Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)n1ccc2ccc([N+](=O)[O-])cc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
To a solution of 6-nitro-1H-indole (0.250 g, 1.54 mmol) in dry THF (15.4 mL) at −78° C. under nitrogen was added sodium bis(trimethylsilyl)amide (1.850 mL, 1.850 mmol) dropwise via syringe. The resulting solution was stirred for 20 minutes at −78° C., followed by addition of methanesulfonyl chloride (0.14 mL, 1.85 mmol) dropwise via syringe. Following the addition, the cooling bath was removed, and the mixture was allowed to warm to room temperature. After 1 hour, the suspension was filtered, and the resulting solid was taken up in 10 mL of aqueous MeOH and heated to reflux. The hot mixture was filtered to afford a light yellow solid which was dried in vacuo, furnishing Intermediate 64A (0.208 g, 56% yield) as a light yellow solid. HPLC: Rt=3.160 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=241.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d, J=2.01 Hz), 8.18 (1H, dd, J=8.81, 2.01 Hz), 7.98 (1H, d, J=3.78 Hz), 7.92 (1H, d, J=8.81 Hz), 7.05 (1H, d, J=3.78 Hz), 3.55-3.66 (3H, m).
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.C1C2CC(=[O:22])C(C2)C1.N1CCOCC1>C1(C)C=CC=CC=1>[O:22]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: O=C1CC2CCC1C2
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 6.6 g (0.06 mole) of norcamphor and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction toluene was removed under reduced pressure, and the remaining chromanone compound was recrystallized from acetone, and the chromanon compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.1 g of a chromene compound represented by the following formula: ##STR68##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:9]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CN1CCCC1=O>[CH2:30]([N:9]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:16][C:15]2[C:10]1=[N:11][C:12]([C:23]1[CH:28]=[N:27][C:26]([NH2:29])=[N:25][CH:24]=1)=[N:13][C:14]=2[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:31]([CH3:33])[CH3:32]
Reactant: C1CNCCN1
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Piperazine (2.0 g, 23 mmol) and N-methylpyrrolidone (10 ml) were added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (1.0 g, 2.6 mmol) and the resulting mixture was stirred at 130° C. for 4 hours. The reaction mixture was cooled and partitioned with methylene chloride and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. This compound (10 ml in liquid) was stored with N-methylpyrrolidone remaining and used for next step.
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5]O)[CH2:3][OH:4].[Cl-].[Cl-].[Ca+2].F[C:13](F)(F)[C:14]([OH:16])=[O:15].FC(F)(F)C(O)=[O:22].C(#N)C>>[NH2:7][C@H:2]([C:3]([OH:4])=[O:22])[CH2:5][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(CO)(CO)CO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC#N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
The oligopeptides prepared as described in Example 2 were individually dissolved in PSA digestion buffer (12 mM tris(hydroxymethyl)aminomethane pH8.0, 25 mM NaCl, 0.5 mM CaCl2) and the solution added to PSA at a molar ration of 100 to 1. The reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1% (volume/volume). The quenched reaction was analyzed by HPLC on a reversed-phase C18 column using an aqueous 0.1%TFA/acetonitrile gradient. The results of the assessment are shown in FIG. 2. The removal of an asparagine residue from the amino terminus of the oligopeptide results in a significant loss of PSA mediated peptide hydrolysis, while the presence of a glutamic acid residue at the carboxyl end of the peptide appears not to be essential to recognition by PSA.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1
Product: COc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 7 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-methoxyphenyl phosphonic dichloride to yield 1-(4-methoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 7% yield) as a white solid having a melting point of 190°-192° C. and the following analysis:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][CH2:16][CH2:17]O.O1CCCC1.[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:17][CH2:16][O:15][CH3:14])[S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)N(CCOC)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 4.24 %

Procedure:
To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg, 0.102 mmol) in anhydrous toluene. The vial was introduced into a dry box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial. This mixture was shaken until the solution turned clear. To this solution was added a solution of 2-methoxyethanol in anhydrous tetrahydrofuran (1.2 equivalents, 0.082 mmol, 6.24 mg). This mixture was stirred for 10 minutes at ambient temperature. To this mixture was added a solution of Example 36e (0.068 mmol, 31.4 mg) in anhydrous toluene/anhydrous tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixture was stirred at room temperature overnight in the dry box. The reaction mixture was concentrated to dryness and the residue purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide the title compound (4.24%, 1.5 mg). 1H NMR (400 MHz, DMSO d6/D2O) δ ppm 7.49 (d, J=2.75 Hz, 1H), 7.38-7.43 (m, 1H), 7.37 (d, J=2.75 Hz, 1H), 7.35-7.36 (m, 1H), 7.34 (d, J=2.75 Hz, 1H), 7.22-7.27 (m, 1H), 7.05-7.11 (m, 1H), 6.87 (d, J=8.54 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 3.78-3.81 (m, 2H), 3.57 (s, 3H), 3.37 (t, J=5.65 Hz, 2H), 3.20 (s, 3H), 3.16 (t, J=7.32 Hz, 2H), 1.26 (t, J=7.48 Hz, 3H). ESI+ m/z=518.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:37]1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:37]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]2[CH2:27][CH2:28]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CC4)C3)sc12
Yield: 71.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate obtained in Example (213a) (32.0 mg, 0.078 mmol), 4 N hydrochloric acid-1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (24 mg, 0.085 mmol) and sodium carbonate (82 mg, 0.777 mmol), to obtain 29 mg of the title compound (72%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH:7]([N:9]1[C:13](=[O:14])[O:12][N:11]=[C:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]1[CH:49]=[CH:48][C:24]([C:25]([N:27]([C:41]2[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)=[O:26])=[CH:23][CH:22]=1)[CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:4](=[O:5])([O:6][CH:7]([N:9]1[C:13](=[O:14])[O:12][N:11]=[C:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([C:25](=[O:26])[N:27]([C:41]2[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:48][CH:49]=1)[CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)OC(C)n1c(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnn2C)noc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)OC(C)n1c(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCNC4)cc3)cnn2C)noc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
tert-butyl (3R)-3-[{4-[5-(4-{1-[(ethoxycarbonyl)oxy]ethyl}-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (52 mg, 0.08 mmol) was dissolved in DCM (5 mL) and to the solution was added HCl in dioxane (0.5 mL, 4M solution, 2 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was triturated in diethyl ether to yield ethyl 1-{3-[1-methyl-4-(4-{(3-methylpyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1H-pyrazol-5-yl]-5-oxo-1,2,4-oxadiazol-4(5H)-yl}ethyl carbonate as a light yellow solid (40 mg, 80%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:7]1([NH:13][C:14]2[C:19]([CH:20]=[N:21][OH:22])=[CH:18][N:17]=[C:16]3[N:23]([CH2:26][CH3:27])[N:24]=[CH:25][C:15]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[O-].[Na+]>O1CCCC1>[CH:7]1([NH:13][C:14]2[C:15]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:16]=3[N:17]=[CH:18][C:19]=2[C:20]2[CH2:1][C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:22][N:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C=C1CCCC1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
Methylene cyclopentane (0.073 ml, 0.0006 mole) was added to 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (0.1 gm, 0.0003 mole) (example 8) in tetrahydrofuran. The reaction mixture was stirred at room temperature for about 5 minutes. Sodium hypochlorite (5 ml) was added slowly to the reaction mixture over a period of about 5 minutes and the mixture was allowed to stir at room temperature for about 5 h. The organic solvent was evaporated and the residue was extracted in ethyl acetate. The organic layer was concentrated and the title compound obtained was purified by preparative thin layer chromatography.
Reaction SMILES: Br.[NH2:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]3[NH:12][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[C:9]3=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:16][C:14]1([CH3:15])[C:9]2[C:10](=[CH:11][C:5]3[NH:4][C:3]([NH:2][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:7][C:6]=3[CH:8]=2)[NH:12][C:13]1=[O:17]
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(N)nc3cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nc3cc4c(cc3[nH]2)NC(=O)C4(C)C)cc1

Procedure:
3 g. (10.1 mmole) 2-Amino-7,7-dimethyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrobromide are stirred with 2.5 g. p-anisoyl chloride in 50 ml. pyridine for 4 hours at 50° C. The pyridine is subsequently distilled off, the residue is worked up with water, decanted, worked up with ligroin and the residue recrystallised twice from ethanol to give 1.4 g. (40% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[O:9]1[CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:27]1[C:24]1[CH:23]=[CH:22][C:21]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1
Reactant: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCc1ccc(C2OC2CCCC)cc1
Reaction time: 20 h

Procedure:
6.76 g of m-chloroperbenzoic acid (90% content) in 100 ml of dichloromethane are added to a solution of 6.32 g of 1-(4-nonylphenyl)-hex-1-ene (mixture of cis- and trans-isomers) from the preceding stage in 150 ml of dichloromethane while cooling to 0°-5°, and the whole is stirred for 20 hours at 20°. The reaction mixture is washed in succession with 10% strength (w/v) sodium sulphite solution, 5% strength (w/v) sodium carbonate solution and 3 portions of water, dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (19:1) yields in succession the trans- [1(RS),2(RS)-] and the cis-[1(RS),2(SR)-]-isomer in the form of colourless oils.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][N:48]([CH3:64])[C:49]([C:51]1[N:52]=[C:53]([C:60]([F:63])([F:62])[F:61])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][C:55]=12)=[O:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:58][CH2:59][N:54]2[C:53]([C:60]([F:63])([F:61])[F:62])=[N:52][C:51]([C:49]([N:48]([CH3:64])[CH3:47])=[O:50])=[C:55]2[CH2:56]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 10.4 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 22c (200 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 22 (45 mg, yield 11.0%) as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[OH:21][C@@H:20]1[C@H:19]([OH:23])[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]3[CH:47]=[CH:46][N:50]=[CH:49]3)=[O:52])[CH2:3]1)=[N:8][C:9]=2[NH:31][CH2:32][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-yl}-propionamide (Intermediate M) (0.24 g, 394 μmol) and CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by chromatography on silica eluting with 100% DCM changing to 5% MeOH in DCM to afford the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: CCN(CC)CC.I[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[SH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:16][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:18][CH:19]=2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:34][CH2:35]1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Reactant: ICC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(SCC2CCOCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-methoxymethylsulfanylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 77, 1.29 g, 3.28 mmol) in THF (50 mL) was added to a stirred solution of AgNO3 (0.59 g, 3.28 mmol) in EtOH (85 mL) at 40° C. The mixture was protected from light and stirred at 40° C. for 21 h. The solvents were evaporated off under reduced pressure, then the remaining solid was triturated with i-PrOH (60 mL), THF (60 mL), and Et2O (60 mL). After air-drying, the solid was stirred vigorously with CH2Cl2 (200 mL) and 6M HCl (82 mL) for 4 h under Ar. The layers were separated, then the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were filtered through Celite, washed with brine (100 mL) and dried (MgSO4). Filtration and solvent evaporation furnished 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=349.2 [M+H]+. NEt3 (0.14 mL, 1006 μmol) and a solution of 4-iodomethyltetrahydropyran (151 mg, 668 μmol) in anhydrous DMF (3 mL) were added to a stirred solution of this benzenethiol (197 mg, 565 μmol) in anhydrous DMF (7 mL) at 0° C. The mixture was warmed to 20° C., before being stirred for 16 h. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (25 mL) and 2% aqueous citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL), then the combined organic layers were washed with H2O (10 mL), saturated aqueous Na2CO3 (10 mL), H2O (10 mL), and brine (10 mL). After drying (MgSO4), filtration and solvent evaporation gave a residue that was subjected to flash chromatography (IH-EtOAc, 3:1 to 0:1) to furnish the title compound: RTA=3.61 min; m/z (ES+)=447.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[S:29]([O:1][C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:30])=[O:28]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2.03 mL, 11.66 mmol) and Tf2O (1.80 mL, 10.69 mmol) at −78° C., and then it was warmed up to room temperature and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCO3, dried and concentrated to give 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate as crude product (4.4 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH3:9][C:10]([CH:12]=[O:13])=O>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[N:2]=[C:10]([CH3:9])[CH:12]=[O:13]
Reactant: NNc1ccccn1
Reactant: CC(=O)C=O
Solvent: CCO
Product: CC(C=O)=NN(c1ccccn1)c1ccccn1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To 2-hydrazinopyridine (4.36 g, 40 mmol) was added slowly methyl glyoxal (40% aqueous, 3.99 g, 22 mmol) in ethyl alcohol (88 mL). The solution was refluxed for 17 hours and cooled to room temperature, The yellow product which separated was filtered, washed with ethyl alcohol and dried to give methyl glyoxal bis-(2-pyridyl) hydrazone 3.00 g (29%), mp. 196°-198° C. as the free base. The entire product was added to water and hydrogen chloride gas was bubbled through the solution until the solution was clear. The water was evaporated to give the hydrochloride salt, mp. 270°-270° C.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]([CH3:27])=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:28]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]([CH3:27])=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:28])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1sc2nc(C)n(N)c(=O)c2c1C
Product: Cc1sc2nc(C)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c2c1C

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,5,6-trimethylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.77 (m, 12 H) 1.91-1.98 (m, 3 H) 2.08 (d, J=12.0 Hz, 1 H) 2.15 (d, J=12.0 Hz, 1 H) 2.35 (s, 3 H) 2.36 (s, 6 H) 10.76 (s, 1H); MS (ESI+) m/z 386 (M+H)+.