Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]2[C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N2CCCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylainine, The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m). Rf 0.40 (1:1 ether-hexane).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[C:26]([F:27])=[C:25]4[C:20]([C:21](=[O:34])[C:22]([C:31]([OH:33])=[O:32])=[CH:23][N:24]4[CH:28]4[CH2:30][CH2:29]4)=[CH:19][C:18]=3[F:35])[CH2:13][CH2:12]2)[CH2:10]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH2:8][CH:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[C:26]([F:27])=[C:25]4[C:20]([C:21](=[O:34])[C:22]([C:31]([OH:33])=[O:32])=[CH:23][N:24]4[CH:28]4[CH2:30][CH2:29]4)=[CH:19][C:18]=3[F:35])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)CC2
Agent: Cl
Product: NC1CC12CCN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)CC2
Yield: 43 %

Procedure:
According to the procedure of example 1B, the compound of step A (352.2 mg, crude) was hydrolyzed with hydrochloric acid to provide the title product, mp 241° C. (decomp.), 130.7 mg (0.31 mmol, 43% yield for two steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1.Cl>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:23]1[C:31]2[C:26](=[N:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1
Reactant: O=C(O)c1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (177 mg, 1.17 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (2.9 mL of a 1M solution in THF, 2.3 mmol) dropwise. The resulting solution is stirred at room temperature for 15 min. A solution 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (105 mg, 0.59 mmol) in dimethylformamide (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and is then poured into a cold 10% aqueous HCl. solution (30 mL). The reaction mixture is stirred at room temperature for 65 h. The solid which precipitated from solution is collected by filtration, washed with water and purified by chromatography (silica gel, MeOH/EtOAc). The product containing fractions are concentrated to give the title compound as a reddish solid (54 mg, 29%).
Reaction SMILES: [Li].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[CH3:8][C:9]1[CH:10]=[C:11]([C:15](=[O:22])[C:16]([N+]([O-])=O)([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1>CN(C)P(N(C)C)(N(C)C)=O>[N+:2]([C:5]([CH3:7])([CH3:6])[C:16]([CH3:17])([CH3:18])[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)=[O:22])([O-:4])=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cccc(C(=O)C(C)(C)[N+](=O)[O-])c1
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccc(C(=O)C(C)(C)C(C)(C)[N+](=O)[O-])c1
Reaction time: 18 h
Yield: 48 %

Procedure:
The lithium salt of 2-nitropropane (0.52 mol.) was dissolved in 700 ml. of hexamethylphosphoramide and, while under nitrogen, 62.1 g. (0.3 mol.) of 3'-methyl-α-nitroisobutyrophenone was added. The reaction mixture was stirred 18 hours under fluorescent lighting. The mixture was then diluted with 1400 ml. of water and the aqueous mixture was extracted three times with 800 ml. portions of ether. The combined ether extracts were washed three times with water, dried over magnesium sulfate and the ether removed. The residue was crystallized from hexane to give a 48 percent yield of 3-nitro-2,2,3,3'-tetramethylbutyrophenone: m.p. 50°-51° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([N:26]5[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]5)[CH:33]=4)[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccnc(N2CCCCC2)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc(N5CCCCC5)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-piperidin-1-ylisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether=5:6) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]phenoxy]acetate (120 mg, 0.27 mmol, 1.0 eq) in THF (6 mL) at room temperature was added NaOH (1M aqueous solution, 3 mL, 3.0 mmol, 11.1 eq). The reaction was stirred at room temperature for 2 h. The solvent was then removed in vacuo and the solid obtained taken up in water and the aqueous layer acidified to pH 3-6 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give the title compound (I(f)) as a gummy solid (105 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH:14]([O:16][C:17]3[C:22]([C:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH:14]([O:16][C:17]3[C:22]([CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3=CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of tert-butyl 2-(3-(4-methylphenylsulfonamido)cyclobutoxy)-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (499 mg, 1 mmol) and wet Pd—C (50%, 1.0 g) in MeOH (50 mL) was stirred under H2 (40 psi) at 30° C. overnight then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated to give tert-butyl 4-(2-(3-(4-methylphenylsulfonamido)cyclobutoxy)pyridin-3-yl)piperidine-1-carboxylate (476 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 502 calc. for C26H35N3O5S 501.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](=[O:14])([O-])[O-:12].[K+].[K+].[I-].[Na+].[OH-].[Na+]>C(O)C>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:7][CH2:2][CH2:3][CH2:4][C:11]([OH:12])=[O:14])[C:7]=2[CH:8]=[CH:9]1
Reactant: Oc1cccc2occc12
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCCOc1cccc2occc12
Reaction time: 4.5 h

Procedure:
4-Hydroxybenzofuran (4.9 g. 0.0366 M), ethyl 5-bromopentanoata (7.64 g, 0.0366 M), anhydrous potassium carbonate (5.44 g), sodium iodide (0.2 g) and 95% ethanol (20 ml) were refluxed with stirring for 4.5 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give ethyl 5-(4-benzofuranyloxy)pentanoata as an oil. To this oil was added 95% ethanol (130 ml) and 0.5N sodium hydroxide solution (130 ml) and the mixture stirred at room temperature (3 hr). The solution was evaporated to half-volume, diluted with water and extracted with ether. The aqueous phase was treated with charcoal, filtered and acidified with concentrated hydrochloric acid. The precipitated solid was filtered off, washed wall with water and recrystallised from ethanol-water to give 5-(4-benzofuranyloxy)pentanoic acid, m.p. 107.5° -108.5° C. (Found: C. 66.51; H, 5.90. C13H14O4 requires C, 66.65; H, 6.02%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH:28]([NH:33][CH3:34])[CH2:27][CH2:26]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:29]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2cc(OC)ccc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(N(C)CCCN1CCc3cc(OC)c(OC)cc3CC1=O)C2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 6-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 122°-123° C. (decomp.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=O)=O.C(N(CC)CC)C.[C:33]([O:37][CH2:38]C)(=[O:36])[CH:34]=[CH2:35].C(OCC)(=O)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:35]=[CH:34][C:33]([O:37][CH3:38])=[O:36])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=Cc1ccccc1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 3.27 g (8.54 mmol) of 2-[3-(tert-butoxycarbonylamino)propyl]phenyl trifluoromethanesulfonate, 3.62 ml (26 mmol) of triethylamine 1.15 ml (12.8 mmol) of ethyl acrylate and 0.2 g (0.3 mmol) of his (triphenylphosphine) palladium (II) chloride was heated at 110° C. in a sealed heavy-walled Pyrex, Teflon screw-capped flask for 16 hours. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture after it was cooled to 25° C. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was chromotographed on a silica gel column, eluting with a 5 to 25% gradient of ethyl acetate in hexane to afford 1.85 g (68%) of the product as an oil.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[C:24](O)=[O:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[C:24]([NH:12][C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[CH3:13])[N:8]=1)=[O:25]
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2ccccc2Cl)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=368.25.
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=[N:9]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[O:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:12]2[NH:8][N:9]=[CH:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: c1ccc(Cn2nccc2NC2CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1cc(NC2CCOCC2)[nH]n1
Temperature: 50 °C
Reaction time: 9 h
Yield: 87.2 %

Procedure:
A mixture of 1-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (3.00 g), palladium-carbon (10 wt %, 2.33 g) and ethanol (100 mL) was stirred under a hydrogen atmosphere at 50° C. and 5 atm for 9 hr. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.70 g, 87%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].Br[CH2:6][C@H:7]1[C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10][C@@H:9]([CH2:20][OH:21])[O:8]1.C(OCC)C.O>CN(C=O)C>[N:1]([CH2:6][C@H:7]1[C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10][C@@H:9]([CH2:20][OH:21])[O:8]1)=[N+:2]=[N-:3]
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Temperature: 70 °C

Procedure:
Lithium azide (1.0 g, 20 mmol) is added to a solution of [1R,3S] 1-bromomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran (1.77 g, 5.87 mmol), from Step 3, in 20 mL of DMF. The reaction mixture is heated to 70° C. for 1.5 h then cooled to ambient temperature and poured into 50 mL of diethyl ether and 50 mL of water. The layers are separated and the aqueous layer is extracted with 2×50 mL of diethyl ether. The combined ether layers are washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[N:17]1([CH2:23][CH2:24][OH:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[H-].[Na+].[ClH:28].C(O)C>O1CCCC1.C(O)C>[ClH:1].[ClH:28].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=[C:4]([CH3:16])[N:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1
Reactant: OCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(OCCN3CCCCC3)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.17 g of 4-chloro-6-(4-methoxyphenyl)-2-methylpyrimidine and 0.65 g of 2-piperidinoethanol were dissolved in 10 ml of dried tetrahydrofuran. After the addition of 60% sodium hydride 0.2 g, the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, and then was extracted with ethyl acetate. The extract was washed with water and was dried with anhydrous magnesium sulfate, and then this was evaporated in vacuo. The residue was purified with column chromatography with silica gel(Wako gel c-200 150 g, elution with chloroform and then chloroform: methanol=99:1), resulting 1.3 g of oily substance. This was dissolved in 10 ml of ethanol, 3 ml of 20% ethanol hydrochloride was added and evaporated in vacuo. Ether was added to the residue to crystallize. Whereby 1.32 g of crystals were obtained. These were recrystallized with isopropanol, resulting to obtain 0.83 g of crystals. Melting point is 165° to 167° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(CO)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(CO)cc3)cc12
Temperature: 0 °C
Reaction time: 65 h
Yield: 29.8 %

Procedure:
A solution of 6-fluoro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carbaldehyde (65 mg, 0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was treated with 2-methyl-2-butene (2 mL, 18.4 mmol) and cooled to 0° C. A solution of sodium chlorite (410 mg, 4.9 mmol) and sodium dihydrogen phosphate monohydrate (684 mg, 4.96 mmol) in water (3 mL) was added dropwise via an addition funnel. The reaction mixture was warmed to room temperature and stirred for 65 hours. The reaction was partially evaporated in vacuo, and partitioned between water and ethyl acetate. The organic phase was concentrated in vacuo. The crude material was purified using reverse-phase chromatography to give the title compound (20.4 mg).
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]#[N:13])[C:5]2=O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[N:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2[nH]cc(C#N)c(=O)c2n1
Product: Cc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
The suspension of 6-methyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carbonitrile (1.47 g, 7.93 mmol) in POCl3 (25 mL) was heated under refluxing for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with ice water and basified with NH4OH followed by extraction with AcOEt. The organic layer was washed with brine and dried over NaSO4, and concentrated to give 4-chloro-6-methyl-[1,5]naphthyridine-3-carbonitrile as a brown solid (0.92 g, 57.1%). HR-MS-EI (+) m/e calcd for C10H6ClN3 (M+) 203.0250. found 203.0252.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([Br:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23]Br)=[O:5])[CH3:2].[CH2:25]([O:27][C:28](=[O:38])[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([Br:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][N:30]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)C)c(Br)n(-c2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(C(C)(C)C)c(Br)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 5-bromo-2-bromomethyl-4-tert-butyl-1-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 605 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:8](=[O:31])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[C:26]([F:29])([F:28])[F:27])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Br:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>C(Cl)Cl>[Br:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[C:8](=[O:31])[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:30])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=4[C:26]([F:28])([F:29])[F:27])=[CH:13][CH:14]=3)=[CH:40][CH:41]=2)=[O:48])=[CH:45][CH:44]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(OC(=O)c4ccc(Br)cc4)cc3)cc2)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 63 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-9 (500 mg, 0.87 mmol) in DCM (10 mL) was added TEA (304 μL, 2.18 mmol) followed by 4-bromobenzoyl chloride (201 mg, 0.92 mmol). After 1 h, the reaction mixture was diluted with DCM (50 mL) and washed with NaHCO3 (50 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes) to afford 440 mg (63%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-bromobenzoate INT-10 as a white powder. LCMS-ESI (m/z) calculated for C37H34BrF3N2O7: 755; found 754 [M−H]−, tR=2.99 min (Method 10).