Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:4]=1)=[O:2].CN(C=O)C.[H-].[Na+].[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][CH2:37]I)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:11]([O:10][C:9]([N:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH2:37][CH2:36][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[C:32]([O:34][CH3:35])=[O:33])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a dry 2-5 mL microwave vial under N2 is added tert-butyl (5-formylthiazol-2-yl)carbamate (100 mg, 0.438 mmol) and anhydrous DMF (2.5 mL). The resulting dark solution stirred at room temp for 5 min, treated with sodium hydride (22.13 mg, 0.876 mmol), flushed with N2 for 15 min, then treated with material from Example 115 (301 mg, 0.876 mmol) and securely capped. The resulting dark solution is stirred at room temp for 30 min, then heated in a microwave heating unit for 15 min at 80° C. under high power. The reaction is diluted with ethyl acetate (200 mL), washed with water (6×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, the solvent removed in vacuo and the resulting residue purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using 100% CH2Cl2 to 75% EtOAc/CH2Cl2 over 11 column volumes to give 176.7 mg (91%) of the title compound as a thick oil, LC/MS (Condition A): ret. T=3.83 min, (M+Na) 466.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:12]>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:12])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Add sodium hydride (5.91 g, 147.8 mmol) to a rapidly stirred solution of 2-bromo-3-pyridinol in DMF (anhydrous, 200 mL). After 30 minutes, add iodomethane (9.2 mL, 147.8 mmol) and stir under N2 for 2.5 hours. Quench with water and concentrate. Partition residue between Et2O and water, separate layers. Extract from aqueous layer with Et2O (×2), dry combined layers over MgSO4 and concentrate. Purify residue by flash chromatography on silica gel eluting with 0-25% EtOAc/hexanes to afford 2-bromo-3-methoxy-pyridine (21.0 g, 83%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:3].[Br:10][CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br-:10].[CH3:1][N+:2]([CH3:3])([CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)CCBr
Reactant: CN(C)CCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)CC[N+](C)(C)CCC(C)(C)C
Product: [Br-]
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A mixture was prepared containing 1 g (0.77×10−2 moles) of N,N,3,3-tetramethylbutylamine (Aldrich) and 1.917 g (1.16×10−2 moles) of 1-bromo-3,3-dimethylbutane (Prolabo) and about 4 ml of isopropanol. Next, 1.23 g (1.16×10−2 mole) of sodium carbonate was added. This suspension was heated under reflux for 2 days at a temperature of 100° C. A white solid appeared and after this time, about 5 ml of diethylether was added to the reaction mixture to increase the quantity of precipitate. The isopropanol and diethylether were then evaporated off at 30° C. using a rotary evaporator. The organic product formed was extracted from the reaction mixture using dichloromethane. Three successive extractions with 10 ml of dichloromethane were carried out. The organic phase obtained was evaporated using a rotary evaporator. The white solid formed was washed with dry diethylether and filtered over a nylon membrane (diameter=0.2 μm). 0.8 g (0.27×10−2 moles) of N,N-dimethyl-N,N-di(3,3-dimethylbutyl)ammonium bromide (DMDMBA-Br) was obtained. The nature of the species obtained was verified by proton nuclear magnetic resonance; the results of this analysis are given below:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]([CH3:48])[CH2:44][C:45](=O)[CH3:46].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH3:42][N:43]([CH3:48])[CH2:44][CH:45]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:46]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)CN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CN(C)C)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-dimethylamino-propan-2-one (0.296 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 32 mg (57%) of the title compound as a yellow solid. MS (ESI) m/z 560.4 (M+H)+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.[C:25]([O:31][CH2:32]CCl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:25]([O:31][CH2:32][N:22]1[N:23]=[N:24][C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:13]=3)[CH:19]=2)=[N:21]1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Reactant: CC(C)(C)C(=O)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), chloroethyl pivalate and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 1.10 (9H, s), 5.41 (2H, s), 6.70 (2H, s), 7.28-7.30 (1H, m), 7.38-7.40 (2H, m), 7.52-7.54 (1H, m), 7.81-7.83 (3H, m), 7.94 (1H, s), 8.51 (1H, s), 8.68 (1H, d, J=5.1 Hz). [M+H] Calc'd for C22H22ClN7O2, 452. Found, 452.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][C:28]1[CH:27]=[CH:26][C:25]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Yield: 26 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.54 mmol) and [4-(4-methyl-1,4-diazepan-1-yl)phenyl]amine (0.11 g, 0.54 mmol) were stirred in N,N-dimethylformamide (3 mL) with triethylamine (0.3 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol. The crude material is dissolved in a minimum of 5% methanol in chloroform and then passed through a Florisil plug, eluting with 5% methanol in chloroform. The filtrate is concentrated under reduced pressure to give and then dried under vacuum to give (4Z)-6-bromo-4-({[4-(4-methyl-1,4-diazepan-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (64 mg, 26%) as a rust colored powder.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10E)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2E,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1739 cm-1, 1675 cm-1, 1629 cm-1, 1449 cm-1, 1370 cm-1, 948 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[C:11]([C:15]1[CH:19]=[C:18]([NH2:20])[NH:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[NH2:20][C:18]1[N:17]([C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:10])[CH:9]=2)[N:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:19]=1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: OCc1cc(F)cc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1cc(N)n(-c2cc(F)cc(CO)c2)n1
Temperature: 150 °C
Yield: 23.9 %

Procedure:
Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added to a mixture of 3-bromo-5-fluorobenzylalcohol (1.00 g, 4.88 mmol), 3-tert-butyl-1H-pyrazole-5-amine (678 mg, 4.88 mmol), copper (I) iodide (46.0 mg, 0.24 mmol) and potassium carbonate (1.41 g, 10.2 mmol). Trans-N,N′-dimethylcyclohexanediamine (154 μL, 0.98 mmol) was added and the reaction heated to 150° C. for 18 h using microwave irradiation. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (307 mg, 24%). LCMS (Method 4): Rt 2.34 min, m/z 264 [MH+].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][C:11]2C=CC=[CH:13][CH:12]=2)[N:4]=1.[NH4+:17].[Cl-]>N>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][C:13]#[N:17])[N:4]=1
Reactant: Nc1cccc(SCc2ccccc2)n1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Product: N#CCCCSc1cccc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-amino-6-benzylthiopyridine hydrochloride (47.2 g.) in liquid NH3 (700 ml.) was stirred while Na (17.0 g.) was added in small portions. When the addition was complete NH4Cl (21.9 g.) was added and then the mixture was evaporated to dryness. The residue was dissolved in a mixture of EtOH (100 ml.) and H2O (100 ml.) and the mixture treated with 4-bromobutyronitrile (23 ml.) and stirred at room temperature for 18 hours. The solution was evaporated to dryness and the residue was partitioned between 2N aqueous HCl and ether. The aqueous phase was basified with 10N aqueous NaOH and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated to dryness to give 4-(2-aminopyrid-6-ylthio)butyronitrile (36.1 g.) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=1.[OH-:21].[Na+]>CN(C=O)C>[Br:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:3]2([O:21][C:3]3([O:10][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=4)[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][CH:2]3[Cl:1])[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][CH:2]2[Cl:1])=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: BrCc1ccc(CBr)cc1
Reactant: COc1ccc(O)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(Cl)C(OCc2ccc(CBr)cc2)(OC2(OCc3ccc(CBr)cc3)C=CC(OC)=CC2Cl)C=C1
Reaction time: 4 h
Yield: 72.4 %

Procedure:
Add 5 g of 2-chloro-4-methoxyphenol to a mixture of 17 g of α,α'-dibromo-p-xylene to a stirred mixture of 2.5 g of 50:50 (w/w) NaOH:H20 and 50 mL of DMF. Stir the so-formed mixture for 4 hours. Partition the reaction mixture with methylene chloride and water. Separate the organic layer and remove the solvent by rotary evaporation to obtain a solid residue. Purify the residue on a silica gel chromatography column using pure hexane to pure methylene chloride as the eluants to provide 8 g of 1-[4-bromomethylbenzyloxy]-2-chloro-4methoxyphenyl ether.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2[C:32]([C:35](O)=[O:36])=[N:33][NH:34][C:28]=2[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:35]([C:32]3[C:29]4[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][C:28]=4[NH:34][N:33]=3)=[O:36])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (11, 93 mg, 0.33 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (88 mg, 0.33 mmol), and diisopropylethylamine (0.17 mL, 0.99 mmol) in DMF (6.0 mL) was added EDCI (76 mg, 0.40 mmol) and HOBt (54 mg, 0.40 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (43) as a white film (110 mg, 67%): 1H NMR (300 MHz, DMSO-d6) δ 13.16-12.76 (m, 1H), 7.82-7.71 (m, 1H), 7.62-7.50 (m, 1H), 7.33-7.18 (m, 1H), 4.92-4.76 (m, 1H), 4.74-4.59 (m, 1H), 4.53-4.39 (m, 2H), 3.54 (t, J=5.7 Hz, 2H), 3.21-3.01 (m, 2H), 2.86-2.69 (m, 1H), 2.66-2.53 (m, 2H), 1.83-1.62 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1.Br[CH2:37][CH2:38][OH:39].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH2:31][CH2:32][N:33]([CH2:37][CH2:38][OH:39])[CH2:34][CH:35]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1
Reactant: OCCBr
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCNCC6)cn5)C4)c3n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCN(CCO)CC6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (71 mg, 0.14 mmol) was dissolved in DMF (2 ml), and then 2-bromoethanol (16 μl, 0.22 mmol), K2CO3 (100 mg, 0.72 mmol), and Et3N (100 ul, 0.72 mmol) were added, followed by stirring at room temperature overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give 2-(4-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (10 mg, 13%).
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:17]([NH:16][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]4)=[O:18])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(N2CCCCCC2)cc1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-azepanyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.53 (s, 1H), 8.28 (d, 1H, J=8 Hz), 7.74 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.50 (t, 1H, J=8 Hz), 7.14 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.66 (d, 2H, J=9 Hz), 4.20 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.63 (s, 3H), 1.71 (m, 4H), 1.45 (m, 4H). MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N4O.0.3H2O: C, 73.18; H, 7.32; N, 14.22. Found: C, 73.08; H, 7.38; N, 14.22.
Reaction SMILES: C(OC([N:8]([C:26]1[CH:30]=[C:29]([CH3:31])[N:28](C(OC(C)(C)C)=O)[N:27]=1)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[C:12](=[O:22])[N:11]([CH:23]([CH3:25])[CH3:24])[N:10]=1)=O)(C)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:23]([N:11]1[N:10]=[C:9]([NH:8][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:20])=[CH:16][CH:17]=2)[C:12]1=[O:22])([CH3:25])[CH3:24]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(C(=O)N4CCOCC4)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-[tert-Butoxycarbonyl-(1-tert-butoxycarbonyl-5-methyl-1H-pyrazol-3-yl)-amino]-3-isopropyl-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (13 mg, 0.025 mmol) was dissolved in DMF (2 ml). To this was added morpholine (6.4 mg, 0.075 mmol) and the reaction mixture was cooled to 0° C., 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (15 mg, 0.03 mmol) and TEA (0.014 ml, 0.1 mmol) were added consecutively and the reaction mixture stirred at RT for 24 hours. After this time, the reaction mixture was partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue (13.0 mg, 0.02 mmol) was dissolved in a 20% TFA/DCM solution (2 ml) and the reaction mixture was stirred for 48 hours. After this time, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to give the corresponding 2-Isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(morpholine-4-carbonyl)-2H-phthalazin-1-one (Example M-2). 1H-NMR: (400 MHz, D6-DMSO) 9.40 (1H, s), 8.50 (1H, d), 8.23 (1H, s), 7.91 (1H, d), 6.36 (1H, s), 5.28-5.21 (1H, m), 4.12-3.30 (8H, obscured) 2.26 (3H, s), 1.33 (6H, d) MS (ESI+)=(M+H)+ 397.21.
Reaction SMILES: [NH2:1][C@H:2]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:3]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].C[B:32]1[O:37]B(C)OB(C)O1.O1CCC[CH2:41]1>>[CH:25]1([C@@H:2]2[C:3]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=3)[O:4][B:32]([O:37][CH3:41])[NH:1]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCOC1
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Reactant: CB1OB(C)OB(C)O1
Product: COB1N[C@H](C2CCCCC2)C(c2ccc3ccccc3c2)(c2ccc3ccccc3c2)O1
Reaction time: 1 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-bis(2-naphthyl)ethanol (79.1 mg, 0.2 mmol) and dry tetrahydrofuran (2 mL) and trimethylboroxine (27.2 μL, 0.24 mmol) were added to a dry flask under an atmosphere of nitrogen, then stirred for 1 hour to form a solution of (R)-4-cyclohexyl-5,5-bis(2-naphthyl)-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added and the reaction was stirred for 30 minutes. Then, a solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (3 mL) was added at the rate of 9 mL/hr by means of a syringe pump. After 2 hours, methanol was added to quench the reaction, followed by 0.5 N ethanolic HCl (0.4 mL). The solvent was removed by evaporation under vacuum and the resulting residue was chromatographed on silica gel (hexane/ethyl acetate 25:2). Combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (130 mg, 93% yield, 98.3% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C#N)cn2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A mixture of 2 g (14 mmol) 6-chloronicotinonitrile (commercially available) and 0.88 g (7 mmol) N,N-diisopropylethylamine in 20 ml water and 4 ml DMF was heated to 80° C. During 2 min 1.98 g (17 mmol) N-ethylpiperazine was added and stirred at 80° C. for 1 h. 100 ml 1M aq. Na2CO3 solution was added and the mixture was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed twice with 100 ml brine each and dried with MgSO4. After evaporation the residue was purified with flash chromatography on Alox eluting with a gradient of ethyl acetate/heptan to yield 1.4 g (45%) of the title compound as slightly yellow crystals. (m/e): 21702 (MH+; 100%).