Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:39]([O:42][C:43](Cl)=[O:44])[CH2:40][CH3:41]>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:27][C:43](=[O:44])[O:42][CH2:39][CH2:40][CH3:41])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Reactant: CCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)N[C@@H]1C[C@H](CC)N(C(C)=O)c2ccc(-c3ccc(CN4CCCCC4)cc3)cc21
Reaction time: 0.67 h

Procedure:
(cis)-1-Acetyl-2-ethyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 5) (50 mg, 0.128 mmol) was dissolved in dichloromethane (DCM) (2 mL), mixed with DIPEA (0.045 mL, 0.255 mmol) and propylchloroformate (0.019 mL, 0.166 mmol, Aldrich) and stirred under nitrogen. After 40 minutes the reaction was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a colourless solid (38 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 8% 2M methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg). LCMS (Method C): Rt=0.83, MH+=478
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.[O:45]=[C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([CH2:56][C:57]2[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60](O)=[O:61])=[N:48][NH:47]1>CC(N(C)C)=O.O>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:60]([C:59]3[CH:58]=[C:57]([CH:65]=[CH:64][CH:63]=3)[CH2:56][C:49]3[C:50]4[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46](=[O:45])[NH:47][N:48]=3)=[O:61])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (150 mg, 0.47 mmol), diisopropylethylamine (102 mg, 0.8 mmol) and 1-(4-fluorophenyl)piperazine (65 mg, 0.47 mmol) were added sequentially at ambient temperature to a stirred solution of 3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A)(100 mg, 0.36 mmol) in dry dimethylacetamide (1 ml), the mixture was stirred at ambient temperature for 4 hours and allowed to stand at ambient temperature for 16 hours, then it was added dropwise to stirred cold water (10 ml). After 30 minutes, the resulting solid was collected by filtration, washed with water (2×1 ml) and hexane (1 ml), dried in vacuo and purified using preparative HPLC to give 4-{3-[4-(4-fluorophenyl)piperazin-1-ylcarbonyl]benzyl}-1(2H)-phthalazinone (21)(76 mg) as a cream solid; m/z (M+H)+. 443; HPLC Purity 90%; HPLC Retention time 4.00 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][N:14]=3)[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][N:14]=4)[N:10]=[N:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Product: c1ccc2c(-c3cn(-c4ccc(N5CCOCC5)nc4)nn3)n[nH]c2c1
Temperature: 120 °C

Procedure:
A suspension of 3-[1-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazole (13 mg; 0.04 mmol; 1.0 eq.) in morpholine (0.5 mL) was heated in MW at 120° C. for 4.5 h. The precipitate obtained was filtered, washed with Et2O and dried under vacuum at 50° C. to afford the title compound as a beige solid. 1H NMR (DMSO-d6) δ: 13.33 (s, 1H), 9.18 (s, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.16 (dd, J=2.6, 9.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.43 (m, 1H), 7.23 (m, 1H), 7.07 (d, J=9.1 Hz, 1H), 3.72 (m, 4H), 3.55 (m, 4H). HPLC (Condition A): Rt 3.21 min (purity 97.3%). MS (ESI+): 348.3, MS (ESI−): 346.3.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Cl[CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[S:40]1[CH:41]=[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: ClCc1csc2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 15 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, and then a solution of 132 mg (0.72 mmol, 1.1 equiv) of 3-chloromethylbenzo[b]thiophene (Wolf, G.; Zymalkowski, F. Arch. Pharm. 1976, 279) in 1 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 5/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 222 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.79 (m, 2H), 7.44-6.93 (m, 15H), 6.88 (dd, 1H, J=1.5, 8.1), 5.03 (m, 1H), 4.42 (d, 1H, J=16.6), 4.09 (d, 1H, J=16.6), 3.85 (s, 3H), 3.80 (t, 1H, J=6.6), 3.61 (m, 2H), 1.10 (t, 6H, J=6.8); low resolution MS (FAB)m/e 604 (MH+), 439.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([NH:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[O:10]
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-(methyloxy)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 280 mg, 1.08 mmol), 3-pyridinamine (204 mg, 2.17 mmol), EDC (312 mg, 1.63 mmol) and HOBT (249 mg, 1.626 mmol) in DMF (5 ml) was stirred under nitrogen at 25° C. overnight. The reaction mixture was then poured into water (20 ml), filtered and the solid was washed with water and dried to yield the title compound as a white solid. 150 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12](S(C3C=CC=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Levorotatory (−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(phenyl)sulfonyl]piperazine (100 gm) is added to 30% hydrobromic acid in acetic acid (271 ml). The suspension is stirred at 25-30° C. for 1 hour, heated to 60° C. and maintained for 4 hours. Water (1000 ml) is added to reaction mass and cooled to 25-30° C. The precipitate formed is filtered off and washed with water (250 ml). Toluene (500 ml) is added to the aqueous layer and basified with 50% aqueous solution of sodium hydroxide. Toluene layer is separated, distilled under reduced pressure and the residue left is recrystallised from boiling hexane (160 ml). The solution is filtered and allowed to recrystallise first at ambient temperature, and then in an ice bath. The product is filtered off, washed with hexane and dried to obtain 55 gm of levorotatory (−)-1-[(4-chloro phenyl)phenylmethyl]piperazine [M.R: 89-93° C.; [α]D25=−15.6 (c=1, methanol); Chiral Purity by HPLC: 99.7%].
Reaction SMILES: [C:1]([O:20]CC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.CCOC([C@@H](N[C@@H]1C(=O)N2N(CCC[C@H]2C(O)=O)CCC1)CCC1C=CC=CC=1)=O.O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCCN2CCC[C@@H](C(=O)O)N2C1=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)O
Temperature: 37.77777777777778 °C
Reaction time: 2 h

Procedure:
1.500 Grams of ethyl stearate, 6.25 mg of PGE 2, and 62.5 mg of oleic acid were placed in a Pyrex test tube and heated to about 100° F. on a hot plate with periodic agitation. The mixture rapidly melted to afford a clear solution. A standard laboratory micropipette (Justor 1100 BG manufactured by Nichiryo and available from Sigma, St. Louis. Mo. USA with volume dispensed adjustable from 10.0 to 100.0 microliters; and Sigma pipette tips—catalog #B-6429) was repeatedly dipped into this solution and aspirated with the volume set at 37 microliters. The solution rapidly solidified at ambient room temperature (71° F.) and the resultant suppository was removed by pressing a paper clip into the tip of the pipette. Approximately 100 suppositories were made in a two hour period using this method. Subsequent weighing showed that 96% of the suppositories weighed 31±0.5 mgs. Similar results were obtained when palmitic acid was substituted for oleic acid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:25][OH:26])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22]
Reactant: NO
Reactant: C=C(C)n1c(=O)n(CC(=O)c2ccccc2F)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=C(C)n1c(=O)n(CC(=NO)c2ccccc2F)c2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a stirred solution of 1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (1.3 g, 4.2 mmol) in ethanol (50 ml) was added hydroxylamine hydrochloride (0.84 g, 12.2 mmol) followed by pyridine (1.7 ml, 21.0 mmol) at ambient temperature. The resulting mixture was warmed to 80° C. for 6 h, cooled to ambient temperature and concentrated. The remaining residue was diluted with water, 1M HCl and ethyl acetate. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.0 g (73%) of the desired product as an oil which solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:37][O:36][C:4]1[C:3]([O:2][CH3:1])=[CH:35][C:7]2[CH2:8][CH:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)CCC2

Procedure:
To a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.0 g) obtained in Example 62 in ethanol (50 ml) is added 10% palladium-carbon (50 mg), followed by catalytic reduction in a stream of hydrogen. The reaction mixture is filtered off, and the filtrate is concentrated under reduced pressure. To the residue is added ether, and the mixture is stirred to obtain 1-(2,3-dimethoxy-5,6,7,8-tetrahydrobenzocyclohepten-6-ylcarbonyl)-4-(3,4,5-trimethoxy-benzoyl)piperazine as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH:7]=[C:6]([C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][C:35]=1[CH3:45])=[O:31])[C:5]2=[O:46].[OH-].[Li+].Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:25][C:26]([F:29])([F:27])[F:28])[CH:7]=[C:6]([C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:36][C:35]=1[CH3:45])=[O:31])[C:5]2=[O:46]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Reaction time: 8 h

Procedure:
550 mg (0.698 mmol) of the compound of Example 2 are provided in 10 ml of dioxane, 3.5 ml of a 1M solution of lithium hydroxide in water are added and the mixture is stirred overnight. The reaction mixture is acidified with 1N hydrochloric acid and freed from the solvents on a rotary evaporator. The residue is taken up in DMSO and separated by preparative chromatography (method 5). 330 mg (72% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (118.9 mg, 0.34 mmol) and triphenylphosphine (133.5 mg, 0.51 mmol) in methylene chloride (848 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (102.7 mg, 0.58 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. The reaction mixture was then treated with 2-aminopyridine (95.8 mg, 1.02 mmol). The resulting reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (37.1 mg, 26%) as a light yellow solid: mp 151-153° C.; EI-HRMS m/e calcd for C20H21F3N2O3S (M+) 426.1225, found 426.1220.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([O:18]CC)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24].[Cl-].[NH4+]>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([NH2:24])=[O:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CC(=O)OCC
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(N)=O

Procedure:
Ethyl (4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetate (0.80 g), a solution of ammonia in methanol (35 mL of 7 N), and ammonium chloride (0.50 g) were heated in a sealed pressure vessel at 150° C. for 20 hours. The volatiles were removed under reduced pressure, and the solid residue was triturated with saturated aqueous sodium bicarbonate for one hour, isolated by filtration, and washed with water. The solid was recrystallized from methanol/water, and the crystals were washed sequentially with 25% aqueous sodium hydroxide (2×25 mL) and water (2×25 mL) and dried overnight in a vacuum oven at 70° C. to provide 0.120 g of 2-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetamide as light tan crystals, mp>300° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[N:25]=[C:24]([Cl:26])[NH:23][C:22]2=[CH:27][CH:28]=[CH:29][C:21]=12>CN(C)C=O>[ClH:26].[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]2[NH:23][C:22]3=[CH:27][CH:28]=[CH:29][C:21]3=[C:20]([N:11]3[CH2:12][CH2:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]3[CH3:9])[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)[nH]c2cccc1-2
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1c1nc(Nc2ccc(F)cc2)[nH]c2cccc1-2
Product: Cl
Yield: 13.5 %

Procedure:
After 4-fluoroaniline(0.40 ml, 4.2 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chlorocyclopenta[d]pyrimidine(0.60 g, 2.0 mmol) and dimethylformamide(5 ml), 0.11 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:40]=[CH:39][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[ClH:41]>ClCCl.O1CCOCC1>[ClH:41].[N:1]1[N:2]=[C:3]([C:19]2[CH:40]=[CH:39][C:22]([C:23]([N:25]3[CH2:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH2:30]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoyl)piperidin-4-yl)carbamate (0.25 g, 0.47 mmol) in dichloromethane (10 mL) was added 4N HCl in dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 20 hours. The solids were filtered off, washed with ether and dried under vacuum, yielding (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)(4-aminopiperidin-1-yl)methanone hydrochloride as a yellow solid (0.21 g, 88%). M.p.=258-263° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.83 (br.s, 1H), 8.25-8.18 (m, 3H), 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.48-7.42 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.0, 1.2 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.94 (dd, J=8.0, 4.4 Hz, 1H), 4.55-4.4 (m, 1H), 3.7-3.65 (m, 1H), 3.35-3.25 (m, 1H), 3.22-3.05 (m, 1H), 3.0-2.8 (m, 1H), 2.2-1.85 (m, 2H), 1.6-1.4 (m, 2H); LCMS [M+H]: 438.
Reaction SMILES: [Na+].[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3ncccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.9 %

Procedure:
The crude (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (˜0.928 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.27 g, 0.928 mmol) and 047-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.494 g, 1.3 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (2 mL). The mixture was stirred at 25° C. for 1.5 h. Triethylamine (0.697 mL, 5 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with ethyl acetate (˜15 mL) and the product solidified. The solid was collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.03 g, 0.064 mmol, 6.9%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-1.05 (2H, m), 1.18-1.46 (4H, m), 2.26 (1H, d, J=3.1 Hz), 2.36 (1H, d, J=9.5 Hz), 2.45 (1H, d, J=3.0 Hz), 3.15 (1H, d, J=9.4 Hz), 4.13 (1H, d, J=15.6 Hz), 4.86 (1H, d, J=15.6 Hz), 7.01-7.05 (2H, m), 7.16-7.20 (2H, m), 7.39-7.42 (1H, m), 7.50 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 8.26 (1H, dd, J1=4.6 Hz, J2=1.5 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13, found 469.2 [M+H+].