Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of mesylate 97 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (60 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0–5° C. for 1 h. The white precipitate was collected by filtration, washed with water (2×40 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (phthalimide 98, 3.12 g, 91.8% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H13FN2O4, LCMS (EI) m/e 341 (M++H).
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:7]2([CH2:16][C:17]([O:19][CH3:22])=[O:18])[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1(c2ccccc2)CC=C2C=CC=C2O1
Solvent: CO
Solvent: O
Product: COC(=O)CC1(c2ccccc2)CC=C2C=CC=C2O1
Yield: 228.2 %

Procedure:
A solution of 20.45 g of the product of Step B, 200 ml of methanol and 6 g of p-toluene sulfonic acid was refluxed for one hour and the solution was brought to dryness, then poured into water. Extraction was carried out with methylene chloride and the extracts were dried, filtered and concentrated to obtain 21.33 g of the desired product with a Rf =0.33 (eluant: hexane - methylene chloride (60-40)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:26])(=[O:18])[CH3:17].O>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(C)=O)c2cc1OC
Temperature: 170 °C
Reaction time: 144 h
Yield: 3.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (220 mg) and 2-acetyl-4-methylphenol (300 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 170° C. for 6 days. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (12 mg, yield 4%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[CH2:18])[C:15](Cl)=[O:16].O>C(OCC)C>[CH3:18][C:14](=[CH2:13])[C:15]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1CCNC1
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mmole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.Br[C:16]1[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=1)[CH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:21]1=[O:31].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[Cl:35][C:32]1[C:18]([CH2:19][CH:20]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:21]2=[O:31])=[C:17]([Cl:36])[CH:16]=[CH:34][C:33]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=1
Reactant: O=C1C(Cc2c(Cl)ccc(Br)c2Cl)CCN1C1CCCCC1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Place 3-(ethoxycarbonyl)phenylboronic acid (670 mg, 3.46 mmol), 3-(3-bromo-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one (Example 50) (700 mg, 1.73 mmol), and Pd(PPh3)4 (173 mg, 0.173 mmol) into a flask and purge with nitrogen. Add DME (50 mL) and 2M sodium carbonate (5 mL) and heat to 75° C. for 24 hr. Cool reaction, add DCM and wash with saturated sodium bicarbonate. Dry, filter, and concentrate organic layer. Purify by silica gel (30-45% EtOAc in Hex). Dissolve ester in ethanol (3 mL) and water (1 mL) and add KOH (291 mg, 5.18 mmol. Stir for 1 hour at room temperature. Strip off solvent and add water. Bring to a pH of 2 with 1M HCl. Filter precipitate to give 727 mg (94%) of title compound as a white solid. Mass spectrum (apci) m/z=446.2 (M+H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:9]2[C:8]=1[Br:17].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:17][C:8]1[C:9]2[N:10]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:11]=[CH:12][C:7]=1[NH:6][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1cn2ccc(N)c(Br)c2n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A mixture of sodium bicarbonate (0.74 g, 8.81 mmol) and amine 18 (1.00 g, 4.42 mmol) in 50 mL of dry CH2Cl2 was treated over a period of fifteen minutes with ethyl chloroformate (2.40 g, 22.1 mmol). 4-Dimethylaminopyridine (0.08 g, 0.65 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Then, water (25 mL) was added and the solution was extracted with CH2Cl2 (3×25 mL). The extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: compound 19 (461 mg, yield: 35%); mp 137-138° C.; 1H NMR (200 MHz, CDCl3) δ 1.34 (t, 3H, J=7 Hz), 2.45 (s, 3H), 4.26 (q, 2H, J=7 Hz), 7.24 (brs, 1H), 7.31 (s, 1H), 7.81 (d, 1H, J=7.4 Hz), 7.92 (d, 1H, J=7.4 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.4, 60.8, 102.5, 109.7, 111.3, 125.1, 133.3, 142.4, 143.0, 153.8. Starting material 18 (0.31 g, 31%).
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[NH:4][CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[N:11]([N:4]1[CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7][S:2][CH2:3]1)=[O:12]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCSCN1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CSCCC1C(=O)O
Reaction time: 3 h

Procedure:
To a suspension of DL-tetrahydro-1,3-thiazine-4-carboxylic acid hydrochloride (48.6 g, 0.26 mol) in 666 mL of AcOH was added to the solution of 27.4 g (0.40 mol) of NaNO2 in 333 mL of water over 16 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (300 mL) was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to dryness and crude 3-nitroso[1,3]thiazinane-4-carboxylic acid was obtained as brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[CH:13][C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:12]1[N:11]=[N:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc(-c2c(F)cccc2F)n[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1-c1ncc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 3-(2,6-difluorophenyl)-[1,2,4]triazin-6(1H)-one is placed in 20 ml of dioxane and at room temperature 0.73 g of POCl3 is added. Then, within a period of 5 min, 0.48 g of triethylamine in 3 ml of dioxane is added dropwise and stirring is carried out at room temperature for 30 min. The reaction mixture is then poured into ice-water and extracted with ethyl acetate, and the organic phase is separated off and concentrated. In this way 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine is obtained in the form of a yellow oil. The crude product is reacted further without purification.
Reaction SMILES: C(O)(=O)C.[O:5]([CH2:12][C:13]1[CH:14]=[C:15]([NH:19][N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH2:22])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]1[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=2)[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH:22]1
Reactant: NC(=O)C(N)=NNc1cccc(COc2ccccc2)c1
Reactant: O=Cc1ccccc1F
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)C1=NN(c2cccc(COc3ccccc3)c2)C(c2ccccc2F)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Into 15 ml of acetic acid saturated with nitrogen, 2.84 g (0.01 mol) of oxamide 3-(phenoxymethyl)phenylhydrazone was dissolved, and 1.36 g (0.011 mol) of 2-fluorobenzaldehyde was added to the thus formed solution under nitrogen atmosphere and the mixture was stirred for 16 hours at room temperature. After adding water saturated with nitrogen to the mixture, the precipitated crystals were collected by filtration and dried under vacuum. The thus dried crystals were recrystallized from a mixed solvent, saturated with nitrogen, of ethyl acetate and n-hexane to obtain 3.38 g of 5-(2-fluorophenyl)-4,5-dihydro-1-[3-(phenoxymethyl)phenyl]-1H-1,2,4-triazole-3-carboxamide melting at 176°-178° C. in a yield of 86.7%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][C@H:27]5[CH2:31][CH2:30][CH2:29][N:28]5C(OC(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][C@H:27]5[CH2:31][CH2:30][CH2:29][NH:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OC[C@H]5CCCN5C(=O)OC(C)(C)C)c4n3)cnc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COCCOc1ccn2c(-c3ccc4cccc(OC[C@H]5CCCN5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 40.7 %

Procedure:
(R)-tert-butyl 2-((2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)methyl)pyrrolidine-1-carboxylate (241 mg, 0.47 mmol) was dissolved in 10 mL of chloroform, followed by addition of 4.0M HCl in dioxane (4.65 ml, 9.3 mmol). The reaction was allowed to stir for 30 hours at ambient temperature at which time all starting material was consumed by LC/TLC. The reaction was concentrated in vacuo, followed by flash column chromatography (eluting with a 1-20% MeOH/DCM gradient), affording an oil on concentration. The crude oil was treated with 1000 uL of 4.0 M HCl in dioxane, affording the desired product (80 mg, 41% yield). MS APCI (+) m/z 419.1 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8]2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1=NOC(Cc2ccc(F)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OCC1=NOC(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of solution of [5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-yl]-methanol (80 mg, 0.38 mmol), TEA (57 mg, 0.57 mmol) in DCM (10 ml), methanesulfonyl chloride (43 mg, 0.38 mmol) was added slowly at 0° C. and the mixture was stirred at room temperature for 3 hrs. Aqueous NaHCO3 was added to the reaction mixture and extracted with methylene dichloride. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain Methanesulfonic acid 5-(4-fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl ester (82 mg, 75%) as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:33]I.O>CC#N>[F:1][C:2]1[CH:9]=[C:8]([I:33])[C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: II
Reactant: COc1ccc(F)c(C=O)c1
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COc1cc(C=O)c(F)cc1I
Temperature: 80 °C
Yield: 82 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (Oakwood, 6.000 g, 38.9 mmol) and Selectfluor (13.79 g, 38.9 mmol) in 40 mL MeCN was treated with iodine (10.87 g, 42.8 mmol) and was heated to 80° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and was extracted with DCM. The organic were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-20% EtOAc/heptane) gave 2-fluoro-4-iodo-5-methoxybenzaldehyde (8.92 g, 31.9 mmol, 82% yield) as a 3:1 mixture with starting material. (M+H)+=281.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.I[CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: COc1nc(N)ccc1C(=O)CCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCC(CCC(=O)c2ccc(N)nc2OC)CC1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 1-(6-amino-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone (step 1, 175 mg, 0.665 mmol), 1-iodobutane (0.083 ml, 0.732 mmol) and potassium carbonate (184 mg, 1.33 mmol) in tetrahydrofuran (5 ml) was refluxed for 6 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml), washed with water (5 ml) and brine (10 ml) and dried over potassium carbonate. Removal of solvent gave the pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:10) to give pale yellow solid, which was washed with acetonitrile to afford 107.0 mg (50%) of the title compound as pale yellow solids.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(O)(=O)=O.[CH2:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:16]1[O:18][CH2:17]1>>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:9][CH2:17][CH:16]([OH:18])[CH2:15][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOCC1CO1
Reactant: CCCCCCCCO
Agent: CS(=O)(=O)O
Product: CCCCCCCCOCC(O)COCCCCCCCC
Temperature: 95 °C
Yield: 7 %

Procedure:
Octyl alcohol (11.7 g; 0.09 mol) and methanesulfonic acid (0.50 g; 5.50 mmol) were placed in a 100-ml four-necked flask and heated up to 95° C. while stirring them under nitrogen. Octyl glycidyl ether (17.1 g; 0.09 mol) was then added dropwise over 10 minutes, and the resultant mixture was stirred for 8 hours as it was. After completion of the reaction, the reaction mixture was washed with a 4N aqueous solution (40 ml) of sodium hydroxide and additionally twice with water (40 ml) and then purified by column chromatography on silica gel (developing solvent: hexane) to obtain 2.0 g of 1,3-dioctyl glyceryl ether (9,13-dioxa-11-heneicosanol) as a colorless transparent oil (yield: 7%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:17])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)NC(C)(C)C)ccc1CBr
Temperature: 30 °C

Procedure:
A mixture of 3 g of N-tert-butyl-4-methyl-3-methoxybenzamide, 2.4 g of N-bromosuccinimide and 0.16 g of benzoyl peroxide in 40 ml of carbon tetrachloride is stirred at 30° C. while irradiating in the visible spectrum for 48 hours. The solvent is evaporated and then, successively, 25 ml of water are added, extraction is carried out with diethyl ether, drying is carried out over MgSO4, the solvent is evaporated and the residue is chromatographed on silica gel, elution being carried out with an 8/2 (v/v) cyclohexane/ethyl acetate mixture. The expected reactant is isolated after crystallization from isopropyl ether; M.p.=114° C.
Reaction SMILES: F[C:2](F)([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=[C:4](I)[CH2:5][OH:6].[OH2:19].Cl.[NH2:21]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:14][C:9]([F:15])([C:10]([F:13])([F:12])[F:11])[C:8]([F:17])([F:16])[C:2]1[O:19][N:21]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: NO
Reactant: O
Reactant: OCC(I)=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCc1cc(C(F)(F)C(F)(F)C(F)(F)F)on1

Procedure:
14.94 g of 4,4,5,5,6,6,7,7,7-nonafluoro-2-iodo-2-heptene-1-ol was dissolved in 150 ml of ethanol, and 70 ml of water, 5.17 g of hydroxylamine hydrochloride and 25.67 g of potassium carbonate were then added. The mixture was stirred and heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.53 g of (5-heptafluoropropyl-isoxazol-3-yl)methanol.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15]O)=[CH:14][C:9]=2[N:8]=[N:7]1>C(OCC)C.O>[Br:2][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH3:5])[N:7]=[N:8][C:9]=2[CH:14]=1
Reactant: BrP(Br)Br
Reactant: Cn1nnc2cc(CO)ccc21
Solvent: O
Solvent: CCOCC
Product: Cn1nnc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus tribromide (0.230 ml, 2.45 mmol) is added to a stirred solution of (1-methyl-1H-1,2,3-benzotriazole-5-yl)methanol (0.4 g, 2.45 mmol) in diethyl ether (25 ml) under an inert atmosphere of Argon. After stirring overnight at room temperature, the reaction mixture is diluted with water (5 ml) and stirred vigorously for 10 minutes. The organic portion is separated, washed with water (2×5 ml), brine (2×5 ml) and concentrated in vacuo to yield the titled product which is used crude in the next step. (MH+226).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (200 mg, 0.99 mmol) was coupled to 3-chloro-phenylboronic acid (130 mg, 0.83 mmol) using Method F to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:43][CH2:44][S:45](Cl)(=[O:47])=[O:46].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][N:23]([S:45]([CH:44]=[CH2:43])(=[O:47])=[O:46])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 13) (0.891 mg, 2 mmol) and DIPEA (0.77 g, 6 mmol) in CH2Cl2 (100 mL) was added dropwise 2-chloroethanesulfonyl chloride (0.49 g, 3 mmol) at 0° C. After addition, the reaction mixture was stirred at 0° C. for additional 2 hrs. The reaction mixture was quenched with water (100 mL). The organic layer was washed successively with aqueous HOAc (1%, 100 mL) and aqueous NH3, and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (9:1) gave 0.589 g (55% yield) of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole: mp (MeOH) 229-232° C.; 1H NMR (CDCl3) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H), 7.54 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.47 (dd, J=16.6, 9.9 Hz, 1H), 6.27 (d, J=16.6 Hz, 1H), 6.05 (d, J=9.9 Hz, 1H), 4.06 (s, 3H), 4.00-3.97 (m, 4H), 3.89-3.79 (m, 6H), 2.78 (m, 3H), 2.17 (br dd, J=13.6, 3.0 Hz, 2H), 2.01 (ddd, J=25.2, 11.7, 4.1 Hz, 2H); Anal. Calcd. for C23H27F2N7O4S: C, 51.6; H, 5.1; N, 18.3. Found: C, 51.7; H, 5.2; N, 18.25%.