Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[C:13]2=[CH:14][NH:15][C:16]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:12]2[C:11](=[O:23])[N:10]([CH3:24])[C:9]1=[O:25].Br[CH2:27][CH:28]([S:41][C:42]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CC(N(C)C)=O>[O:39]=[C:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:40])[N:30]1[CH2:29][CH:28]([S:41][C:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:27][N:15]1[C:16]([C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[C:12]2[C:13]([N:8]([CH3:7])[C:9](=[O:25])[N:10]([CH3:24])[C:11]2=[O:23])=[CH:14]1
Reactant: O=C1c2ccccc2C(=O)N1CC(CBr)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (1.537 g, 4.72 mmol) was added to a solution of 1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Nd) (0.652 g, 2.359 mmol) and 2-(3-bromo-2-(tritylthio)propyl) isoindoline-1,3-dione (2.011 g, 2.59 mmol) in dimethylacetamide (10 ml) and the mixture was stirred at 55° C. for 16 hours. The mixture was cooled to room temperature, partitioned between water (150 ml) and ethyl acetate (150 ml). The organic layer was separated, washed with brine (150 ml), dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-75% EtOAc/hexane afforded the title compound.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.CCOCC>[CH:21]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ccc2ncn(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.300 g, 1.33 mmol) was dissolved in THF and NaH (0.050 g, 2.0 mmol) was added portionwise. The resulting mixture was heated in a sealed tube for 1 h and then cooled to room temperature. Bromocyclopentane (0.20 g, 17.8 mmol) was added and the reaction was heated to 70° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether and the combined organic portions were washed with brine, dried over MgSO4 and purified by preparative HPLC. The resulting 5-(benzyloxy)-3-cycloheptyl-3H-imidazo[4,5-b]pyridine was then dissolved in DCM and diluted with excess sulfuric acid. The resulting solution was stirred for 30 minutes at room temperature then acidified with the addition of 1 M aqueous hydrochloric acid. The solvent was removed from the organic layer and the residue was purified via preparative HPLC to give the title compound (0.0284 g). LCMS m/z=204.31 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 2H), 1.80-1.95 (m, 2H), 2.0-2.1 (m, 2H), 2.15-2.30 (m, 2H), 4.95-5.05 (m, 1H), 6.88 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 9.35 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4'-methylphenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetate/hexane) to afford 4-(4'-methylphenoxy)phenol.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>C1COCC1>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[O:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydride (492.0 mg, 12.30 mmol) was added to a solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2.095 g, 10.41 mmol) in THF (20 mL) and the reaction stirred at 0° C. for 15 minutes. A suspension of 4-chloro-3-nitro-pyridine (1.5 g, 9.461 mmol) in THF (10 mL) was added and the reaction allowed to warm slowly to ambient temperature over 2 hours. The reaction was quenched with water and the mixture was partitioned between EtOAc and brine. The combined organic extract was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether) to give tert-butyl (3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate as a pale yellow solid (2.65 g, 87% Yield, 93% ee). MS (ES+) 324.1.
Reaction SMILES: CN([CH2:4][C:5]1OC(CSCCN)=CC=1)C.[CH2:15]([S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25])(=[O:19])=[O:18])[CH3:16]>>[CH2:15]([S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25])(=[O:19])=[O:18])[CH2:16][CH2:4][CH3:5]
Reactant: CCS(=O)(=O)Nc1cccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CCCCS(=O)(=O)Nc1cccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 100 %

Procedure:
In the same manner, by reacting 0.02 mole of 2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 mole of 4-nitrophenyl 3-ethanesulfonamidobenzoate and, respectively, with 0.02 mole of 4-nitrophenyl 3-butanesulfonamidobenzoate, there is obtained
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]1(B(O)O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)[nH]1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc3ccccc23)[nH]1
Yield: 81.6 %

Procedure:
Argon gas was bubbled 15 min through a solution of 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol, 2.04 g), 1-naphthylboronic acid (30.0 mmol, 5.16 g), 2M aqueous sodium carbonate (20 ml), and DMF (150 ml). The mixture was then treated with tris(dibenzylidienacetone)dipalladium (0) (0.50 mmol, 0.46 g), and triphenylarsine (2.0 mmol, 0.61 g), then heated to reflux under argon for 12 h. The mixture was partitioned between ethyl acetate (500 ml) and water (150 ml). The organics were filtered through celite, washed with brine (3×50 ml), then concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 2.05 g (81%) of 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ9.37 (1H, s), 8.22-8.17 (1H, m), 8.16-7.89 (2H, m), 7.59-7.50 (4H, m), 7.88 (1H, dd, J=3.9, 2.7), 6.22 (1H, dd, J=3.8. 2.6), 3.88 (3H, s).
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:14]([NH:16][CH3:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:4]2[C:3]([C:1]#[N:2])=[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:6][C:5]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:22][CH:21]=1
Reactant: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of 4-cyano-3-iodo-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (0.055 g, 0.14 mmol), 4-chlorophenylboronic acid (0.046 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.014 mmol) and sodium carbonate (0.046 g, 0.44 mmol) in 1,2-dimethoxyethane (0.71 mL) and water (0.37 mL) was allowed to stir at 80° C. overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give 3-(4-chlorophenyl)-4-cyano-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (69) (0.030 g, 57%).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([N:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]1[CH3:25])[CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][CH:11]([N:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]1[CH3:25])[CH2:10]2
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2
Temperature: 25 °C
Yield: 66 %

Procedure:
2.2 g (6.65 mmol) 1-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole was dissolved in 150 ml ethanol and 2.09 g (33.23 mmol) ammonium formate and 0.4 g palladium hydroxide (20% on carbon) were added. The mixture was refluxed for 2.5 hrs. The mixture was cooled to ambient temperature and filtered through celite. The solvent was removed under reduced pressure and the crude product was purified by column chromatography CH2Cl:CH3OH:NH4OH (95:5:0.5) to afford 1.06 g of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][OH:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: NO
Reactant: COC(=O)c1ccc(Br)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NO)c1ccc(Br)cc1O
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A solution of methyl 4-bromo-2-hydroxybenzoate (Intermediate 22) (0.7 g) in dioxan (5 ml) was added dropwise to a solution of hydroxylamine hydrochloride (0.32 g) and sodium hydroxide (0.42 g) in water (10 ml) then stirred at room temp. for 18 h. The dioxan was removed under vacuum and the residue was stirred with 2N hydrochloric acid to give a precipitate which was collected by filtration, washed with water and dried to give the title compound as an off-white solid (0.63 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C@H:17]([NH:16][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]([CH3:20])[CH3:19])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CNCCC1c1ccc(F)cc1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(c2ccc(F)cc2)C(C)(C)C1

Procedure:
The title compound was prepared from 4-(4-fluorophenyl)-3,3-dimethylpiperidine and Boc-D-Val-OH using the procedure described in Example 581, Step 5. MS (ESI+)=351.40, (M-tert-Bu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.CCN(C(C)C)C(C)C.[N:48]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][C@H:49]1[C:58]([OH:60])=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30][C:58]([CH:49]2[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:57][N:48]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:60])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:29])[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 52 %

Procedure:
N-[(1R)-1-[(4-Chlorophenyl)methyl]-2-(4-{2-[methyl-(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-(tert-butoxy)carboxamide (Step 2) (327 mg, 0.593 mmol) was stirred with 25 mL of HCl satd EtOAc. The resulting crude material was diluted with EtOAc and washed with a satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. This material was treated with DIEA (115 μl, 0.660 mmol), Boc-L-Tic-OH (167 mg, 0.602 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (500 mg, 1.68 mmol), and HOAT (99 mg, 0.727 mmol) according to the procedure for preparation XIX. The crude was purified by flash chromatography (SiO2, 10% EtOAc in CH2Cl2) and concentrated in vacuo to yield tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (219 mg). MS (ESI, pos. ion) m/z: 710 (M+H), (ESI, neg. ion) m/z: 708 (M−H). Calc'd for C36H44ClN5O6S: 710.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[K+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Product: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
In an oven-dried flask was placed 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (2.0 g, 4.90 mmol), phenylboronic acid (627.5 mg, 5.15 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (1:1) (200.14 mg, 0.24 mmol). Degassed acetonitrile (53 mL) was added, followed by 1.0 M aqueous sodium carbonate solution (7.4 mL) and 1.0 M aqueous potassium acetate solution (7.4 mL). The reaction mixture was degassed under N2 for 5 minutes more and stirred at 80° C. under N2 for 1 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water and the layers were separated. The organic layer was washed with water (3×) and brine, dried over Na2SO4 and concentrated to an oil. The crude product was purified using flash column chromatography (Si-PPC gradient elution, solvent: 0-60% ethyl acetate in heptanes) to give 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a solid (1.45 g, 82.47%). 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J=0.9 Hz, 1H), 8.08 (d, J=0.9 Hz, 1H), 7.94-7.88 (m, 2H), 7.55-7.48 (m, 2H), 7.48-7.41 (m, 1H), 5.86 (dd, J=8.6, 2.6 Hz, 1H), 4.07-3.97 (m, 1H), 3.80 (ddd, J=12.3, 8.9, 3.8 Hz, 1H), 2.54 (qd, J=9.0, 5.5 Hz, 1H), 2.24-2.11 (m, 2H), 1.89-1.67 (m, 3H). LC/MS: m/z 274.1 (des-THP) [M+1]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.6 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethyl]-1,2-benzenediamine (212 mg, 0.75 mmol) and pyridine (4 mL) in chloroform (2 mL) at 0° C. was treated with a solution of 4-methoxybenzoyl chloride (128 mg, 0.75 mmol) in chloroform. The mixture was allowed to warm to room temperature and stir for 17 h. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with 1 N NaOH (2×), water (3×), brine (1×), dried (K2CO3), and concentrated. The residue was purified by RPHPLC, yielding 52 mg (17%) of the title compound as a hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[C:17]1(=[O:24])[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1.CC(C)(O)C#N.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]([CH:18]2[C:19](=[O:23])[CH2:20][CH2:21][CH2:22][C:17]2=[O:24])=[O:16])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2cccnc12
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)C1C(=O)c1ccc([N+](=O)[O-])c2cccnc12
Reaction time: 4 h

Procedure:
1.0 g of 5-nitro-8-quinolinecarboxylic acid together with 0.5 g of 1,3-cyclohexanedione and 1.0 g of dicyclohexylcarbodiimide were stirred in 15 ml of acetonitrile at room temperature for about 12 hours. 0.7 g of triethylamine and 0.2 ml of acetone cyanohydrin were then added. After 4 hours, the reaction solution was poured into aqueous sodium carbonate solution and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, the solvent was distilled off and the residue was chromatographed over silica gel.
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.[CH:16](=[N:23]/[OH:24])\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>CC#N>[CH:16](=[N:23][O:24][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Reactant: O/N=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(ON=Cc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
(Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (330 mg, 1.56 mmol), (E)-benzaldehyde oxime (286 mg, 2.36 mmol) and DBU (0.007 mL, 0.05 mmol) were combined in MeCN (0.5 mL) and the mixture was stirred at room temperature for 48 hr. The solvent was removed under reduced pressure and the residue purified via preparative HPLC to give tert-butyl 5-(benzylideneaminooxy)-3-oxoazepane-1-carboxylate as a brown oil (127 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13]C(=O)OC(C)(C)C)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CO>CO>[ClH:1].[Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:10][CH:11]([NH2:13])[CH2:12]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2nccnc2Cl)C1
Agent: Cl
Solvent: CO
Product: NC1CC(Oc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
To a mixture of tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (2.8 g, 9.61 mmol) in MeOH (20 mL) was added HCl/MeOH (20 mL, saturated with HCl gas), and then stirred at RT for 1 hour. The reaction mixture was concentrated to give 3-((3-chloropyrazin-2-yl)oxy)cyclobutanamine hydrochloride (2.2 g, 9.61 mmol, 100%). ESI-MS (M+1): 200 calc. for C8H10ClN3O 199.
Reaction SMILES: [NH2:1]C1C=CC(C)=CC=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([NH2:1])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 132.6 %

Procedure:
To an ice cold stirred solution of p-toluidine (5.00 g, 47 mmol) and triethylamine (6.5 ml, 51 mmol) in dry THF (100 ml) under argon was slowly added benzenesulphonyl chloride (5.9 ml, 47 mmol). A white precipitate formed. The ice bath was removed and the reaction stirred at ambient temperature for four hours. THF was evaporated under reduced pressure and the resulting oil partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (100 ml). The organic layer was separated and washed with 2M hydrochloric acid (3×75 ml), water (75 mi), 5% sodium hydrogen carbonate (3×75 ml) and finally water (75 ml). 4-he solution was then dried over MgSO4, filtered and evapourated to give the crude sulphonamide, which was crystallised from ethyl acetate/hexane to give N-4-methylbenzll phenylsulphonamide (9.8 g, 85%) as a white crystalline solid.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH2:4][CH2:3]1.C[Al](C)C.[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33](OCC)=[O:34])=[O:27])[CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33]([NH:16][C:13]2[CH:14]=[CH:15][N:10]3[N:9]=[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)[N:17]=[C:11]3[CH:12]=2)=[O:34])=[O:27])[CH2:23][CH2:24][CH2:25]1
Reactant: Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To an nitrogene purged suspension of 2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (80 mg, 0.313 mmol) and N-ethyldiisoppropylamine (120 ul, 0.688 mmole) in dioxane (3 ml) is added trimethyl aluminium (2 M solution in toluene, 0.47 ml, 0.94 mmol). The resulting solution is stirred for ½ hour at room temperature. Then ethyl 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylate (75 mg, 0.313 mmol) in dioxane (0.7 ml) is added and the mixture is heated to reflux in a sealed vessel and stirred for 19 hours. Purification of the reaction mixture by chromatography on a 12 g RediSep silica cartridge (eluent dichloromethane+4% methanol) affords 4-(azetidine-1-carbonyl)-1-methyl-N-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (106 mg, 82.5%) as an off-white solid. mp.: 232-4° C. MS: m/z=411.3 (M+H+).