Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42]Cl>CN(C=O)C.CCOCC.Cl>[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[C:4]([OH:3])=[O:35])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(CCl)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccc(C(F)(F)F)cc4)C(=O)O)cc3)N(C)C2=O)cc1C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.06 mL of 3,4-dimethylbenzyl chloride is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 ml). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 54 mg (56%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.6 Hz), 7.16 (d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 6.99-6.94 (m, 3H), 6.75 (d, 2H, J=8.4 Hz), 4.33, 4.25 (ABq, 2H, J=14.8 Hz), 4.07 (bs, 1H), 3.97-3.93 (m, 2H), 3.70-3.65 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.32, 3.16 (ABq, 2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.85 (s, 3H), 2.28-2.20 (m, 1H), 2.22 (s, 3H), 1.96-1.88 (m, 1H), 1.50 (s, 3H). HRMS (ES+) m/z exact mass calcd for C32H36N2O5F3 (m+1) 585.2576, found 585.2578.
Reaction SMILES: C[C:2]1[CH:8]2[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7]2)[C:4](=[O:5])[CH:3]=1.I([O-])(=O)(=O)=[O:13].[Na+].[OH2:18]>C(#N)C.C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[C:2]([C@H:8]1[CH2:7][C@@H:6]([C:4]([OH:13])=[O:5])[C:9]1([CH3:11])[CH3:10])(=[O:18])[CH3:3]
Reactant: O
Reactant: CC1=CC(=O)C2CC1C2(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(−)-Verbenone (615 mg, 4.09 mmol) was dissolved in a mixture of acetonitrile (2.0 mL), CCl4 (2.0 mL) and water (3.0 mL). Sodium periodate (3.59 g, 16.79 mmol) and ruthenium(III) chloride hydrate (18.68 mg, 0.090 mmol) were added and the resulting biphasic mixture was stirred vigorously at room temperature for 24 hrs. The reaction mixture was then diluted with DCM, washed with H2O and extracted with DCM (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid as a pale yellow oil, which was used without further purification. MS ESI calc'd. for C9H15O3 [M+H]+ 171. found 171.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][CH:15]=[C:16](SC)[N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:22][C:23]2[S:24][C:25]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=CNCCSCc1ccc(CN(C)C)o1)[N+](=O)[O-]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Nc2nc3ccc([N+](=O)[O-])cc3s2)o1
Yield: 58 %

Procedure:
By reacting 1-[[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethylamino]-2-methylthio-2-nitroethene with 2-amino-6-nitrobenzothiazole, according to the procedure described in Example 4, the product was obtained in a 58% yield.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[O:6]=[C:7]([N:10]([C:17]1([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH3:9].[C:27](=[O:30])([O-:29])[O-].[Na+].[Na+].[I-].[K+]>CC1C=CC=CC=1>[C:23]([OH:25])(=[O:24])[C:27]([OH:29])=[O:30].[CH:5]1([CH2:4][N:20]2[CH2:21][CH2:22][C:17]([N:10]([C:7](=[O:6])[CH2:8][CH3:9])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19]2)[CH2:3][CH2:2]1
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCNCC1
Reactant: BrCC1CC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CC2CC2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 4.5 parts of (bromomethyl)cyclopropane, 4.8 parts of methyl 4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate, 5 parts of sodium carbonate, 0.3 parts of potassium iodide and 63 parts of methylbenzene is stirred and refluxed for 4 h. The reaction mixture is cooled and filtered. The filtrate is washed with water, dried, filtered and evaporated. The oily residue is dissolved in petroleumether. The solution is filtered and the filtrate is evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in 2-propanone. The salt is filtered off and dried, yielding methyl 1-(cyclopropylmethyl)-4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate ethanedioate; mp. 171.4° C.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[NH:41]1[CH2:51][CH2:50][CH2:49][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]1>>[CH3:34][C:33]1[CH:32]=[CH:31][O:30][C:29]=1[C:27]([NH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:17]=[C:12]([C:10]([N:9]=[S:7]([CH2:3][C:4]([N:41]3[CH2:51][CH2:50][CH2:49][C@H:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]3)=[O:5])([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:8])=[O:11])[CH:13]=[N:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)[C@H]1CCCN(C(=O)CS(=O)(=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)c2ccccc2)C1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and ethyl nipecotate were reacted to give the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Rh].C(O)C>[CH:1]1([CH:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1OCCC1c1ccccc1
Agent: [Rh]
Solvent: CCO
Product: O=C1OCCC1C1CCCCC1
Yield: 92.1 %

Procedure:
Stir a mixture of 3-phenyl-dihydro-furan-2-one (9.0 g), rhodium on carbone (5%, 3.62 g) and ethanol (220 mL) on a hydrogenation parr shaker at 60 psi, 60° C. for 18 hours. Remove the reaction from the parr shaker and filter the mixture through celite, concentrate the filtrate to afford 8.6 g (92%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:30][CH2:31]2)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)N1CCNCC1
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(=O)N1CCN(Cc2nc3ccccc3c(OCc3ccccc3)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (200 mg), 1-hexanoylpiperazin (130 mg), potassium carbonate (111 mg), and DMF (6 mL) was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 4-(benzyloxy)-2-[(4-hexanoylpiperazin-1-yl)methyl]-3-methylquinoline (241 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH:28]=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
The product from Step B was dissolved in methanol (20 mL) with naphthalene-1-carboxaldehyde (0.67 mL, 4.7 mmol), sodium cyanoborohydride (0.350 g, 5.6 mmol) at pH 6 (adjusted with acetic acid) and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with ethyl acetate in hexane, and the title compound isolated as an oil. NMR (CDCl3, 300 MHz) d 8.34 (1H, d, J=7 Hz), 7.85 (1H, dm, J=7 Hz), 7.79 (1H, m), 7.51 (2H, m), 7.39 (2H, m), 4.34 (1H, d, J=12 Hz), 3.98 (1H, br s), 3.91 (1H, dd, J=12, 6 Hz), 3.75 (3H, s), 3.60 (1H, br s), 3.44 (1H, d, J=12 Hz), 3.27 (1H, t, J=3 Hz), 3.19 (1H, d, J=12 Hz), 3.09 (1H, td, J=10, 3 Hz), 2.42 (1H, br s), 1.44 (9H, s).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].C([Li])CCC>O1CCCC1.CCCCCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)(=[O:38])=[O:39])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried 500 mL three necked round bottom flask was equipped with a magnetic stir bar, a nitrogen inlet, a septum, and a stopper. The flask was purged with nitrogen then charged with a solution of 5.083 g (28.2 mmol) of 3,4-methylenedioxyphenylacetic acid and 220 mL of anhydrous tetrahydrofuran. The contents were stirred at -78° C. and 5.11 mL of triethylamine (36.7 mmol) and 3.82 mL (31.0 mmol) of trimethylacetyl chloride were successively added. The reaction mixture was stirred at -78° C. for 15 minutes, then at 0° C. for one hour. In a separate oven dried flask, a solution of 10.120 g (50.8 mmol) of 4-(i-propyl)benzenesulfonamide dissolved in 110 mL of tetrahydrofuran was treated with 20.31 mL of a 2.5N solution of n-butyllithium in hexane at -78° C. A heavy precipitate of the deprotonated sulfonamide formed during the addition which prevented stirring. The flask and its contents were then warmed to room temperature and 60 mL of dimethylsulfoxide were added which effected solution of the lithiated sulfonamide. The solution of the lithiated sulfonamide was then transferred via cannula to the stirred 0° C. reaction mixture containing the mixed anhydride. After the addition was complete, the reaction mixture was stirred an additional 3 hours, then it was quenched by addition of excess 10% aqueous NaHSO4. The majority of the THF was next removed in vacuo, and the remainder of the mixture was partitioned between EtOAc and saturated brine. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 2.5% MeOH--CHCl3. The purified fractions were combined, evaporated and then recrystallized from methylene chloride-hexane to afford 6.623 g (65%) of the title compound as an off-white crystalline solid which had: mp=262°-3° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27]CC4C=CC=CC=4)=[C:16]([O:19]CC4C=CC=CC=4)[CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[N:5][N:4]=[N:3]1.[ClH:35]>C(O)C>[ClH:35].[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21
Agent: Cl
Solvent: CCO
Product: Cn1nnnc1SCC1=NCCc2cc(O)c(O)cc21

Procedure:
A mixture of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 6,7-dibenzyloxy-3,4-dihydroisoquinoline (1g), 99% ethanol (10 ml) and concentrated hydrochloric acid (10 ml) was refluxed for 3 hours. After the reaction the solvent was distilled off and the residue was crystallized from a mixture of isopropanol and ether to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 6,7-dihydroxy-3,4-dihydroisoquinoline hydrochloride (0.75 g), mp 130°C (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:23][CH3:24])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 5-(4-chlorophenyl)-2-methyl-3-furancarboxylic acid (4.7 g), potassium carbonate (2.8 g) and ethyl iodide (3.7 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 95%) as a yellow crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2ccc(Br)cn2)cc1
Yield: 71 %

Procedure:
The same procedure described for 1 was used by employing 2,5-dibromopyridine (1 equiv.) and 4-formylphenyl boronic acid (1 equiv.). Yield 71%, mp 120-121° C. 1H NMR (DMSO-d6); δ 7.97 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.7 Hz, 1H), 8.16 (dd, J=2.4, 8.7 Hz, 1H), 8.26 (d, J=8.4 Hz, 2H), 8.80 (d, J=2.4 Hz, 1H), 10.08 (s, 1H). MS (ESI) m/e (rel. int.): 262 (M+, 100), 232 (30), 153 (55). Anal. Calc. for C12H8BrNO: C %, 54.99; H %, 3.08. Found C %, 54.75; H %, 3.14.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:56][CH2:55][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][NH:68][CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:53][CH2:52]1>CC(N(C)C)=O>[F:47][C:48]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:49]=1[O:50][CH:51]1[CH2:52][CH2:53][N:54]([C:57]2[N:58]=[C:59]3[CH2:70][CH2:69][N:68]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:67][C:60]3=[N:61][C:62]=2[NH:63][CH:64]([CH3:66])[CH3:65])[CH2:55][CH2:56]1
Reactant: N#CCC(=O)O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)CC#N)C2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-cyanoacetic acid (8.3 mg, 0.097 mmol) in DMA (0.3 mL) at room temperature was added DIPEA (33.9 μL, 0.194 mmol), followed by HATU (36.9 mg, 0.097 mmol). This mixture was stirred for 5 min, then was treated with a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (33.5 mg, 0.065 mmol) in DMA (0.35 mL). The reaction mixture was heated at 60° C. for 30 min. The reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (5.5 mg, 14%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.75 (t, J=5.9 Hz, 0.8H), 2.85 (m, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.75 (t, J=5.8 Hz, 1.2H), 3.89 (t, J=5.9 Hz, 0.8H), 4.00 (m, 2H); 4.14 (m, 1H), 4.48 (m, 1H), 4.50 (s, 0.8H), 4.60 (s, 1.2H), 6.88 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 471.5.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:30]1>CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: O=C(N[C@@H]1CCCNCC1)OCc1ccccc1
Solvent: CS(C)=O
Product: O=C(N[C@@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1)OCc1ccccc1
Temperature: 95 °C

Procedure:
A solution containing 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.075 g, 0.20 mmol) and (R)-benzyl azepan-4-ylcarbamate (0.298 g, 1.20 mmol) in Dimethyl sulfoxide (1.20 mL) was heated at 95° C. for 18 h. The reaction was quenched with water and then extracted with EtOAc 2×. The combined organic layer was dried with Na2SO4, filtered and concentrated. The crude product was dried under high vacuum overnight to give benzyl (4R)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate which was dissolved in Methylene chloride (2.56 mL) at −10° C. and treated with slowly with 1.00 M of Boron tribromide in Methylene chloride (0.600 mL). The reaction was stirred at RT for 7 h. The mixture was concentrated. The crude product was diluted in water and washed with EtOAc. The aqueous layer was basified to pH 11 then extracted with EtOAc. The combined organic layers was dried Na2SO4, filtered, and concentrated. The crude product was submitted for rHPLC to give 249 (21 mg, 27% yield). ESI MS m/z=386.1 (M+1). 1H NMR (500 MHz, DMSO) δ 9.21 (d, J=12.7 Hz, 2H), 8.96 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.00-3.78 (m, 2H), 3.76-3.57 (m, 2H), 2.89 (s, 1H), 2.00 (d, J=30.7 Hz, 2H), 1.85-1.55 (m, 3H), 1.44-1.31 (m, 1H)
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[C:8]1([C:14]2[C:15]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[N:16][C:17]3[CH:18]=[CH:19][N:20]4[CH:26]=[N:25][N:24]=[C:21]4[C:22]=3[CH:23]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:1][C:2]([S:5](/[N:7]=[CH:31]/[C:30]1[CH:33]=[CH:34][C:27]([C:15]2[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][C:22]3[C:21]4=[N:24][N:25]=[CH:26][N:20]4[CH:19]=[CH:18][C:17]=3[N:16]=2)=[CH:28][CH:29]=1)=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Racemic 2-methyl-2-propane-sulfinamide (7-1, 647 mg, 5.3 mmol), cupric sulfate (1.70 g, 7.30 mmol), and aldehyde 4-2 (511 mg, 1.45 mmol) were stirred in methylene chloride (10 mL) for 5 d at 50° C. After cooling to rt, the mixture was filtered through celite, concentrated to a minimum volume and purified via automated silica gel chromatography (0-10% MeOH in CH2Cl2 over 30 min) to give the title compound as a brown foam. LRMS m/z (M+1) Calcd: 454.2. Found 454.2
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CC(=O)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1ccc(Cl)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OC
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 10.6 g (48.2 mmol) of 2-bromo-4-chloroanisole in 30 ml of triethylamine was treated with 1 0.1 ml (81.2 mmol) of ethyl acrylate, 1.23 g of tri-o-tolylphosphine, and 0.45 g of palladium(II) acetate in an argon atmosphere. The reaction mixture was stirred at 100° C. for 2 days, then diluted with EA and filtered through Celite. The filtrate was washed with 1 N HCl and saturated NaCl solution, dried over Na2SO4, and concentrated. After chromatographic purification over SiO2 using EA/heptane (1:8) as an eluent, 0.85 g of the title compound resulted as a pale yellow oil.