) and triethylamine (17.9 mL, 129 mmol) were dissolved in ethyl acetate (141 mL) and cooled to -1° C. (ice/salt bath). A solution of 4-nitrophenyl chloroformate (26.0 g, 129 mmol) dissolved in ethyl acetate (106 mL) was added dropwise over 50 minutes at an internal temperature of 0°-4° C. An ethyl acetate flask rinse (20 mL) was also added. Salts precipitated from solution throughout the addition. The yellow mixture was stirred another 1 hour 45 minutes at 0°-2° C., then a solution of dilute HCl (3.1 g, 31 mmol of conc. HCl in 103 mL water) was added at once. The mixture was stirred for 0.5 hours while warming to 15° C., then stirring was stopped. The organic layer was washed twice with aqueous 5% K2CO3 solution (2×70 mL), then dried with Na2 SO4 (30 g). After filtration the solution was concentrated under vacuum on a rotary evaporater (bath temperature of 41° C.) to a brown oil (38 g). The crude 5-(p-nitrophenyoxycarbonyloxymethyl)-thiazole was dissolved in ethyl acetate (282 mL), then cooled in an ice bath to 2° C. Dry HCl gas (7.1 g, 195 mmol) was bubbled in slowly over 50 minutes (temperature 2°-4° C.). After stirring for another 1 hour 45 minutes at 2°-4° C., the solid precipitate was collected on a sintered glass funnel under a nitrogen blanket and the flask was washed out with 50 mL cold ethyl acetate which was used to rinse the filter cake. The cake was dried on the funnel under strong nitrogen purge for 15 minutes then dried in a vacuum oven at 50° C. with a nitrogen purge to provide 29.05 g of the title compound as tan powder, m.p. 131°-135° C. (dec.). 1H NMR (DMSO-d6) δ 9.21 (d, 1H), 8.27 (m, 2H), 8.06 (d, 1H), 7.52 (m, 2H), 5.54 (s, 2H). 13C NMR (DMSO-d6) δ 157.3, 155.2, 151.8, 145.3, 143.7, 131.9, 125.5, 122.7, 62.1.
Reaction SMILES: [C:1]12([C:8]3[CH2:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+].O>C(O)C.C(OCC)C>[CH:2]12[CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH:1]2[C:8]1[CH:12]=[CH:11][C:10](=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1
Reactant: C1=CCC(C23CCC(CC2)C3)=C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1C1CC2CCC1C2
Yield: 99.5 %

Procedure:
A 500 mL round bottom flask was charged with a solution of norbornylcyclopentadiene (7.39 g, 46.1 mmol) and benzophenone (8.41 g, 46.2 mmol) in 100 mL absolute ethanol. NaOMe (5.50 g, 102 mmol) was added and the orange solution was stirred for 61 days before 100 mL H2O and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to provide 14.88 grams of red oily material. This was subjected to Kugelrohr distillation under high vacuum at 80-100° C., leaving behind 9.30 grams of red oil. This was Kugelrohred at 100-160° C. to afford 7.05 grams of product as a viscous red oil (47.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:29]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc(C(=O)c2ccccc2)c1
Yield: 56.2 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with 3-benzoylbenzoyl chloride (0.18 g, 0.73 mmol) to provide 0.19 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-benzoylbenzamide as a white crystalline solid, m.p. 103-105° C. 1H NMR (500 MHz, DMSO-d6) δ8.70 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 8.16 (broad s, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.67 (broad s, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.32 (q, J=6.0 Hz, 2H), 1.91 (quintet, J=7.0 Hz, 2H), 1.59 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 463.2022 (463.2008 calcd for C28H25N5O2).