Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[O:3]1[CH2:8][CH2:7][CH:6](O)[CH2:5][CH2:4]1.[I:10][C:11]1[NH:15][N:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[I:10][C:11]1[N:15]([CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[N:14]=[CH:13][CH:12]=1
Reactant: Ic1ccn[nH]1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccnn1C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a round-bottomed flask equipped with a stirring bar and a N2 tee, tetrahydro-2H-pyran-4-ol (1.05 g, 10.31 mmol), 5-iodo-1H-pyrazole (2.00 g, 10.31 mmol), triphenylphosphine (3.33 g, 12.68 mmol), (g, mmol) and THF (22.9 mL) were added. Followed by the addition of DIAD (2.71 g, 13.4 mmol), the resulting mixture was stirred at room temperature for 3 hrs. The mixture was removed most solvents in vauo, and ethyl acetate (200 mL) was added. The resulting solution were washed with H2O (50 mL×1), brine (50 mL×1), and dried over Na2SO4. The organic phase was filtered and removed solvent in vacuo, and passed a silica gel column (ethyl acetate: hexanes=0:100 to 100:0), off-white solids were obtained as the desired product. 920 mg (yield 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.47 (m, 1H), 6.62-6.38 (m, 1H), 4.48 (tt, J=11.4, 4.3 Hz, 1H), 3.96 (ddt, J=11.8, 4.7, 1.2 Hz, 2H), 3.49 (td, J=12.0, 2.1 Hz, 2H), 2.00 (dddd, J=13.1, 12.0, 11.2, 4.6 Hz, 2H), 1.90-1.71 (m, 2H) ppm; MS (ESI+) m/z 279.30 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:19][OH:20])[C:17]#[N:18].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(N(CC)CC)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:19][O:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:17]#[N:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(=NO)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(Cl)cc2Cl)cc1
Yield: 77.2 %

Procedure:
To toluene (200 ml), (2,4-dichlorophenyl)-hydroxyiminoacetonitrile (8.60 g, 40 mmol) prepared in the Step 27-1-1, tosyl chloride (9.50 g) and triethylamine (5.0 g) were added, and the mixture was heated under reflux for 5 hours. After being allowed to cool, the mixture was washed with water and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (11.4 g, 77%).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][C:6]4[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=4)[C:10]=3[N:11]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3cccc(Cl)c3C)nc1-2

Procedure:
The title compound was prepared from 7-methoxy-4,5-dihydronaphto[1,2-D][1,3]thiazol-2-amine hydrobromide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (30.7 mg) with purity >90%. MS (pos) m/z 421.1.
Reaction SMILES: [NH:1]1[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].[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].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:16]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:17]([C:21]([N:1]1[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])=[O:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Val-Pro-OBzl was prepared by dissolving H-Pro-OBzl (20 g, 83 mmol) in 50 mL of chloroform and adding Boc-Val-OH (18.0 g, 83 mmol), HOBt (23.0 g, 165 mmol), NMM (9.0 mL, 83 MMOL) and DCC (17.0 g, 83 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was filtered and solvent was evaporated. Ethyl acetate was added and insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl, 5% NaHCO3, and saturated aqueous NaCl. It was dried over Na2SO4, filtered and evaporate to give a white solid (30 g, 75 mmol, 90%). ESI/MS calculated for C22H32N2O5+H: 405.2. Found 405.6.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.B1([O-])O[O:17]1.O.O.O.O.[Na+]>C1COCC1>[OH:17][CH:3]1[CH2:4][CH2:5][CH:1]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2]1
Reactant: O=C(OCc1ccccc1)C1CC=CC1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The benzyl cyclopent-3-ene-1-carboxylate (2.0 g, 9.89 mmol) was dissolved in 20 mL of THF and cooled to 0° C. under nitrogen. Borane-THF complex (0.95 mL, 9.89 mmol) was added via syringe and the mixture was stirred for 30 minutes at 0° C. Sodium perborate tetrahydrate solution (100 mL of 0.33 M aqueous solution) was added, and after 30 minutes the reaction mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine and then dried over sodium sulfate. Filtration and concentration provided the crude product which was purified by chromatography on silica gel eluting with 10 to 30% EtOAc in hexanes to provide benzyl 3-hydroxycyclopentanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]1=[O:39])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]2=[O:39])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)N1C(=O)C(NC(=O)[C@H](C)N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title compound was prepared as a solid (mp.=208–209° C.). The product was purified by slurrying in ether/hexanes (1:1).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([NH2:30])=[O:29].O>C1COCC1>[C:15]([C:13]1[C:14]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=[C:8]([C:19]3[CH:20]=[N:21][N:22]([CH2:27][C:28]([NH2:30])=[O:29])[CH:23]=3)[C:9]=2[C:10]([O:17][CH3:18])=[N:11][CH:12]=1)#[N:16]
Reactant: NC(=O)CBr
Reactant: COc1ncc(C#N)c2c1c(-c1cn[nH]c1)cn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1cnn(CC(N)=O)c1)cn2C1CCCC1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (55.3 mg) in THF (2 mL) was added sodium hydride (dispersion in mineral oil, 14.4 mg) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added 2-bromoacetamide (29.8 mg) at 0° C., and the reaction mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate and THF. The combined organic layers was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (27.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of 3-fluoro-4-methyl-benzoic acid (2.5 g, 16.2 mmol) in acetone (27.0 mL) was treated with potassium carbonate (5.83 g, 42.2 mmol) and dimethyl sulfate (6.14 g, 4.6 mL, 48.7 mmol). The reaction was stirred at 25° C. for 24 h and then was heated to 90° C. for 8 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. for 6 days. At this time, the reaction was filtered through a sintered glass funnel. The potassium carbonate cake was washed thoroughly with acetone. The filtrate was concentrated in vacuo. The residue was then taken up in ethyl acetate (30 mL) and triethylamine (7 mL) and stirred at 25° C. for 30 min. The solution was then transferred to a separatory funnel and washed with water (1×75 mL), a 2N aqueous hydrochloric acid solution (1×75 mL), and a saturated aqueous sodium chloride solution (1×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-fluoro-4-methyl-benzoic acid methyl ester (2.26 g, 82.9%) as a light yellow oil. ES+-HRMS m/e calcd for C9H9O2F [M+H+] 169.0660. Found 169.0659. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.70 (dd, J=7.8, 1.5 Hz, 1H) 7.62 (dd, J=10.3, 1.5 Hz, 1H) 7.46 (t, J=7.8 Hz, 1H) 3.85 (s, 3H) 2.31 (d, J=1.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:38])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)C3CCCCC3)ccc2O1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and cyclohexanecarbonyl chloride as a yellow oil (79%). HPLC, Rt: 6.01 min (Purity: 98.2%).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[H-].[Na+].Br[CH:14](O)[CH2:15][CH3:16].C(OCC)(=O)C>O1CCCC1>[CH2:14]([O:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH2:15][CH3:16]
Reactant: CCC(O)Br
Reactant: OCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOCCOCCOCCO
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Triethylene glycol (19.5 g, 0.13 mol) was dissolved in tetrahydrofuran (150 mL) and sodium hydride (2.60 g, 0.065 mol) was added portion wise over 0.5 h and the reaction was stirred for an additional 1 h. Then 1-bromopropanol (8.0 g, 0.065 mol) dissolved in tetrahydrofuran (30 mL) was added dropwise via addition funnel and the reaction was stirred overnight at room temperature. Crude reaction mixture was filtered through Celite, washed CH2Cl2, and evaporated to dryness. The resultant oil was dissolved in CH2Cl2 (250 mL), washed sat. NaCl (250 mL), H2O (250 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 1 a yellowish oil (2.24 g, 18% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C@H:16]([C:24]([OH:26])=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.[CH3:28][NH:29][O:30][CH3:31].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:31][O:30][N:29]([CH3:28])[C:24](=[O:26])[C@@H:16]([NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 81.2 %

Procedure:
Triethyl amine (40 g, 0.4 mol) was added to a suspension of Boc-L-phenylalanine (90 g, 0.34 mol) and N,O-dimethylhydroxylamine hydrochloride (36.5 g, 0.37 mol) in DCM (500 mL) at 0° C. with stirring. The suspension was stirred for 10 min and EDCI (HCl salt, 72 g, 0.37 mol) was added. The suspension was stirred for further 3 hours at 0° C. The mixture was quenched with saturated aqueous NaHCO3 (1 L). The layers were separated, and the aqueous phase was re-extracted with DCM (500 mL×3). The combined organic phases were washed with water (1 L×3), 5% KHSO4 aqueous (1 L×3), saturated aqueous NaHCO3 (1 L×3), and brine (1 L×1), was dried (Na2SO4), and was concentrated to dryness. The crude material was further purified by flash chromatography (silica gel, EtOAc/Hexane=1:1) and afforded (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate (85.1 g, 81% yield) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.1-57.26 (m, 5H), 5.25 (bs, 1H), 4.95 (m, 1H), 3.63 (s, 3H), 3.14 (s, 3H), 2.83-3.07 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:15])[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=1.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:5]=3)[N:15]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:17]
Reactant: Cc1cc(C(=N)NO)cc(CC(C)C)n1
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Product: CCc1cc(-c2nc(-c3cc(C)nc(CC(C)C)c3)no2)cc(C)c1O

Procedure:
2-Ethyl-4-[3-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared from N-hydroxy-2-isobutyl-6-methyl-isonicotinamidine and 3-ethyl-4-hydroxy-5-methyl-benzoic acid; LC-MS: tR=0.90 min, [M+1]+=352.17.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:32]([O:39][C:40]([NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:41])[NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](=[O:51])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:46][CH2:45]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1cc(C)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-methyl-2-(methyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml) were added HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol). The mixture was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.201 mmol). The reaction was stirred for 2 h then it was loaded onto PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH: DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Solvent was evaporated under a stream of nitrogen to give title compound (13 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.ClC1C=CC=C(C(OO)=[O:47])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:47]1[CH2:38][CH:37]1[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CO3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.1 g), m-chloroperbenzoic acid (1.8 g) and acetonitrile (10 mL) was stirred at 50° C. for 15 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 20%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2CCc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(CCc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-chloro-7-cyano-4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 399 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.C[CH2:12][O:13][CH2:14]C.C(Cl)OC>CCOCC.CN(C=O)C.O>[CH3:12][O:13][CH2:14][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccccc1O
Reactant: CCOCC
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil; 1.2 eq) in Et2O/DMF (5:1, 0.2M) a solution of o-cresol in Et2O (1 eq, 2M) was added dropwise over 15 min. A solution of MOMCl in Et2O (1.1 eq, 2M) was added and the mixture was stirred for 30 min then poured into H2O and extracted with Et2O. The combined organic extracts were washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound. The product was used in the next step without further purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH3:11][C:12]([CH3:23])([CH3:22])[CH2:13][CH2:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17].[SiH4]>C(O)C.O1CCCC1>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Si:15]([CH2:14][CH2:13][C:12]([CH3:23])([CH3:22])[CH3:11])([O:18][CH3:19])[O:16][CH3:17])[CH3:10]
Reactant: CO[Si](CCC(C)(C)C)(OC)OC
Reactant: CCc1ccccc1Br
Agent: [Mg]
Agent: [SiH4]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccccc1[Si](CCC(C)(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Under an atmosphere of dry nitrogen a magnetically stirred suspension of anhydrous tetrahydrofuran (Aldrich, 300 mL) and magnesium turnings (Aldrich, 1.2 g, 49 mmol) was treated dropwise at room temperature with 1-bromo-2-ethylbenzene (Aldrich, 6.1 mL, 44 mmol). After minutes the reaction mixture began to reflux mildly. After the addition was complete the reaction mixture was heated to reflux overnight (18 h). A separate flask was flushed with dry nitrogen and then charged with anhydrous tetrahydrofuran (Aldrich, 100 mL) and 3,3-dimethylbutyl-trimethoxysilane (Huls, 11.4 mL, 49 mmol). The Grignard solution was cooled to room temperature and then added to the silane solution at room temperature via stainless steel cannula. The reaction mixture stirred at room temperature overnight (18 h). Ethyl alcohol (Aldrich, 5 mL) was added to quench any remaining Grignard. The reaction mixture was concentrated on a rotary evaporator and distilled in vacuum to give 3.7 g (30%) of the title compound as a colorless oil (b.p. 107–108° C. at 0.5 mm Hg, 99% GC-purity): C16H28O2Si (Mw=280).