Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.[C:34](O)(=O)[CH3:35].[C:38]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:35]4[CH2:34][CH2:38]4)[CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ncnn2c(C3CCN(C4CC4)CC3)cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
To a solution of 5-(3-amino-2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.228 mmol) in MeOH (2.3 mL) was added acetic acid (0.13 mL, 2.28 mmol, 10.0 eq), 3 Å molecular sieves (50 mg), [1-(ethoxycyclopropyl)-oxy]timethylsilane (0.28 mL, 1.37 mmol, 6.0 eq), and sodium cyanoborohydride (64.5 mg, 1.03 mmol, 4.5 eq). The reaction mixture was stirred at 60° C. under N2 for 18 h. The mixture was cooled to rt and aqueous, saturated NaHCO3 solution (1.0 mL) was added to quench the reaction. The mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The MeOH was removed and the residue was crystallized from DCM-ether-hexane to provide the title compound (35.5 mg, 32.5%) as pink solid. 1H NMR (300 MHz, DMSO-d5) δ 7.87 (s, 1H), 7.70 (d, 1H), 7.34 to 7.29 (m, 2H), 7.27 to 7.21 (m, 3H), 7.15 (s, 1H), 6.73 (dd, 1H), 6.52 (s, 1H), 6.37 (s, 2H), 5.38 (s, 2H), 3.12 to 3.00 (m, 3H), 2.28 (t, 2H), 1.96 (d, 2H), 1.67 to 1.56 (m, 3H), 0.43 to 0.39 (m, 2H), 0.31 to 0.27 (m, 21-1); ES-MS m/z 479.2 [M+H]+, RT (min) 1.80.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCN)C1=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCNC(C)=O)C1=O
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Acetic anhydride (0.2 g) was added dropwise to a solution of 3-(2-aminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.50 g, 1.43 mmol) in pyridine (2 ml) with stirring under cooling with ice. The mixture was left standing overnight at room temperature. To this solution was added saturated aqueous NaHCO3 (30 ml), and the mixture was extracted with benzene. After drying of the extract, the solvent was removed therefrom by evaporation under reduced pressure, giving the intended 3-(2-acetylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.52 g, 92% yield) in oily form. IR (CHCl3) [cm-1 ]; 3430, 2920, 2850, 1665, 1590, 1580, 1365. NMR (δ, CDCl3 ppm); 1.95 (3 H, s), 3.93 (0.45 H, dd, 990 and 3.63 Hz), 4.03 (0.55 H, ddd, 9.24, 3.63 and 1.65 Hz), 5,75 (0.55 H, d, 1.65 Hz), 5.76 (0.45 H, s), 6.06-6.11 (1 H, m).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:20])[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.O>[C:1]([CH2:3][CH:4]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][CH2:7]1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(O)CC#N)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A solution of tert-butyl 4-(3-cyano-2-hydroxypropyl)-1,4-diazepane-1-carboxylate (3.2 g, 11 mmol) and triethylamine (3.1 mL, 22 mmol) in DCM (60 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (1.2 mL, 16 mmol). After stirring at 0° C. for 1 hour, the reaction solution was diluted with water and DCM. The organic layer was washed with water twice, dried over MgSO4, filtered, and concentrated to give the desired product as oil (4 g, 98%). The crude product was used immediately in the next step. LCMS calculated for C15H28N3O5S(M+H)+: m/z=362.1.
Reaction SMILES: [Li]CCCC.CCCCC.[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)([CH3:14])([CH3:13])[CH3:12].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].[Br:36]N1C(=O)CCC1=O>C1COCC1.C(OCC)C>[Br:36][C:21]1[C:20]2[C:24](=[CH:25][C:17]([O:16][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:27])[CH3:26])=[CH:18][CH:19]=2)[N:23]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)cn([Si](C)(C)C(C)(C)C)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A 1.6 M solution of BuLi in pentane (6.57 ml, 10.5 mmol) was added to a solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (2 g, 8.1 mmol) in THF (40 ml) at −78° C. within 20 min under an argon atmosphere. The reaction mixture was stirred for 20 min at −78° C. tert-Butyldimethylsilyl chloride (1.6 g, 10.5 mmol) was added and the reaction mixture was stirred for 10 min at −78° C. and for 1 h at RT. The mixture was chilled to −78° C., N-bromosuccinimide (1.6 g, 8.9 mmol) was added and stirring was continued for 1 h at −78° C. and for 1 h at RT. The solution was diluted with diethyl ether and washed with saturated aqueous NaHCO3 solution and water. The ether phase was dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, n-heptane/ethyl acetate 1:19) to give 2.64 g (6 mmol, 74%) 3-bromo-1-(tert-butyl-dimethyl-silanyl)-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole as brown solid.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:36]=[CH:35][C:34](=[O:37])[N:33]([CH2:38][CH:39]=O)[C:32]=2[N:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:39][CH2:38][N:33]4[C:34](=[O:37])[CH:35]=[N:36][C:31]5[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[N:41][C:32]4=5)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 0.16 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 3 mL of dichloromethane, 0.10 g of (6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 26 μL of acetic acid and 0.15 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash basic silica gel column chromatography using an eluent of chloroform to obtain 0.15 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[CH2:40][CH:41]([C:47]([O:49][CH3:50])=[O:48])[CH2:42]2.O>ClCCl>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:37][C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH2:40][CH:41]([C:47]([O:49][CH3:50])=[O:48])[CH2:42]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)C1Cc2cccc(N)c2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
337 mg (0.821 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl chloride (enantiomer 1; Example 81A) were dissolved in 8 ml of dichloromethane, and 83 mg (0.821 mmol) of triethylamine were added. 157 mg (0.821 mmol) of methyl 4-amino-2,3-dihydro-1H-indene-2-carboxylate (enantiomer 1; Example 89A), dissolved in 2 ml of dichloromethane, were added to the mixture. The mixture was stirred at room temperature overnight. Water was then added, and the reaction solution was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 3:1→1:1). This gave 182 mg (0.32 mmol, 39% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([Cl:14])(=[O:13])=[O:12])[C:4]=2[O:3]1.C([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=2[O:36][CH2:37][CH2:38][F:39])[CH2:25][CH2:24]1)(OC(C)(C)C)=O>>[ClH:14].[F:39][CH2:38][CH2:37][O:36][C:30]1[C:29]([N:26]2[CH2:25][CH2:24][NH:23][CH2:28][CH2:27]2)=[CH:34][C:33]([NH:35][S:11]([C:10]2[C:4]3[O:3][C:2]([F:15])([F:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc2c1OC(F)(F)O2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ccc2OCCF)CC1
Product: Cl
Product: O=S(=O)(Nc1ccc(OCCF)c(N2CCNCC2)c1)c1cccc2c1OC(F)(F)O2

Procedure:
The compound was prepared as described for Example 9 using commercially available 2,2-Difluoro-benzo[1,3]dioxole-4-sulfonyl chloride and 1-(N-boc-piperazin-4-yl)-2-(2-fluoroethoxy)-5-aminobenzene from Example 11.
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH3:8][N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11].[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:8][N:9]1[C:13](=[O:14])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:10]1=[O:11]
Reactant: CN(C(=O)Cl)C(=O)Cl
Reactant: CNC(=N)SC
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CSC1NC(=O)N(C)C(=O)N1C
Yield: 75 %

Procedure:
23.2 g (0.1 mole) of N,S-dimethyl-isothiourea hydroiodide were initially introduced into 100 ml of water and 250 ml of benzene. 15.6 (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 12 g (0.3 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels with vigorous stirring. The reaction took place strongly exothermically. The mixture was stirred for a further hour, any product which precipitated was filtered off, and the benzene phase was separated off, dried over calcium chloride and evaporated in vacuo. The residue, together with the filter residue, was recrystallized from isopropanol. 14 g (75%) of 1,3-dimethyl-4-methylmercapto tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder of melting point 137°-139° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5].[C:19](=O)=O.C[Mg]Cl.[Cl-].[NH4+]>C1COCC1.C(OCC)C.C(O)C>[C:12]1([C:9]2[N:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:19])=[CH:7][N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C=O
Reactant: CON(C)C(=O)c1cnc(-c2ccccc2)nc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)c1cnc(-c2ccccc2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution consisting of N-methoxy-N-methyl-2-phenylpyrimidine-5-carboxamide (Step I, 1.80 g, 7.39 mmol) in anhydrous THF (20 mL) was cooled in a −60° C. bath (ethanol, CO2(s)). Methylmagnesium chloride (Aldrich, 3.0 M in THF, 2.75 mL, 8.14 mmol) was subsequently added dropwise to the reaction mixture. The reaction mixture was stirred for 30 minutes in the −60° C. bath and was subsequently allowed to warm to room temperature over one hour. The crude reaction mixture was then poured into a separatory funnel that contained diethyl ether (200 mL) and saturated ammonium chloride (150 mL). The organic layer was separated and the aqueous layer was washed again with diethyl ether (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid as the crude product. The crude solid was triturated with a hexane-ethyl acetate (9:1 v/v) mixture (20 mL). The precipitate in solution was filtered to afford the title compound as a white solid (1.15 g, 78% yield); Rf 0.72 with 1:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 9.25 (s, 2H), 8.53 (dd, 2H), 7.58 (m, 3H), 2.63 (s, 3H); MS (APCI+) m/z 199.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>CCO>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=[C:4]1[CH2:3][CH2:2][NH2:1]
Reactant: N#CCCN
Reactant: Nc1ccccc1S
Solvent: CCO
Product: NCCc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of 50 mg of 3-aminopropionitrile and 596 mg of 2-aminothiophenol in EtOH (15 mL) was heated at reflux for six h. After cooling the solution to room temperature, the reaction was concentrated and the residue was purified by silica gel chromatography to afford the title compound as a red oil. MS (M+H)+=179.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]C2C=CN=C(C3C=CC=CC=3)N=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.B(OC)(OC)OC.OO.[F:35][C:36]1[C:41]([F:42])=[C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:39]=[CH:38][C:37]=1[C:48]1[N:53]=[CH:52][C:51]([OH:54])=[CH:50][N:49]=1>C1COCC1>[F:35][C:36]1[C:41]([F:42])=[C:40]([CH2:43][CH2:44][C@H:45]2[CH2:8][CH2:7][C@H:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:46]2)[CH:39]=[CH:38][C:37]=1[C:48]1[N:49]=[CH:50][C:51]([OH:54])=[CH:52][N:53]=1
Reactant: c1ccc(-c2nccc(CCC3CCCCC3)n2)cc1
Reactant: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Agent: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ncc(O)cn3)c(F)c2F)CC1
Yield: 57 %

Procedure:
--Quantities bromopyrimidine 16 (3.72 g, 8.25 mmol), 1.6M butyllithium (5.7 ml, 9.1 mmol), trimethyl borate (1.9 ml, 16.5 mmol), THF (80 ml), 30% hydrogen peroxide (3.7 ml, 33 mmol). The experimental procedure was as described for compound 33. The crude product was purified by flash chromatography (10 to 30% ethyl acetate-light petroleum) to give the hydroxypyrimidine 48 (1.82 g, 57%) (from MeOH), m.p. 157.3° C.; νmax /cm-1 (KBr) 2920, 2720, 2580, 1505, 1430, 1280, 1240 and 1180 δ 0.85 (7H, m), 1.05-1.38 (10H, m), 1.50 (2H, m), 1.73 (4H, t), 2.68 (2 H, t, ArCH2), 7.01 (1H, ddd, 5'-H), 7.55 (1H, ddd, 6'-H), 8.37 (2H, s, 4- and 6-H) and 9.7 (1H, br s); m/z 388 (M+), 317 (M+ -C5H11), 235, 222 and 204.
Reaction SMILES: C([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[C:35]([CH:9]([P:4](=[O:3])([OH:5])[OH:8])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:36]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(C#N)P(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of {1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was added TMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). The reaction solution was allowed stir at room temperature for one hour before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg (60%) of the desired product. 1H NMR (300 MHz, CD3OD) δ 1.86 (s,3H), 2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J=7.2 Hz, 2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 15.28 ppm; MS (m/z) 380 [M−H]−, 382 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].[C:21]([O-])(=[O:23])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([CH:21]=[O:23])=[CH:15][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCN(CCOC(C)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
55.8 g of phosphoryl chloride cooled with ice was added to 26.6 g of N,N-dimethyl formamide. To this, a solution of 63.0 g of the 2-(N-ethylanilino)ethyl acetate and 40 ml of N,N-dimethyl formamide was added slowly at room temperature. The resulting solution was stirred for 6 hours at room temperature for reaction, and then was poured in an aqueous solution of 150 g of sodium acetate that was being cooled with ice water. The organic layer was extracted with ethyl acetate. The solvent was then distilled off under reduced pressure and purified by chromatography on silica, to obtain 60.2 g of 2-(ethyl(4-formylphenyl)amino)ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][O:28]C(=O)C)[C@H:20]([O:21]C(=O)C)[C@@H:15]2[O:16]C(=O)C)[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1.C(O)C>ClCCl>[NH:1]([C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][OH:28])[C@H:20]([OH:21])[C@@H:15]2[OH:16])[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: OC[C@@H]1O[C@H](n2c(Nc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 336 h
Yield: 5 %

Procedure:
Aniline (5 ml) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (35 mL) and stirred at 80 ° C. for 14 days. The reaction mixture was concentrated and the aniline was distilled off under high vacuum at 80° C. The brown residue was dissolved in methanol (50 mL) and K2CO3 was added. This solution was stirred for 18 h. The solution was filtered, concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15 methanol:dichloromethane to give a white solid (0.024 g, 0.06 mmol, 5%). MS (AP+): m/z (rel. intensity) 410 (19.39, M+1); 1H NMR (DMSO-d6) d 9.09 (s, 1H, NH), 7.83 (s, 1H, Ar-H), 7.78 (d, 1H, Ar-H, J=7.9 Hz), 7.58 (s, 2H, Ar-H), 7.31 (t, 2H, Ar-H, J=7.9 Hz), 6.99 (t, 1H, Ar-H, J=7.5 Hz), 5.95 (d, 1H, H-1', J=7.8 Hz), 5.86 (t, 1H, OH, J=4.4 Hz), 5.38 (d, 1H, OH, J=7.6 Hz), 5.30 (d, 1H, OH, J=4.2 Hz), 4.33 (apparent dd, 1H, H-4', J=13.4 Hz, J=7.8 Hz), 4.11 (apparent t, 1H, H-2', J=4.8 Hz), 4.05 (s, 1H, H-4'), 3.79-3.71 (m, 2H, H-5').
Reaction SMILES: [CH2:1]([Cl:3])Cl.CCC(C1O[C@]2(OC3CC=C(C)[C@@H](OC4O[C@@H](C)[C@H](OC5O[C@@H](C)[C@H](O)[C@@H](OC)C5)[C@@H](OC)C4)[C@@H](C)C=C[CH:26]=[C:27]4COC5[C@H](O)C(C)=[CH:33][CH:32]([C:38]([O:40][C@@H](C3)C2)=[O:39])[C@:31]45O)C=C[C@@H]1C)C.C([OH:69])(C)C.CCC([C@H]1O[C@]2(O[C@@H]3CC=C(C)[C@@H](O[C@@H]4O[C@@H](C)[C@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](OC)C5)[C@@H](OC)C4)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(O[C@@H](C3)C2)=O)[C@]45O)C=C[C@@H]1C)C>C1C=CC=CC=1>[Cl:3][C:1]1[CH:26]=[CH:27][CH:31]=[C:32]([C:38]([O:40][OH:69])=[O:39])[CH:33]=1
Reactant: CCC(C)C1O[C@]2(C=C[C@@H]1C)C[C@@H]1CC(CC=C(C)[C@@H](OC3C[C@H](OC)[C@@H](OC4C[C@H](OC)[C@@H](O)[C@H](C)O4)[C@H](C)O3)[C@@H](C)C=CC=C3COC4[C@H](O)C(C)=CC(C(=O)O1)[C@]34O)O2
Reactant: CC(C)O
Reactant: ClCCl
Agent: CCC(C)C1O[C@]2(C=C[C@@H]1C)C[C@@H]1CC(C/C=C(\C)[C@@H](OC3C[C@H](OC)[C@@H](OC4C[C@H](OC)[C@@H](O)[C@H](C)O4)[C@H](C)O3)[C@@H](C)/C=C/C=C3\COC4[C@H](O)C(C)=CC(C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O[C@H]4C[C@H](OC)[C@@H](O)[C@H](C)O4)[C@H](C)O3)[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O[C@H]4C[C@H](OC)[C@@H](O)[C@H](C)O4)[C@H](C)O3)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Solvent: c1ccccc1
Product: O=C(OO)c1cccc(Cl)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 4.7 mg of 85% metachloroperbenzoic acid and 0.5 ml of fresh methylene chloride is prepared, is placed in a test tube, fitted with a septum and immersed in a dry ice acetone bath. There was added a solution of 0.5 ml of methylene chloride containing 20 mg of avermectin B1a/B1b. The reaction mixture is stirred under nitrogen at -70° C. for two hours and at -30° C. for 30 minutes. Then the reaction mixture was placed in an ice bath for 4 hr. and in a refrigerator for 2 days. The reaction mixture was placed on an 8×8 inch chromatography plate with a layer of 250 microns of silica gel and developed with 5% isopropanol in benzene three times. Two fractions are observed: the faster moving fraction weighing 6.4 mg; a slower moving fraction weighing 8.2 mg. The mass spectral and nuclear magnetic resonance analysis of both fractions indicate that the slow moving fraction was avermectin B 1a/B1b-8,9-epoxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[CH:23])[N:19]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[C:23][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(Br)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(Br)c3n2)n1
Yield: 10.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.97 mmol) and 8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (242 mg, 0.97 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 36 mg of 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 10%) as a yellow oil.