Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C)c2)cc1
Yield: 71.6 %

Procedure:
The title compound (D24) (48 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-methylbenzyl bromide (0.046 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 3 hrs; 60° C.)
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13].[OH-].[Na+:16].CCO>O>[Na+:16].[NH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:14])=[O:2]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)[O-])cccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A suspension of 2-amino-3-nitro-benzoic acid methyl ester (785 mg, 4 mmol) and sodium hydroxide (194 mg, 4.4 mmol) in mixed solvent of EtOH (2 mL) and water (2 mL) was heated at 80° C. for 5 h. After it was cooled to the room temperature, the red colored precipitate was formed and dried at 40° C. under reduced pressure to afford the crude product.
Reaction SMILES: [Br:1]Br.[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([CH2:29][CH2:30][CH3:31])[C:18]=2[CH3:32])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1>ClCCCl>[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([CH2:29][CH2:30][CH3:31])[C:18]=2[CH2:32][Br:1])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1
Reactant: CCCn1c(C)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c1=O
Reactant: BrBr
Solvent: ClCCCl
Product: CCCn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Bromine (400 mg, 2.5 mmol) in 0.5 ml 1,2-dichloroethane was added to 8-fluoro-3-methyl-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (344 mg, 0.84 mmol, see example 3) in 1,2-dichloroethane (20 mL) at 60° C. The reaction mixture was stirred for 15 minutes at 60° C. The reaction mixture was concentrated in vacuo to give crude 3-bromomethyl-8-fluoro-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide, which was used in the next step without purification. LC-MS (m/z) 489.5 (MH+); tR=1.55.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)[C:12]1=[O:31])C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)[C:12]1=[O:31]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc(N2CCC(N3CCC[C@H](N)C3=O)CC2)nc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
(S)-benzyl-1′-(5-ethylpyrimidin-2-yl)-2-oxo-[1,4′-bipiperidin]-3-ylcarbamate (2.176 g, 4.973 mmol) was dissolved in MeOH and 10% Pd/C (1 g) was added and stirred in a parr shaker at 30 psi overnight. The reaction was filtered through GF/F paper and separated on the reverse phase Horizon system to give (S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-[1,4′-bipiperidin]-2-one (0.280 g, 0.9229 mmol, 18.56% yield) as a clear oil. Mass spectrum (apci) m/z=304.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH3:33])[CH2:15][C:16]3[C:17]([CH3:32])=[N:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:20][CH:21]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[OH-].[Li+].Cl>C1COCC1.CCOC(C)=O>[CH3:33][N:14]([CH2:15][C:16]1[C:17]([CH3:32])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)=[N:20][CH:21]=1)[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[CH:6]=[CH:7]2
Reactant: COC(=O)Cn1ccc2cc(N(C)Cc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CN(C)c1ccc2c(ccn2CC(=O)O)c1
Yield: 68.9 %

Procedure:
70 mg (0.15 mmol) (5-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-amino}-indol-1-yl)-acetic acid methyl ester and 0.3 ml 1N lithium hydroxide solution were stirred for 2 h in 0.5 ml THF at RT. To the reaction mixture was added 0.6 ml 1N HCl and then the mixture was taken up in AcOEt and washed with water. The crude product was suspended in ether/heptane 1:19. The resulting crystals were filtered off to provide 47 mg of pure (5-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-amino}-indol-1-yl)-acetic acid.
Reaction SMILES: Cl.[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[C:56](Cl)(=[O:58])[CH3:57]>O>[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH:25][C:56](=[O:58])[CH3:57])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCN
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCNC(C)=O
Reaction time: 1 h
Yield: 79 %

Procedure:
1,3-Di-O-(n-hexadecyl)-2-O-(3-aminopropyl)-glycerol hydrochloride (1.0 g., 1.6 mmoles) was added to a mixture of potassium carbonate (830 mg., 6.0 mmoles) and benzene (75 ml.). Acetyl chloride (150 mg., 1.9 mmoles) was then added and the resulting mixture stirred for one hour at reflux. Additional acetyl chloride (150 mg., 1.9 moles) was added and the reaction mixture stirred for another hour at reflux. TLC analysis showed that the reaction was essentially complete. The reaction mixture was cooled, water (75 ml.) added, and the resulting mixture extracted with ether (3×100 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated in vacuo to yield the named compound [800 mg., 79% yield, m.p. 53°-54° C., ir (CHCl3) 3400 and 1670 cm-1, n.m.r. (CDCl3) δ 1.97 (s, 3, --NHCOCH3)].
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:26]=[CH:27][C:14]([C:12]4[N:13]=[C:9]([CH2:8][O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[NH:10][CH:11]=4)=[CH:15][CH:16]=3)=[CH:25][CH:24]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ccc(Oc3ccc(-c4c[nH]c(COc5ccccc5)n4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and paramethylphenylisocyanate (0.089 g, 0.67 mmol) in 3 ml of tetrahydrofuran is stirred for 24 hours at ambient temperature. The precipitate formed is filtered then the solid is stirred in a mixture of solvents such as isopropyl ether/ethyl acetate/isopropanol (5/4/1). After filtration then drying, a solid in the form of a beige powder is obtained with a yield of 73%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][S:20][C:21]2[NH:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][S:20][C:21]2[NH:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1n[nH]c(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CSc2nc(CCC(=O)O)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionate (550 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionic acid as crystals. Recrystallization from methanol-ethyl acetate gave colorless prism crystals (410 mg, yield 79%). melting point: 170–171° C.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=[O:20])[CH2:18]Br.Br>>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[C:14]([O:13][CH3:12])[CH:15]=3)=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: Cc1[nH]c2ncccc2c1C
Agent: Br
Product: COc1cccc(C(=O)Cn2cccc3c(C)c(C)nc2-3)c1

Procedure:
The title compound was prepared on a 0.9 mmol scale fr 2,3-dimethylpyrrolo[2,3-b]pyridine and m-methoxyphenacyl bromide in the same manner as described in example 27 giving 228 mg (70%) pure product as the hydrobromide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C(=O)C>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
39 mg of 4-hydroxyphenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid, aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex company, eluent; hexane: ethyl acetate=2:1] to obtain tert-butyl 2-(benzamido)-4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [CH2:1]([OH:45])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]4CO)O[C@@H]3CO)[O:11][C@@H:10]2[CH2:40][OH:41])[C@H:5]([OH:42])[C@@H:4]([OH:43])[C@@H:3]1[OH:44].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]([OH:45])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:40][OH:41])[C@H:5]([OH:42])[C@@H:4]([OH:43])[C@@H:3]1[OH:44]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]4CO)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Maltotetraose is the preferred α(1→4) linked glucan for use in the present invention. Maltotetraose is an oligosaccharide consisting of four α(1→4) linked glucose units and is commercially available from Sigma Chemical Company, St. Louis, Missouri, or Boehringer Mannheim, GmbH, Mannheim, West Germany. Where maltotetraose is employed as the α(1→4) linked glucan, the kinetic assay proceeds as follows: Maltotetraose substrate is hydrolyzed by α-amylase in the test sample to yield two moles of maltose per mole of substrate. The enzyme maltose phosphorylase (MP) catalyzes the phosphorolysis of each mole of maltose to one mole each of glucose and β-D-glucose-1-phosphate. The enzyme β-phosphoglucomutase (β-PGM) converts the β-glucose-1-phosphate to glucose-6-phosphate which is then oxidized to 6-phosphogluconate with the concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH in the reaction catalyzed by G-6-PDH.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](B(O)O)=[CH:4][C:3]=1[F:14].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH2:24][CH:23]1[CH3:36])=[O:21])([CH3:18])([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O=O>O1CCCC1.C1(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)C=CC=CC=1.C(OCC)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]=[C:25]([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[C:3]([F:14])[CH:4]=2)[CH2:24][CH:23]1[CH3:36])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: OB(O)c1cc(F)c(F)c2ccoc12
Reactant: CC1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)OC(C)(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CC(c2cc(F)c(F)c3ccoc23)=CCN1C(=O)OC(C)(C)C
Yield: 73.5 %

Procedure:
A mixture of 0.5 gm (2.53 mMol) 4,5-difluorobenzofur-7-ylboronic acid, 0.872 gm (2.53 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 0.806 gm (3.8 mMol) potassium phosphate, and 0.146 gm (0.127 mMol) tetrakis(triphenylphosphino)palladium in 10 mL tetrahydrofuran was placed under vacuum and pressurized with nitrogen three times to exclude oxygen. The reaction mixture was heated at reflux for 3 hours and was then poured into 250 mL diethyl ether and filtered through a pad of celite. The filter pad was washed with 200 mL diethyl ether and the combined filtrates were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane followed by 9% ethyl acetate in hexane. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.65 gm (74%) 1-(tert-butoxycarbonyl)-2-methyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine. A solution of 0.62 gm (1.77 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-(4,5-difluorobenzofur-7-yl)-1,2,3,6-tetrahydropyridine in 10 mL 4 M hydrogen chloride in dioxane was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue slurried in diethyl ether to provide 0.44 gm (86%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:33]=[CH2:34])[CH:32]=2)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:10]1[C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:33]=[CH2:34])[CH:32]=3)[N:7]=[CH:6][C:5]=2[CH:8]=[N:9]1
Reactant: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Reactant: C=Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: C=Cc1cncc(-c2cc3c(cn2)cnn3COCC[Si](C)(C)C)c1
Temperature: 150 °C
Yield: 143.5 %

Procedure:
A mixture of 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (1.074 mmol; 304.8 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-vinyl-pyridine (1.611 mmol; 372.3 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.1074 mmol; 89.5 mg), potassium acetate (1.611 mmol; 1.6 mL) and sodium carbonate (1.611 mmol; 1.6 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 5 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford trimethyl-[2-[[6-(5-vinyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl]silane (543.4 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C:11]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Fc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 11 h
Yield: 34.4 %

Procedure:
To N,N-dimethylformamide 0.5 mL solution of 4-fluorobenzyl chloride 35 mg were added tert-butyl 2-amino-4-phenylbenzoate 54 mg and potassium carbonate 55 mg at room temperature, and it was stirred at 80° C. for 11 hours. After the reaction mixture was cooled to room temperature, sodium iodide 30 mg was added to it at room temperature, and it was stirred at 80° C. for 4 hours and 40 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=100:1] to give tert-butyl 2-(4-fluorobenzylamino)-4-phenylbenzoate 26 mg of a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[CH3:17][S:18]([O:9][CH:6]1[CH2:7][CH2:8][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(O)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C

Procedure:
A solution of 1-isopropylpyrrolidin-3-ol (2.0 ml) and triethylamine (2.5 ml) in toluene (25 ml) was cooled to 0° C. and methanesulphonyl chloride (1.4 ml) was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and stirred for a further 2 h. The reaction was filtered and the filtrate evaporated to an oil which was used immediately.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=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:1][C:2]1[N:7]=[C:6]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: Clc1ccnc(Cl)n1
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: CCOC(C)=O
Solvent: COCCOC
Product: Clc1nccc(-c2cccnc2Cl)n1
Temperature: 90 °C

Procedure:
To 2,4-dichloropyrimidine (2.00 g, 13.4 mmol), 2-choropyridine-3-boronic acid (3.16 g, 20.1 mmol) and Pd(PPh3)4 (1.55 g, 1.30 mmol), was added DME (30.0 mL) and 1 M NaHCO3 (13.0 mL). The resulting mixture was heated to 90° C. for 17 hours, then diluted with EtOAc and extracted with saturated sodium carbonate, water, and brine. The organics were dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether and dried to yield the title compound. MS m/z=226 [M+H]+. Calc'd for C9H5Cl2N4: 225.12.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(O)=O.CCN(CC)CC>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](O)c2ccccc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
Argon was bubbled through a solution of Intermediate 1b (8.00 g, 31.1 mmol) and [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 0.06 g, 0.93 mmol) in dry DMF (100 mL) for 10 min. A premixed combination of formic acid (2.4 mL, 62.2 mmol) and Et3N (8.60 mL, 62.2 mmol) was added, and the mixture stirred at 50° C. for 24 h. The mixture was cooled to room temperature and concentrated to ˜25 mL. Water (70 mL) was added and the resulting precipitate filtered, and washed with DCM (3×30 mL) and diethyl ether (30 mL) to leave a solid (4.75 g). The filtrate was decanted to leave a dark solid. Subsequent purification by FCC using 0-30% EtOAc in cyclohexane gave a solid. This was combined with the first obtained solid to give a beige solid (5.93 g, 74%). 1H NMR (400 MHz, d6-DMSO): 1.60-1.83 (2H, m), 2.06-2.17 (2H, m), 4.60 (1H, m), 5.08 (1H, m), 5.28 (1H, d), 7.07 (1H, m), 7.25 (1H, ddd), 7.28 (1H, ddd), 7.50 (1H, dd), 9.78 (1H, d).