Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].[CH2:33]([O:35][C:36](=[O:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](Cl)=[O:43])[CH3:34]>CC#N>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:45])=[O:43])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrocbloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82–84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86–7.65 (m, 3H), 5.18–5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97–2.83 (m, 1H), 2.64–2.48 (m, 2H), 2.30–2.15 (m, 4H), 2.08–2.04 (m, 1H), 1.56–1.47 (m, 4H), 1.32–1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6](N)=[CH:5]2.[FH:13].N1C=CC=CC=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:13])=[CH:5]2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1cc2cc(Br)ccc2cn1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
To a mixture of 6-bromoisoquinolin-3-amine (0.710 g, 3.18 mmol) in pyridine hydrofluoride (10 mL, 3.18 mmol) at −78° C. was carefully added sodium nitrite (0.26 g, 3.82 mmol). The reaction mixture was stirred at −78° C. for 5 minutes. The reaction mixture was warmed to room temperature over 40 minutes. The mixture was poured into an ice bath, and the pH was adjusted to >9 with Na2CO3. The mixture was filtered to recover a yellow-purple solid. The solid was dissolved in EtOAc-water with stirring. The mixture was extracted with EtOAc (3×200 mL). The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in DCM-MeOH and adsorbed onto silica gel. Purification by chromatography on silica gel (EtOAc 0-7% in hexane) provided the product (500 mg, 70%). LCMS (API-ES) m/z: 226, 228 (M+H+).
Reaction SMILES: C([NH:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:8]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:3][C@@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])=[C:8]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 2.8 h
Yield: 39.8 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (13.70 g, 26.5 m mol) in methanol (65 ml) was added dropwise conc. HCl (11.0 ml) at room temperature and the mixture was stirred at the same temperature for 2.8 hours. The mixture was poured into a mixture of ethyl acetate and ice water and adjusted to pH 7 by addition of 5N NaOH aq. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ethyl acetate to give diphenylmethyl 7β-amino-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (5.16 g).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)[CH3:18].O>CN(C=O)C>[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:20]1)[CH3:18]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CCN1CCC(O)C1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
0.655 g (0.00297 mol) of (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.580 g (0.0036 mol) of 1,1′-carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension (cooled at 0° C.) of 1-ethylpyrrolidin-3-ol (0.390 ml g, 0.0033 mol) and HNa (0.078 g, 0.0033 mol) in 4 ml of dry DMF. After stirring 15 h at room temperature the reaction mixture was treated with water and extracted three times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent: CHCl3 plus isopropanol 0%→5%) to obtain 610 mg (65%) of the title product as an oil.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:5]2=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)CCC>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.O1CCOCC1>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[C:5]2[N:6]([C:2]([C:30]3[CH:35]=[N:34][CH:33]=[CH:32][N:31]=3)=[CH:3][N:4]=2)[N:7]=[CH:8][CH:9]=1
Reactant: Cc1ccncc1-c1ccnn2c(I)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1ccnn2c(-c3cnccn3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A microwave vial was charged with a mixture of 3-iodo-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, TFA (66 mg, 0.147 mmol), 2-(tributylstannyl)pyrazine (162 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and dioxane (4 mL) was stirred at RT for 5 min. under nitrogen. The resulting mixture was heated to 114° C. for 15 h in microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep. HPLC to give 18.2 mg (30%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.86 (1H, d, J=1.76 Hz), 8.97 (1H, s), 8.86 (2H, dd, J=16.12, 5.29 Hz), 8.66-8.79 (1H, m), 8.59 (1H, d, J=2.52 Hz), 8.56 (1H, s), 8.10 (1H, d, J=6.04 Hz), 7.54 (1H, d, J=4.78 Hz), 2.57 (3H, s); LC (Conditions B & C): >95% purity. LC/MS: Rt=1.05 min. LC/MS (Condition A): 289.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: Fc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ncccc2F)CC1
Yield: 6.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-fluoropyridine (100 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (9 mg), a yellow solid, in 7% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)Cc2cccc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (41) was prepared as follows: A solution of 3-bromo-phenylacetic acid (2.0 g, 9.3 mmol) and oxalyl chloride (36.4 g, 0.287 mol) in 80 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 3-bromo-phenylacetic acid (1.1 eq.) in CH2Cl2 was added to mixture of 100 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (1.31 g, 7.22 mmol) in 100 mL of CH2Cl2. The reaction mixture was stirred overnight at r.t. Another portion of acid chloride (0.1 eq.) in 10 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixtures. Yield is 2.59 g (95%).
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C@@H:21]3[CH2:25][C@H:24]([S:26][C:27]4[C@H:28]([CH3:51])[C@@H:29]5[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]5[C:31]=4[C:32]([O:34]CC4C=CC([N+]([O-])=O)=CC=4)=[O:33])[CH2:23][N:22]3[CH3:52])=[O:20])[CH2:14][CH2:13]2)=O)=CC=1)([O-])=O.O1CCCC1.[ClH:60]>O>[ClH:60].[N:15]1([C:19]([C@@H:21]2[CH2:25][C@H:24]([S:26][C:27]3[C@H:28]([CH3:51])[C@@H:29]4[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]4[C:31]=3[C:32]([OH:34])=[O:33])[CH2:23][N:22]2[CH3:52])=[O:20])[CH2:16][CH2:17][CH2:18][NH:12][CH2:13][CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCCNCC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 1.3 g of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]-1-methylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 2.6 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, after which the residue was purified by reverse phase column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B), using water as the eluent. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 260 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Br:11])=[CH:9][C:10]=1[I:14]
Reactant: COC(=O)Nc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1cc(C)c(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 5.00 g (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester in 50 mL acetonitrile were added at 0° C. 4.84 g N-iodosuccinimide and 0.18-mL trifluoromethanesulfonic acid. The mixture was stirred 18 h at room temperature. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 5.800 g of the title compound as white crystals melting at 140-141° C.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCCN1CCC(O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCCN3CCC(O)C3)cc12
Yield: 10.6 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (2.00 g) and 4-(3-hydroxypyrrolidin-1-yl)butyronitrile (0.8 g), 3-[3-(3-hydroxypyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (157.5 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[CH3:16][C:17]1O[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[N:19][N:18]=1>O1CCCC1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:17]([CH3:16])=[N:18][N:19]=[C:20]2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nnc(-c2ccc(C#N)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C#N)cc2)n1-c1ccc(Cl)cc1

Procedure:
Trifluoroacetic acid (600 μl, 8.1 mmol) was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzonitrile (Journal für Praktische Chemie, 1994; 336(8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% aqueous 0.88 ammonia (120 mL), and then the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with ether and a minimum volume of ethyl acetate to afford the title compound as a white crystalline solid, 2.82 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:37]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)C.[CH2:20](N)[CH2:21][NH2:22]>CCOCC>[CH2:20]1[NH:11][C:7](=[C:6]2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3](=[O:2])[CH:13]=[CH:12]2)[NH:22][CH2:21]1
Reactant: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Reactant: NCCN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1C=CC(=C2NCCN2)C=C1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of the imidate ester HCl 34 (650 mg, 2.63 mmol) in abs. ethanol was added ethylenediamine (0.53 ml, 7.89 mmol) at 0° C. and the mixture was stirred for 16 hrs at room temperature. Ether was added and the resulting precipitates were collected by filtration and dried in vacuo to give 490 mg (90% yield) of the desired cyclic amidine 35. 1H NMR (600 MHz, DMSO-d6) δ 8.38 (d, 1H, J=3 Hz), 7.45 (dd, 1H, J=9, 2.4 Hz), 3.79 (s, 4H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13]1.CO>C(OCC)C>[O:18]=[C:17]1[NH:16][C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:14]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:13][N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2]
Reactant: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)nc1=O
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCCCCCCCN1NC(c2ccccc2)=C(c2ccccc2)NC1=O
Yield: 81 %

Procedure:
A mixture of methyl-3-oxo-5,6-diphenyl-1,2,4-triazine-2(3H)-nonanoate (1.90g' 4.5mmol), 5N N (2.72mL, 13mmol) and methanol (30mL) was heated on a steam bath for 30 minutes. The volatiles were removed in vacuo and the residue diluted with water and dilute HC1 solution until pH=1 The mixture was extracted with CH2C12, the combined extracts dried over sodium sulfate and concentrated to give an oil. Chromatography on a column of silica gel using diethyl ether as eluent gave 3-oxo-5,6-diphenyl-1,2,4-triazine-2(lH)-nonanoic acid (1.50g, 81%) which crystallized on standing and had mp 97-100° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]([CH3:22])=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl-].[Cl-].C([Al+2])C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:34]([C:5]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:2]([CH3:1])[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]=1[CH3:22])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Reactant: O=C(Cl)c1ccccc1
Agent: CC[Al+2]
Agent: CC[Al](Cl)Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5.25 h
Yield: 91.5 %

Procedure:
In a small vial charged with ethyl 2-(2,5-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (143.7 mg, 0.355 mmol) in DCM (4 mL), at 0° C., was added dropwise a solution of ethylaluminum dichloride (444 μL, 0.444 mmol) in toluene. The reaction mixture turned deep rose color and benzoyl chloride (61.9 μL, 0.533 mmol) was added. The resulting mixture became orange and slowly was allowed to warm to rt. The reaction was stirred 5.25 h and then cooled once again and an additional 800 μL of EtAlCl2 and 150 μL of benzoyl chloride were added. The reaction was once again allowed to warm to room temperature slowly with stirring and stirred an additional 15.25 h at room temperature. The reaction was then quenched by the addition of water and dichloromethane and the water layer was extracted with DCM (3×). The organic layer was dried with MgSO4, and concentrated under vacuum. The crude product was added to a 40 g ISCO silica gel column and purified with a gradient of 0% to 60% EtOAc/hexanes. The product was obtained as a light orange foam (165.2 mg, 0.325 mmol, 91% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.92 (dd, 1H), 7.68 (dd, 2H), 7.46 (t, 1H), 7.38-7.32 (m, 3H), 7.20 (t, 1H), 7.10 (d, 1H), 4.56 (s, 2H), 4.30 (s, 2H), 4.24 (q, 2H), 3.23-3.17 (m, 4H), 2.03 (s, 3H), 1.98 (s, 3H), 1.84-1.78 (m, 4H), 1.29 (t, 3H). MS m/z: 509.40 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.S(Cl)(Cl)=O.C(OC([N:25]1[CH2:29][CH2:28][CH:27]([NH:30][CH2:31][C:32]([CH3:42])=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[CH2:26]1)=O)(C)(C)C>C(N(CC)CC)C>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[CH:33]=[C:32]([CH3:42])[CH2:31][N:30]([CH:27]1[CH2:28][CH2:29][NH:25][CH2:26]1)[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CC(=Cc1ccc(F)cc1F)CNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(CC(C)=Cc2ccc(F)cc2F)C2CCNC2)cc1OC
Yield: 35 %

Procedure:
Experimental condition analogous to Example 18 were used with 3,4-dimethoxybenzoic acid 0.12 g (0.68 mmol), thionyl chloride 2 ml (1.68 mmol). The obtained acyl chloride was reacted with 3-[3-(2,4-difluoro-phenyl)-2-methyl-allylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester 0.2 g (0.56 mmol), triethylamine 0.2 ml. The reaction yielded the free amine, which was converted to the HCl salt 90 mg as an off-white solid: Yield: 35%.
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: O=C(Cl)c1cccc(C(=O)c2ccccc2)c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
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).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:23]([C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH:23]([C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]2)=[CH:37][CH:36]=1)#[N:39]
Reactant: N#Cc1ccc(C(Br)c2cccc(C#N)c2)cc1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(C#N)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from ethyl 3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorobenzoate and 3-[bromo(4-cyanophenyl)methyl]benzonitrile as described in Preparation 17, Part 5; Mass Spectrum: m/e=514.