Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[OH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[N:14]#[C:15]Br>C(Cl)Cl>[C:15]([N:11]1[CH2:12][CH2:13][CH:8]([OH:7])[CH2:9][CH2:10]1)#[N:14]
Reactant: OC1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCC(O)CC1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62 (m, 2 H), MS m/z 212.1 (M+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)=[O:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: [N-]=[N+]=NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
The title compound (194 mg, 0.63 mmol) produced in step (vi) of Reference Example 8 was dissolved in 10 ml of tetrahydrofuran and 1 ml of water, 852 mg (3.1 mmol) of triphenylphosphine was added to the solution, and the mixture was stirred at 60° C. for 5 hr. The reaction solution was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 5:1) to give 177 mg (yield 100%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.57 g, 10 mmol), benzylamine (1.20 mL, 11 mmol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in toluene (40 mL) was heated at reflux under a Dean-Stark trap for 22.75 hours. The mixture was cooled to room temperature and concentrated under vacuum to provide a yellow gummy solid (3.86 g), used without further purification. 1H NMR (300 MHz, CDCl3) δ9.25 (bt, J=6 Hz, 1H), 7.4-7.1 (m, 5H), 4.42 (d, J=6 Hz, 2H), 4.11 (s, 2H), 3.71 (s, 3H), 3.49 (t, 2H), 2.38 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[N:13][C:12]=2[NH:11][N:10]=1.C=O.[CH:41](O)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH3:41])[CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCNCC1
Reactant: O=CO
Agent: C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCN(C)CC1
Temperature: 110 °C
Yield: 23 %

Procedure:
To 4-{1-methyl-8-(methyloxy)-9-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrogen trifluoroacetate (47 mg, 0.11 mmol) was added 37% aqueous formaldehyde (10 μL) and formic acid (150 μL). The mixture was heated to 110° C. for 1.5 h before cooling to rt. The mixture was diluted with a 1:1 mixture of water:acetonitrile and purified by preparative HPLC. The fractions containing desired product were combined, concentrated, and lyophilized to provide 4-(1-methyl-8-(methyloxy)-9-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol trifluoroacetate (14.1 mg, 0.026 mmol, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ9.93 (br m, 2H), 7.87 (d, 1H), 7.48 (d, 2H), 7.44 (d, 1H), 6.96 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 3.00-2.96 (q, 2H), 2.83 (s, 3H), 2.74 (d, 3 h), 2.18 (m, 1H), 2.09 (br d, 2H), 1.61-1.52 (m, 2H); MS (EI) for C25H28N4O3: 433 (MH+).
Reaction SMILES: C([O-])([O-])=O.[Ca+2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH2:15])[C:9]=2[O:8][CH2:7]1.[I:16](Cl)(=O)=O.I(Cl)(=O)=O.C[N+](C)(C)CC1C=CC=CC=1>C(Cl)Cl.CO.O>[I:16][C:11]1[C:10]2[O:6][CH2:7][O:8][C:9]=2[C:14]([NH2:15])=[CH:13][CH:12]=1
Reactant: O=I(=O)Cl
Reactant: Nc1cccc2c1OCO2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(I)c2c1OCO2
Temperature: 25 °C
Yield: 62.4 %

Procedure:
CaCO3 (3.9 g) was added to a mixture of 1,3-benzodioxol-4-amine (4.11 g) in DCM (40 ml) and CH3OH (20 ml). This mixture was stirred at room temperature. N,N,N-trimethyl benzenemethanaminium dichloroiodate (11.5 g) was added portionwise at room temperature. The resulting reaction mixture was stirred for 15 minutes at room temperature. The mixture was diluted with water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 80/20). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 3.5 g (46.9%) of 7-iodo-1,3-benzodioxol-4-amine (intermediate 2-a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([NH2:10])=[CH:6][C:7]=1[O:8][CH3:9].[CH:12](OCC)(OCC)OCC>C(O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]2[NH:10][CH:12]=[N:11][C:4]=2[CH:3]=1
Reactant: COc1cc(N)c(N)cc1Br
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: COc1cc2[nH]cnc2cc1Br

Procedure:
To a stirred mixture of 4-bromo-5-methoxybenzene-1,2-diamine (3.8 g, 18 mmol) from Step 1 of this Example and triethyl orthoformate (50 mL) was added formic acid (1 mL). The mixture was heated at reflux for 3 h, then concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and a 1 N aq Na2CO3 (100 mL). The EtOAc layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 5-bromo-6-methoxy-1H-benzo[d]imidazole (4.0 g) as a brown oil. The material was used in the next step without further purification. LCMS (ESI) m/z 228 and 230 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl.O>CCOCC>[C:7]([C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1cccs1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Bromothiophene (9.7 ml., 0.1 mole), benzoyl chloride (11.6 ml., 0.1 mole) and stannic chloride (11.5 ml., 0.1 mole) were combined in 100 ml. of methylene chloride and stirred at room temperature for 4 hours. The reaction mixture was cooled to room temperature, water (65 ml.) was added and the two phase system stirred for 20 minutes. Ether (165 ml.) was added, the organic phase was separated, back-washed with 20 ml. of 1 N sodium hydroxide and twice with 20 ml. of water, and concentrated to an oil (20.8 g.) which crystallized on standing. The crude was melted by warming with 25 ml. of hexane (two phases formed) and cooled to yield purified crystalline 5-benzoyl-2-bromothiophene (16.5 g., m/e 266/268).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20]([C:23](=[O:45])[CH:24]([NH:28][C:29](=[O:44])[CH:30]([N:32](C(OCC3C=CC=CC=3)=O)[CH3:33])[CH3:31])[CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20]([C:23](=[O:45])[CH:24]([NH:28][C:29](=[O:44])[CH:30]([NH:32][CH3:33])[CH3:31])[CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C)C(C)C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A 500 mL Parr bottle was charged with crude 16 (50 mg, 0.08 mmol) and 10% Pd-on-carbon (50 mg) in reagent grade MeOH (3 mL). The mixture was pressurized to 50 PSI H2 then shaken for 2 h. The catalyst was removed by filtration through Celite® and the solids were washed with MeOH and EtOAc. The filtrate was concentrated in vacuo. The crude product was purified by RP-HPLC (2″ Dynamax® C18, 10-70% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 20 mg (51%) of 17 after lyophilization.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:19][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:20])=[C:2]([N:35]3[C:29]4[C:30](=[N:31][CH:32]=[C:27]([N:24]5[CH2:25][CH2:26][O:21][CH2:22][CH2:23]5)[CH:28]=4)[C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:34]3)[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine (40 mg, 0.138 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (37.9 mg, 0.138 mmol), sodium tert-butoxide (26.4 mg, 0.275 mmol) and XPhos precatalyst (10.4 mg, 0.014 mmol) in toluene (4 mL) at 110° C. for 2 h. Purification by reverse phase HPLC (10 to 50% acetonitrile in water) gave 1′-(2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.59 (1H, d, J=1.0 Hz), 8.57 (1H, d, J=5.9 Hz), 7.69 (1H, d, J=2.3 Hz), 7.51 (1H, dd, J=5.9, 1.0 Hz), 7.15-7.22 (2H, m), 6.94-7.01 (1H, m), 5.82 (1H, d, J=2.3 Hz), 4.12-4.21 (2H, m), 3.94-4.05 (2H, m), 3.71-3.81 (4H, m), 3.59 (2H, tt, J=11.4, 2.8 Hz), 2.93-3.07 (4H, m), 2.28-2.45 (5H, m), 1.72-1.88 (2H, m). Mass Spectrum (ESI) m/e=530.2 (M+1).
Reaction SMILES: C([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[OH2:39]>Cl>[NH2:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:21])[OH:18])[C:6]([OH:39])=[O:7]
Reactant: O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 2-acetamido-2-(1-benzylpiperidin-4-yl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (510 mg, 0.97 mmol) in 6 N HCl (15 mL) was heated to a gentle reflux for 16 h. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (15 mL) and washed with dichloromethane (3×25 mL). The aqueous layer was concentrated to give an off-white solid that was purified by HPLC (5-95% acetonitrile in water). The fractions containing product were concentrated, redissolved in deionized water (15 mL), frozen in liquid nitrogen and lyophilized to give 2-amino-2-(1-benzylpiperidin-4-yl)-6-boronohexanoic acid (210 mg, 62%) as its dihydrochloride salt and trihydrate. 1H NMR (D2O, 500 MHz) δ 7.37-7.43 (m, 5H), 4.21 (s, 2H), 3.51 (brt, J=10 Hz, 2H), 2.92-2.99 (m, 2H), 2.02-2.10 (m, 2H), 1.66-1.84 (m, 4H), 1.41 (dq, J1=13.0 Hz, J1=4.0 Hz, 1H), 1.29-1.35 (m, 2H), 1.23-1.28 (m, 1H), 1.08-1.12 (m, 1H), 0.68 (t; J=8.0 Hz, 2H). ESI MS found for C18H29BFN2O4 m/z [331.6 (M+1−18) 13%, 313.6 (M+1−2×18) 100%, 329.6 (M−1−18) 100%]. Anal. Calcd for C18H29BN2O4×2HCl×3H2O: C, 45.49; H, 7.85; N, 5.89. Found C, 45.60; H, 7.10; N, 5.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][Mg]Cl.[Al:12](Cl)([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][CH:14]([CH3:16])[CH3:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][Al:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[Al](Cl)CC(C)C
Reactant: COc1ccccc1C[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccccc1C[Al](CC(C)C)CC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
150 ml (39 mmol) of (2-methoxybenzyl)magnesium chloride as 0.26 molar solution are added dropwise over the course of 3 hours at 0° C. to 6.83 g (38.7 mmol) of iBu2AlCl in 250 ml of tetrahydrofuran. The mixture is slowly brought to room temperature and stirred at room temperature for 18 h. The solvent is removed under reduced pressure (0.05 mbar), and the residue is suspended in 125 ml of n-pentane. The mixture is subsequently filtered through a D4 frit. After removal of the n-pentane, fractional distillation gives (2-methoxybenzyl)diisobutylaluminium as colourless, viscous liquid having a boiling point of 85° C. at 0.05 mbar.
Reaction SMILES: [Cl-].[Br-].ClC1N=C2N=C(CCC)NC2=C(C)C=1.Br.[Br:18][C:19]1[N:24]=[C:23]2[N:25]=[C:26]([CH2:28][CH2:29][CH3:30])[NH:27][C:22]2=[C:21]([CH3:31])[CH:20]=1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(=O)C.CN(C=O)C>[CH2:34]([N:25]1[C:23]2=[N:24][C:19]([Br:18])=[CH:20][C:21]([CH3:31])=[C:22]2[N:27]=[C:26]1[CH2:28][CH2:29][CH3:30])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCc1nc2nc(Br)cc(C)c2[nH]1
Reactant: BrCc1ccccc1
Agent: Br
Agent: CCCc1nc2nc(Cl)cc(C)c2[nH]1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1

Procedure:
7-Methyl-2-propylimidazo[4,5-b]pyridine-5-carboxylic acid or the 2-ethyl analog is prepared from 7-methyl-2-propylimidazo[4,5-b]pyridine or the 2-ethyl analog by treatment with m-chloroperoxybenzoic acid to obtain the N-oxide which is then treated with POCl3 to give 5-chloro-7-methyl-2-propylimidazo-[4,5-b]pyridine or 2-ethyl analog. The chloride is then exchanged for a bromide by reaction of 5-chloro-7-methyl -2-propylimidazo[4,5-b]pyridine or the 2-ethyl analog with HBr in acetic acid. The resulting 5-bromo-7-methyl-2-propylimidazo[4,5-b]- pyridine or 2-ethyl analog is treated with NaH in DMF followed by benzyl bromide to obtain 3-benzyl-5-bromo -7-methyl-2-propylimidazo[4,5-b]pyridine or its corresponding 2-ethyl analog which is in turn treated with CuCN in hot pyridine to obtain 3-benzyl -5-cyano-7-methyl-2-propylimidazo[4,5-b]pyridine or the corresponding 2-ethyl analog. The cyano compound is hydrolyzed to 3-benzyl-7-methyl-2-propylimidazo -[4,5-b]pyridine-5-carboxylic acid or the corresponding 2-ethyl analog by treatment with H2SO4 -H2O. This acid is esterified by reaction with MeOH-HCl. The benzyl group is removed by hydrogenation at 1 arm in MeOH-HCl solution using Pd(OH)2 as catalyst. This compound can be alkylated as described earlier and the product methyl ester is converted to the carboxylic acid by treatment with hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([OH:16])=O)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].Cl.[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:16])[NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)c1cnc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Reaction time: 3 h

Procedure:
To a solution of 9.5 g 1H-Pyrrolo[2,3-b]pyridine-2,5-dicarboxylic acid 5-methyl ester in 120 mL DMF and 23.9 mL NEt3, 9.2 g 1-Isopropyl-piperidin-4-ylamine hydrochloride and 11 g BOP-Cl were added at RT and the mixture was stirred for 3 h. After addition of 20 mL of water the reaction mixture was extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with brine (1×50 ml) and then dried over MgSO4. After filtration the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with EtOAc/MeOH 9:7->EtOAc/MeOH/NH3(aq.) 6:4:0.04. The fractions containing the product were evaporated and codestilled with toluene. Yield: 7.2 g.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.Br[C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][CH:43]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:38]4[CH:43]=[N:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(C(F)(F)F)nc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenantroline with 3,4,7,8-tetramethylphenantroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.20 mmol) and 5-bromo-2-trifluoromethylpyridine (59 mg, 0.26 mmol) gave the title compound as a brown oil after purification by preparative HPLC (15 mg, 14%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:18]([Br:19])=[CH:17][S:16][CH:15]=1.CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[C:18]([Br:19])=[CH:17][S:16][C:15]=1[CH:23]=[O:24]
Reactant: Brc1cscc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1scc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (1.3 g, 12.5 mmol) in 15 mL of anhydrous THF was added n-BuLi (4.0 mL, 2.5 M in hexane) at −78° C. After the mixture was stirred at −78° C. for 0.5 h 3,4-dibromothiophene (2 g, 8.3 mmol) in anhydrous THF (20 mL) was added. The mixture was stirred at −78° C. for 15 min., a solution of DMF (670 mg, 9.2 mmol) in THF (5 mL) was added. After being stirred at this temperature for 0.5 h, the mixture was stirred at room temperature for 2 hours. The mixture was quenched with NH4Cl saturated solution, diluted with water, extracted with EtOAc, concentrated, and purified by column chromatography to give 3,4-dibromothiophene-2-carbaldehyde (1.0 g, yield 45%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[O:9])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=3[Cl:17])=[O:9])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccc(Br)nc1)c1cc(Br)ccc1Cl
Product: O=C(c1ccc(-c2ccccc2)nc1)c1cc(Br)ccc1Cl

Procedure:
The above 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone and phenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone as yellow crystals. APCI-Mass m/Z 372/374 (M+H).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@H:34]([O:35]C(=O)C)[C@H:29]([O:30]C(=O)C)[C@H:24]2[O:25]C(=O)C)[C@@H:15]([CH2:46][O:47]C(=O)C)[O:14][C@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[C@@H:23]1([O:22][C@@H:16]2[C@@H:15]([CH2:46][OH:47])[O:14][C@@H:9]([O:10][CH2:11][CH2:12][Br:13])[C@H:8]([OH:7])[C@H:17]2[OH:18])[O:40][C@H:39]([CH2:41][OH:42])[C@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OCCBr)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A solution of NaOMe (0.1 M, 0.6 mL) was added to a solution of 4k (See FIG. 7) (877 mg, 1.18 mmol) in MeOH (6 mL) under N2. After 3 hours, the reaction solution was passed through a Dowex 5OW(H+) plug (4×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl 4-O-β-D-galactopyranosyl-β-D-glucopyranoside (4f) (See FIG. 7) (476 mg, 90%) as a white foam which was used directly in the next step. NaSSO2CH3 (185 mg, 1.38 mmol) was added to a solution of 4f (See FIG. 7) (476 mg, 1.06 mmol) in DMF (24 mL) under N2 and warmed to 50° C. After 21 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (CHCl3:MeOH: AcOH: H2O, 60:30:3:5) to give If (See FIG. 7) (346 mg, 68%) as a hygroscopic foam; [α]28D=+1.5 (c 1.66, H2O); IR (KBr) 3416 cm−1 (br, OH), 1311, 1131 cm−1 (S—SO2); 1H NMR (400 MHz, D2O, COSY) δ 3.10-3.13 (m, 1H, H-2), 3.30 (t, J6.0 Hz, 2H —CH2S—), 3.31 (dd, J1′,2′ 7.8 Hz, J2′,3′ 10.3 Hz, 1H, H-2′), 3.34 (s, 3H, CH3SO2—), 3.38-3.54 (m, 5H), 3.44 (dd, J2′,3′ 10.3 Hz, J3′,4′ 3.3 Hz, 1H, H-3′), 3.57 (dd, J8.4 Hz, J 11.4 Hz, 1H), 3.59 (dd, J4.9 Hz, J7.3 Hz, 1H), 3.70 (br d, J3′,4′ 3.3 Hz, 1H, H-4′), 3.77 (dd, J1.0 Hz, J11.5 Hz, 1H), 3.79-3.83 (m, 1H, —OCHH′—), 3.97-4.02 (m, 1H, —OCHH′—), 4.22 (d, J1′,2′ 7.8 Hz, 1H, H-1′), 4.33 (d, J1,2 7.8 Hz, 1H, H-1); 13C NMR (125 MHz, D2O) δ 36.7 (—CH2S—), 50.8 (CH3SO2—), 61.0, 62.1, 69.4, 69.6, 71.9, 73.5, 73.7, 75.3, 75.9, 76.4, 79.3 (—OCH2—, C-2, C-3, C-4, C-5, C-6, C-2′, C-3′, C-4′, C-5′, C-6′), 103.3, 103.9 (C-1, C-1′); HRMS m/z (FAB+): Found 503.0886 (M+Na+); C15H28O13S2Na requires 503.0869.