Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH3:22].C([O-])(O)=O.[Na+].[CH2:29]([NH2:32])[CH2:30][NH2:31]>C1COCC1.CS(C)=O.CO>[NH2:31][CH2:30][CH2:29][NH:32][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[N:5]([CH2:21][CH3:22])[C:4](=[O:18])[CH:3]=1
Reactant: CCBr
Reactant: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: NCCN
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(=O)cc(NCCN)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 2 (150 mg, 0.57 mmol) in THF-DMSO (6:1, 4 mL) was treated with 60% NaH (26 mg, 0.65 mmol), followed by adding ethyl bromide (300 uL). In a sealed tube, ˜20% crude product in dry MeOH (3 mL) was treated NaHCO3 and ethane-1,2-diamine (200 μL) at 120° C. for 2 h, and purified by LC-MS to give the title compound 16. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.70 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 5.37 (s, 2H), 3.95 (q, J=6.8 Hz, 2H), 3.45 (t, J=5.9 Hz, 2H), 3.11 (t, J=6.1 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H). MS (ES) [m+H] calc'd for C16H20N5O2, 314.2; found 314.2.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:37])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:37])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ((R)-1-{2-[4-(biphenyl-2-ylcarbamoyloxy)-piperidin-1-yl]-acetyl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Intermediate Z2) (1.17 g, 2.24 mmol) in DCM (10 ml) is treated with TFA (5 ml) and stirred at room temperature for 2 hours. The solution is basified by addition of saturated sodium bicarbonate solution and then extracted with DCM. The combined organic portions are washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield the title product. [MH+ 423.20].
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][C:16]1[C:21](Br)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1>[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:15][C:16]1[C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)c(Br)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under an argon atmosphere, to anhydrous THF (40 mL) was added zinc chloride (1.0 M in diethyl ether) (23.7 mL, 23.7 mmol), and to the mixture was added benzyl magnesium chloride (2.0 M in THF) (10.4 mL, 20.8 mmol). After stirring at room temperature for 30 minutes, to the mixture were successively added dichlorobis(triphenylphosphine)palladium(II) (488 mg, 695 μmol) and 2-amino-3,5-dibromo-6-chloropyrazine (4) (4.00 g, 13.9 mmol) at room temperature. The mixture was stirred overnight (15 hours and a half) at room temperature as it was. After to the mixture was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=5/1) to give 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (3.64 g, 12.2 mmol, 87.6%) as a yellow solid. TLC Rf=0.25 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) δ 4.08 (s, 2H), 4.50 (s, 2H), 7.19-7.24 (m, 2H), 7.27-7.37 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 40.1, 123.8, 127.5, 128.4, 129.3, 135.3, 139.5, 144.9, 151.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.[C:24]([NH2:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([NH:32][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Reactant: NC(=O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(NC(=O)c4ccccc4)ccc3=O)ccnc2c1
Temperature: 120 °C

Procedure:
A suspension of 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1 H)-one (220 mg, 586 μmol), benzamide (213 mg, 1759 μmol), n,n′-dimethylethylenediamine (189 μl, 1759 μmol), copper(I) iodide (167 mg, 879 μmol), and cesium carbonate (573 mg, 1759 μmol) in toluene (3 mL) was sparged with argon then heated to 120° C. for 90 min. The mixture was partioned between CH2Cl2 and 5% NaHCO3 and the hazy organic was washed with 30% NH4OH, dried over MgSO4, and concentrated onto silica (10 g) and purified on silica (12 g) eluting with 0 to 6% of 2M NH3 in MeOH/CH2Cl2. A solid crystallized upon evaporation of selected fractions as a white solid. MS (ESI pos. ion) m/z (MH+): 416. Calc'd exact mass for C24H21N3O4: 415. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1 H) 8.62 (d, J=4.5 Hz, 1 H) 8.19 (d, J=9.0 Hz, 1 H) 7.96 (d, J=7.5 Hz, 2 H) 7.51-7.66 (m, 4 H) 7.28 (d, J=2.5 Hz, 1 H) 7.03 (dd, J=9.0, 2.5 Hz, 1 H) 6.92 (d, J=5.5 Hz, 1 H) 6.48 (d, J=10.0 Hz, 1 H), 4.48 (s, 4 H), 3.86 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:14]
Reactant: CCI
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (10.0 g) was mixed with iodoethane (10.5 mL), potassium carbonate (13.5 g) and DMF (130 mL), and the obtained mixture was stirred at 60° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.8 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:15](=O)([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)[O:16]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C>C1COCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[C@H:3]([NH:2][C:15]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:16])[C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)O[C@H]1CCOC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
A mixture of (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (0.05 g, 0.223 mmol), (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate (0.056 g, 0.246 mmol) and Hunig's base (0.078 mL, 0.447 mmol) in THF (2.25 mL) was stirred at room temperature for 12 hours. The solvent was evaporated and the product was purified by chromatography on silica gel eluting with 0-15% ethyl acetate in dichloromethane to give the title compound (0.037 g, 55% yield).
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[NH2:10][C:11]1[N:12]=[C:13]([NH2:34])[C:14]2[C:20]([CH3:21])=[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:18](=O)[NH:17][C:15]=2[N:16]=1.C(O)C>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:12]=[C:13]([NH2:34])[C:14]2[C:20]([CH3:21])=[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:18]([Cl:8])=[N:17][C:15]=2[N:16]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)cc1OC
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2c(Cl)nc3nc(N)nc(N)c3c2C)cc1OC
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of dimethylformamide (17.5 g) in chloroform (75 ml) was added thionyl chloride (28.6 g) in chloroform (25 ml) at 0°-5° C. The reaction mixture was allowed to heat to 55°-60° for about 5 minutes and cooled to 0° C. To the reaction mixture was added over a 20 minute period at 0° C. 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidine (8.2 g). Chloroform (50 ml) was added, and the mixture was heated at reflux for 2.5 hours and cooled. Ethanol in base (50 ml) was added. The resulting brown product was collected by filtration, treated with 2N sodium hydroxide and recrystallized from ethanol to give 7.6 g of crude product. Additional recrystallization from ethanol-water gave 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-chloropyrido[2,3-d]pyrimidine (2 g), m.p. 224°-225° C. (dec.). This was added to ethanol (250 ml) containing potassium hydroxide (0.2 g), 5% palladium on charcoal catalyst (Pd/C, 0.1 g) was added and hydrogenation commenced. Reduction was complete after 4 hours in a Parr low-pressure apparatus at 35-40 psi and gave 2,4-diamino-6-(3,4-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (0.1 g), m.p. 265°-268° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CC(N(C)C)=O>[Br:8][C:9]1[C:17]2[C:16]([N:40]3[CH2:41][CH2:42][C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:39]3)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Triethylamine (3.55 mL, 25.45 mmol) was added to 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 61) (3.28 g, 8.48 mmol) and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (WO2008075109) (3.07 g, 11.88 mmol) in DMA (50 mL) at 20° C. The resulting suspension was stirred at 70° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with water (75 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (3.60 g, 69.7%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].C(OCC)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOCC
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of 300 mg of 1-(2-chloroethyl)-3-(β-D-galactopyranosyl)urea in 2 ml of 99% formic acid was slowly added 150 mg of sodium nitrite in an icebath under stirring. The mixture was stirred for 1 hour under ice-cooling to complete the nitrosation. The reaction mixture was admixed with 50 ml of ethyl ether to deposit an oily substance. The ethyl ether phase was separated from the oily substance by decantation. The operation of adding ethyl ether to and separating the ethyl ether phase from the oily substance by decantation was repeated three times, using 50 ml, 20 ml and 20 ml of the ether, respectively. Thereafter, the oily substance was taken up into 30 ml of methyl alcohol, and the resultant solution was admixed with 3 ml of Amberlite IR-120 (H+ form). The admixture was filtered to remove cation-exchange resin, and the filtrate was concentrated under a reduced pressure, depositing crystals of the titled compound. Yield 210 mg (63.6%). mp. 145° C. (decomposition with foaming). [α]D21.0 +13.0° (c 0.5, H2O).
Reaction SMILES: [C:1]([O:5][C:6](=O)[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:23]1(C)[C:24]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25]C=CC=1.O>C1C=CC=CC=1>[C:1]1([CH3:2])[CH:3]=[CH:25][C:24]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:23][CH:4]=1.[CH2:14]([O:21][C:6](=[O:5])[CH2:7][NH:8][CH2:9][CH2:10][O:11][CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COCCNCC(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COCCNCC(=O)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95°-6° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)c1ccccn1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and picolinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[CH:4]=1.Cl.[NH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:32]([C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([NH:13][CH2:2][C:3]2[S:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[CH:4]=2)[CH:15]=1)=[O:34])([CH3:30])[CH3:31])#[N:33]
Reactant: BrCc1cc2nccnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NCc1cc2nccnc2s1
Yield: 6.2 %

Procedure:
A solution of 6-(bromomethyl)thieno[3,2-b]pyrazine 47 (50 mg, 0.218 mmol), N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (72 mg, 0.218 mmol) and potassium carbonate (90 mg, 0.655 mmol) in acetonitrile (2 mL) was stirred overnight at 50° C. Water was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by HPLC gave the title compound 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(thieno[2,3-b]pyrazin-6-ylmethylamino)phenyl)benzamide 48 (6 mg, 6.23%). NMR (400 MHz, DMSO-d6) 1.71 (s, 6H), 2.16 (s, 3H), 4.72 (d, J=5.5 Hz, 2H), 6.02 (t, J=6.2 Hz, 1H), 6.98 (s, 2H), 7.08 (s, 1H), 7.54 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.92 (t, J=1.6 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 10.00 (s, 1H). (m/z)=442 (M+H)+.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[C:16]([CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[C:15]([CH:42]2[CH2:44][CH2:43]2)[O:14][N:13]=1>O>[CH:42]1([C:15]2[O:14][N:13]=[C:12]([C:6]3[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:16]=2[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([OH:37])=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:43][CH2:44]1
Reactant: Cn1cc(C(=O)OC(C)(C)C)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Solvent: O=CO
Solvent: O
Product: Cn1cc(C(=O)O)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To formic acid (116.5 Kg), add tert-butyl 6-(4-{[3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl]methoxy}piperidyl)-1-methylindole-3-carboxylate (19.102 Kg, 34.45 mol) under a nitrogen atmosphere. Stir the mixture at 20-30° C. for 24-72 hours. Follow by HPLC until no starting material is observed. Add water (286.5 Kg) and stir for at least 1 hour. Add water (133.7 Kg) and stir for at least 30 minutes, repeat with a further addition of water (133.7 Kg) with stirring for at least 30 minutes. Collect the solids by filtration and rinse the filter cake with water (3×30 Kg). Add the wet solids to methanol (75.5 Kg) and stir the suspension for at least 12 hours. Cool the suspension to 0-5° C. and stir for at least 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg) cooled to 0-5° C. and repeat. Dry solids at 50-55° C. for 12-72 hours under vacuum. Add the solids to formic acid (28.5 Kg) and water (2.3 Kg) and stir for 10-20 minutes. Filter the mixture. Add water (49.7 Kg) and stir for 30-60 minutes. Add water (2×36.6 Kg) and stir for at least 30 minutes. Collect solids by filtration and rinse with water (3×15.9 Kg). Add collected solids to methanol (58.2 Kg). Stir for at least 12 hours, cool to 0-5° C. and stir for at least 1 hour. Collect solids by filtration. Wash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg) cooled to 0-5° C., repeat once. Add the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg). Heat the suspension to reflux for 2-3 hours, cool to 0-5° C. and stir 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg) cooled to 0-5° C., repeat once. Dry collected solids at 60-65° C. for 12-72 hours under vacuum to give 13.584 Kg (73%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15]([Cl:18])(Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:18][C:15]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methylpiperazine (0.65 ml) and triethylamine (1.3 ml) in toluene (25 ml) at 0° C. was added dropwise a solution of phosgene in toluene (20%, 5.1 ml) over a period of 15 min. The reaction was allowed to warm to room temperature, stirred for 3 hr, filtered and concentrated to approximately 10 ml under reduced pressure to give a solution of 1-chlorocarbonyl-4-methylpiperazine which was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (300 mg), triethylamine (1101) and 4-dimethylaminopyridine (5 mg) in dichloromethane (10 ml) at room temperature according to the method described in Example 45. Purification of the desired material was achieved by chromatography on silica (Kieselgel 60, 230-400 mesh, Merck) (35 g) eluting with dichloromethane. Appropriate fractions were combined and evaporated to dryness under vacuum to give a material (53 mg) which was further purified by high pressure liquid chromatography on a Dynamax (trade mark) column (21.2×250 mm, 5 μm, ODS-silica, Rainin) eluting at 20 ml per minute with a methanol-water 95:5 mixture. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder. Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([OH:40])(=[O:39])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C(O)C1C=CC=CC=1>C1C=CC=CC=1>[C:13]([O:40][CH2:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:39])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCCC(=O)OCc1ccccc1

Procedure:
Toluene-4-sulfonic acid monohydrate (0.05 g, 0.28 mmol) is added to a suspension of tetracosanedioic acid (5.0 g, 80%, 10.03 mmol) in benzene (180 ml). The mixture is heated to 80° C., whereafter benzyl alcohol (1.08 g, 10.03 mmol) in benzene (10 ml) is added dropwise to the resulting solution. The reaction mixture is refluxed for 20 hours and water is removed azeotropically with a Dean Stark trap. The solvent is removed under reduced pressure and the residue washed with petroleum ether. The product is dissolved in refluxing diethyl ether and purified by flash chromatography on a silica column with methylene chloride/methanol (20:1) as eluant to yield the title compound as a white crystalline solid. 13C NMR (75 MHz, CDCl3): δ 24.0, 28.5, 29.7, 30.9, 34.4, 66.2, 128.2, 128.5, 136.0, 174.1, 176.9.
Reaction SMILES: C([Sn](CCCC)(CCCC)C1C=CN=CC=1)CCC.I[C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C([O:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41](Br)[CH:40]=1)C1C=CC=CC=1.CCCCCC.CCOC(C)=O>C1(O)C=CC=CC=1>[F:45][C:43]1[CH:44]=[C:39]([OH:38])[CH:40]=[C:41]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:42]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: COC(=O)c1ccccc1I
Agent: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: Oc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1-c1cc(O)cc(F)c1

Procedure:
Following the procedures described in Phenol 1, Steps 2 and 3, but substituting O-(3,4-dimethoxy)benzyl-3-fluoro-5-trimethylstannylphenol for 4-tributylstannylpyridine and methyl 2-iodobenzoate for O-benzyl-3-bromo-5-fluorophenol, the title compound was obtained as an oil after chromatography (silica gel; hexane/EtOAc 95:5-85:15)).