Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:5][CH:4]=1)=[O:28]
Reactant: CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
2-[6-(Methylthio)-3-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.085 g, 28%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH3:12][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])=[CH:21][C:20]=1[CH3:31])([CH3:17])[C:14]([OH:16])=[O:15]>>[CH3:17][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=2)=[CH:21][C:20]=1[CH3:31])([CH3:12])[C:14]([OH:16])=[O:15]
Reactant: FC(F)(F)c1ncc(Cl)cn1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Product: Cc1cc(OCCCC#Cc2cnc(C(F)(F)F)nc2)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 24E], 5-chloro-2-trifluoromethyl-pyrimidine (example 28B]) and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by flash chromatography (SiO2, CH2Cl2/MeOH 2.5 to 10%) and precipitation ether/n-pentane yielded the title compound as white powder, mp. 95-97° C., dec.
Reaction SMILES: Cl[CH:2]([CH2:10][C:11]([Cl:17])([Cl:16])[C:12]([F:15])([F:14])[F:13])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:18]C(C)([O-])C.[Na+]>C(O)(C)(C)C.CN(C=O)C>[Cl:16][C:11]([Cl:17])([C:12]([F:15])([F:14])[F:13])[CH2:10][CH:2]1[CH:4]([C:5]([O:7][CH3:18])=[O:6])[C:3]1([CH3:9])[CH3:8]
Reactant: CC(C)(CC(=O)O)C(Cl)CC(Cl)(Cl)C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: COC(=O)C1C(CC(Cl)(Cl)C(F)(F)F)C1(C)C

Procedure:
The (−) enantiomer of the methyl ester of 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoic acid (14.43 gm) was cyclised with sodium t-butoxide base (6.3 gm 100%) in t-butanol/DMF solvent at <0° C. to produce methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate which was isolated by quenching with water and extracting into dichloromethane. After washing with water and brine the product was obtained as a yellow/orange oil (10.1 gm) by topping off the dichloromethane solvent. The product obtained was analysed by GLC, GCMS and NMR to confirm the material was consistent with that of methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate and it had a 80/20 cis:trans ratio.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][SH:20])[CH3:16].C(Cl)Cl>C(N(CC)CC)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][S:20][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4])[CH3:16]
Reactant: CCOC(CS)OCC
Reactant: COC(=O)C(Br)CCCCCCC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CSC(CCCCCCC#N)C(=O)OC)OCC

Procedure:
The starting material is prepared as follows: To the mixture of 13.6 g of methyl 2-bromo-8-cyano-octanoate, 11.6 g of 2,2-diethoxy-ethylmercaptan and 150 ml of methylene chloride, 5.56 g of triethylamine are added dropwise while stirring. After overnight-stirring at room temperature the mixture is evaporated, the residue triturated with diethyl ether, washed with water, dried and evaporated, to yield the methyl 2-(2,2-diethoxyethylmercapto)-8-cyano-octanoate showing NMR bands aft 4.58, 3.71 and 2.75 ppm.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Li]CCCC.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([O:38][CH:39]([CH3:41])[CH3:40])[C:24]([F:37])=[C:25]([CH:36]=1)/[CH:26]=[N:27]/[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH3:19]>C1COCC1>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:27]([CH2:26][C:25]1[CH:36]=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=[C:23]([O:38][CH:39]([CH3:41])[CH3:40])[C:24]=1[F:37])[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH:11]=[CH:10]2
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: Clc1ccc2nc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cc(Cl)ccc3n2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a solution of Intermediate 90.1 (100 mg, 0.412 mmol) in 2 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 324 μL, 0.454 mmol). The mixture was stirred at −78° C. for 10 min, then a solution of Intermediate 7.3 (134 mg, 0.412 mmol) in 0.7 mL THF was added. The mixture was stirred 15 min at −78° C., allowed to warm to rt over 30 min, then was quenched with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 112 mg of Intermediate 90.2 as a pale orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH4+:11].[OH-]>O>[NH2:11][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N)nc1

Procedure:
1-(6-Chloropyridin-3-yl)-ethanone (230 mg, 1.5 mmol), 1 mL 28% aq NH4OH, and catalytic CuSO4.5H2O were heated to 130° C. in a sealed tube for 5 h. The mixture was cooled, diluted with 20 mL water, and washed with 2×25 mL EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (163 mg, 80%).
Reaction SMILES: Cl[P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1.[C:8]([O:13][CH2:14][CH2:15][OH:16])(=[O:12])[C:9]([CH3:11])=[CH2:10]>>[C:8]([O:13][CH2:14][CH2:15][O:16][P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: O=P1(Cl)OCCO1
Reactant: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OCCOP1(=O)OCCO1

Procedure:
The 2-chloro-2-oxo-1,3,2-dioxaphospholane prepared in step (a) was reacted with 2-hydroxyethyl methacrylate to give 2-(2-oxo-1,3,2-dioxaphospholan-2-yloxy)ethyl methacrylate, as follows: Into a thoroughly dried 500 cm3 three-necked round bottomed flask equipped with a mechanical stirrer, drying tube and dropping funnel were placed 2-hydroxyethyl methacrylate (20.0 g, 0.154 mol) and triethylamine (15.6 g, 0.154 mol) was added slowly to the stirred solution, maintained at -20° C. to -15° C., over a period of 0.5 hr, whereupon triethylamine hydrochloride began to precipitate from the solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.OS(O)(=O)=O.[CH3:19][C:20](=[CH2:22])[CH3:21]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2cc(Br)ccc2s1

Procedure:
A mixture of Example 274B and concentrated H2SO4 (0.5 mL) in dichloromethane (100 mL) saturated with isobutylene at room temperature was stirred for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:26])=[O:25])=[CH:22][CH:23]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: CS(=O)c1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Product: CN1CCN(Cc2cc(-c3ccc(S(C)=O)cc3)nn(CC3CC3)c2=O)CC1
Yield: 60.6 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 60.6%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].O>CN(C=O)C>[CH3:17][N:18]([CH3:22])[C:19](=[S:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1ccc(I)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of p-iodophenol (20.0 g, 90.9 mmol) in 1) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane (20.4 g, 181.8 mmol) and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol). The resulting solution was stirred for 3.5 hr at 75° C. After cooling, 300mL of water was added. The solid was collected with suction and was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and evaporated under a reduced pressure. The crude solid was recrystallized from H2O to give the 26.75 g (96%) O-p-iodophenyl dimethylthiocarbamate as a pale a yellow crystalline powder. IR (KBr) 1479, 1207, 827 cm−1; 1H-NMR (400 MHz, CDCl3) δ3.37 (s, 3H), 3.45 (s, 3H), 6.83 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H); MS (FAB) m/z 307 (M++1); Anal. Calcd. for C9H10INOS: C, 35.19; H, 3.28; N, 4.56. Found: C, 35.17; H, 3.35; N, 4.44.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([O:22][C:23](=[O:29])[C:24](OCC)=[O:25])[CH3:21].CCOCC>C(O)(=O)C>[CH2:20]([O:22][C:23](=[O:29])[C:24]([CH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25])[CH3:21]
Reactant: Cc1cc(OCc2ccccc2)c(C)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Cc1c(OCc2ccccc2)cc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
25.7 g of the thus obtained 2,5-dimethyl-3-nitro-O-benzylphenol are added in portions during stirring to a mixture of 17 g freshly prepared potassium-tert.-butylate and 120 ml oxalic acid diethyl ester. After completion of the addition, the mixture is heated to 60° C. for two hours. After cooling, the composition is mixed with 200 ml ether and carefully acidified with diluted acetic acid. The ether phase is washed with neutral water, dried and evaporated. The still present oxalic ester is distilled off in the water jet vacuum at increased bath temperature. The residue is dissolved in ether and the solution is carefully mixed with ligroin. After aspirating and drying, there is obtained 30.6 g (~85° of theory) 2-benzyloxy-4-methyl-6-nitro-phenyl pyruvic acid ethyl ester; m.p. 80°-82° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:21][C:20]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccnc1NCC1CCN(c2ccncc2)CC1
Product: COc1ccc(C(=O)Nc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 15.1 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N2-[1-(4-pyridyl)piperidin-4-ylmethyl]-2,3-pyridinediamine (300 mg, 1.06 mmol) and 4-methoxybenzoyl chloride (200 mg, 1.17 mmol) yielded 67 mg (15%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C([Li])(CC)C.[CH3:16][S:17]SC>C1COCC1>[F:1][C:2]1[C:7]([S:17][CH3:16])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CSSC
Reactant: COc1cc(C)ccc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(C)cc(SC)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 1-fluoro-2-methoxy-4-methylbenzene (1.0 g) and THF (dry) (60 mL) was added sec-butyllithium (1.04 mol/L cyclohexane solution, 13.72 mL) dropwise over a period of 20 min at −78° C. After stirring at −78° C. for 20 min, to the mixture was added dimethyl disulfide (1.41 mL) at the same temperature. The mixture was stirred at −78° C. under argon atmosphere for 1 h. The mixture was quenched with saturated aqueous NH4Cl at −78° C. and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.34 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12>>[CH2:1]([NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Cc1cc(Cl)c2[nH]nc(C)c2n1
Product: C=CCNc1cc(C)nc2c(C)n[nH]c12

Procedure:
The above compound was prepared from allylamine and 7-chloro-3,5-dimethyl-1H-pyrazolo[4,3-b]pyridine in an analogous manner to the preparation of Example 2 giving a pale yellow solid, m.p. 196°-198°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(C#N)cc1

Procedure:
Following General Procedure AP above and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([OH:35])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(Oc1ccc(C#N)cc1)C(Cc1ccc(OCc2ccccc2)c[n+]1[O-])OS(C)(=O)=O
Reaction time: 4.5 h
Yield: 32.4 %

Procedure:
0.7 g of methanesulphonyl chloride was added to a stirred solution of 2.3 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy -3-methylbutyl]pyridine N-oxide and 1 ml of 2,6-lutidine in 10 ml of dichloromethane. The mixture was stirred for 4.5 hours and then a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added. After 2.5 hours a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added and the mixture was stirred for 16 hours. The mixture was then diluted with 50 ml of dichloromethane and washed in succession with 2M hydrochloric acid, water and 10% sodium bicarbonate solution The organic solution was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (9:1) for the elution to give 0.89 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-(methylsulphonyloxy)butyl]pyridine N-oxide in the form of a cream solid of melting point 142° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(N(CC)CC)C.[C:59](OC(=O)C)(=[O:61])[CH3:60]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:59]([CH3:60])=[O:61])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
Erythromycin A (50.0 g, 68.1 mmol) (commercially available from Abbott Laboratories) was dissolved in 600 mL of methylene chloride (CH2Cl2) at ambient temperature. Triethylamine (20 mL) and 10 mL (10.82 g, 106 mmol) of acetic anhydride were added to this solution. The reaction mixture was heated to reflux and 100 mL of CH2Cl2 was distilled from the reaction mixture to remove any traces of water. The reaction mixture was heated at reflux temperature for an additional five hours. After six hours, when the reaction was complete, according to TLC analysis, the reaction mixture was cooled to ambient temperature and transferred to a separatory funnel. The CH2Cl2 solution was washed with 300 mL of ammonium hydroxide/sodium bicarbonate solution containing 2.9% ammonia and 1.8% sodium bicarbonate, dried over anhydrous sodium sulfate and filtered. The CH2Cl2 was removed using a rotary evaporator with a water bath temperature of 30°-40° C. The residue was crystallized from 200 mL of acetonitrile (CH3CN) by first dissolving it in hot CH3CN and allowing the solution to stand overnight at ambient temperature, then cooling it to -25° C. and maintaining this temperature for 24 hours. The product was isolated as white crystals which were washed with cold (-25° C.) CH3CN and dried in a vacuum oven at 50° C. for approximately 64 hours. The 2'-O-acetylerythromycin A was obtained in 83% yield (43.91 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[CH:26][CH:25]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[CH:28][CH:29]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C[Si](C)(C)CCOC(=O)CCCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CCCC(=O)OCC[Si](C)(C)C)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)butanoate (55 mg, 0.20 mmol) in dry THF (4 mL) at 0° C. (ice/water bath), under nitrogen, was added ADDP (102 mg, 0.40 mmol) followed by nBu3P (100 μL, 0.40 mmol), and the mixture stirred with slow warming to rt over 64.5 hours. The mixture was then concentrated under vacuum and the solid residue partitioned between DCM (5 mL) and water (5 mL) using a hydrophobic frit. The layers were separated and the aqueous layer re-extracted with DCM (5 mL) and the combined organic layer reduced. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 7.5:1) afforded the title compound (42 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Na].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>C(C(C)=O)C>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12](\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=2)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: c1c[nH]cn1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCC(C)=O
Product: OCC/C(=C(\c1ccccc1)c1ccc(OCCn2ccnc2)cc1)c1ccccc1

Procedure:
(Z)-4-[4-(2-Bromoethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol (preparation described in U.S. Pat. No. 4,996,225) (4.97 g, 0.0117 mol) is dissolved in methyl ethyl ketone (50 ml) and potassium carbonate (4.8 g, 0.035 mol) and imidazole sodium salt (2.1 1 g, 0.0234 mol) is added to the solution. Mixture is stirred and refluxed for five hours. Then the solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, washed with 2 N aqueous sodium hydroxide solution and with water, dried and evaporated to dryness. The residue is recrystallized from the mixture of toluene and acetonitrile.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][C:31]=3[F:39])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[C:1]([O:4][CH2:5][C:6]([N:8]([CH2:13][C:14]1[N:18]([CH3:19])[C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=3[F:39])[CH:21]=2)=[N:16][CH:15]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)COC(C)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)COC(C)=O
Yield: 46.8 %

Procedure:
The reaction mixture consisting of 206 (300 mg, 0.538 mmol), ammonium chloride (24.75 mg, 0.463 mmol) and iron powder (255 mg, 4.57 mmol) in ethanol (6 mL)/water (3.0 mL) was heated to reflux for 1 h. The reaction mixture was filtered while hot and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-20%, SNAP 25 g cartridge) to give the title compound 207 (133 mg, 0.252 mmol, 47% yield) as a white solid. MS: 528 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Mg]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Br[Mg]Cc1ccccc1
Product: COc1cc(C(=O)Cc2ccccc2)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (3.92 g) and benzylmagnesium bromide (2.0 M diethyl ether solution, 23 ml) to give 3,4,5-trimethoxydeoxybenzoin (3.51 g).