Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O-:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=C[CH:23]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[C:5]([C:9]([O:11][CH3:23])=[O:10])=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=C([O-])c1n[nH]cc1[N+](=O)[O-]
Reactant: c1ccncc1
Reactant: OB(O)Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.84 mmol) in methylene chloride (20 mL) were added phenylboric acid (1.43 g, 11.7 mmol), copper(II) acetate (1.60 g, 8.76 mmol) and pyridine (2 mL, 23.4 mmol), and the mixture was stirred overnight at room temperature under an air atmosphere. After removal of the insolubles by filtration, the filtrate was washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title compound (1.21 g, 83.5%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[C:11]([N+:17]([O-:19])=[O:18])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc(F)cc2s1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2s1

Procedure:
Explaining the above conversion, 6-fluoro-2(3H)-benzothiazolone (V) [G. Mazzone et al: Farmaco, Ed. Sc., 32, (5), 348 (1977)] is reacted with a nitrating agent such as a mixture of sulfuric acid and nitric acid to give 6-fluoro-5-nitro-2(3H)-benzothiazolone (VI). The reaction is accomplished at a temperature of -10° to 10° C. instantaneously or within 5 hours. Sulfuric acid and nitric acid are respectively used in amounts of one equivalent to excess amount and of 1 to 1.2 equivalents to the compound (V).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[C:9]1([C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O1CCCC1.O>[O:24]=[C:23]([CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)CCc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)CCc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.3 mL (0.044 mole) of acetonitrile in 50 mL of tetrahydrofuran was cooled to about -80° C., and 17.7 mL (0.044 mole) of n-butyllithium (2.5M in hexanes) was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes. After this time a solution of 10.3 grams (0.040 mole) of ethyl 3-(3-phenylphenyl)propanoate in 100 mL of tetrahydrofuran was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for one hour. After this time the reaction mixture was allowed to warm to ambient temperature, then was cooled to about 0° C., and 30 mL of aqueous 6N hydrochloric acid was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 30 minutes. The mixture was poured into 200 mL of water, and then it was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. NMR analysis of the residual oil indicated that it was impure. The oil was dissolved in 10:1 methylene chloride and acetone, and the solution was passed through a column of basic alumina that was deactivated to Level III with water. The eluate was concentrated under reduced pressure, yielding 5.9 grams of 3-oxo-5-(3-phenylphenyl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:36][CH:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.096 g, 0.221 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.03 g, 0.221 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.12 g, 1.188 mmol, 5.0 eq) and BOP reagent (0.146 g, 0.330 mmol, 1.5 eq). The reaction mixture was stirred as RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent. Yield: 0.070 g (57.33%). 1H NMR (400 MHz, CD3OD): δ 8.99 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.99-7.93 (m, 2H), 7.79 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.23 (m, 3H), 7.16 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.85-1.82 (m, 2H), 1.61-1.49 (m, 2H). LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:51]=[CH:50][C:31]([O:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47](O)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:30][CH:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([NH:59][CH2:58][C:54]4[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=4)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:50][CH:51]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(CCOc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CCOc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(2-(4-fluorophenoxy)ethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 45% yield: mp 154-155° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.58 (br s, 1H), 8.53-8.45 (m, 1H), 8.26 (s, 1H), 7.72-7.65 (m, 1H), 7.30-7.21 (m, 1H), 6.98-6.86 (m, 2H), 6.85-6.75 (m, 2H), 6.61 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.28-4.15 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 157.6, 154.2, 153.4, 151.0, 149.3, 149.1, 135.8, 133.6, 131.0, 123.7, 121.6, 116.0, 115.9, 115.8, 65.5, 45.3, 41.6, 17.2; MS (ES+) m/z 455.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and Cul (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1)#[N:10]>N1C=CC=CC=1>[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:8][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=1)#[N:10]
Reactant: N#CCc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccnc1O
Solvent: c1ccncc1
Product: N#CCc1ccc(-c2nc3cccnc3o2)cc1
Reaction time: 8 h

Procedure:
Ten grams of 4-(cyanomethyl)benzoic acid is refluxed in 70 mls. of thionyl chloride for four hours. The solvents are removed leaving a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.5 g. of 3-amino-2-hydroxy pyridine in cold pyridine there is added slowly, with cooling, 8 g. of 4-cyanomethyl benzoyl chloride. The mixture is allowed to come to room temperature and stirred overnight. The mixture is added to 300 ml. of ice and the solid amide separated by filtration and recrystallized from methanol. A mixture of 3 g. of the above amide in 50 mls. of phsophorus oxychloride is heated under reflux for 5 hours. The solvents are removed in vacuo and the residue is crystallized from ethyl acetate to give 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])[CH2:22][CH2:23]3)=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: C1COCCN1
Reactant: O=C(O)C1CCN(C(=O)Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)N1CCC(C(=O)N2CCOCC2)CC1

Procedure:
5,5-Dioxo-2-(4-carboxypiperidinocarbonylamino)dibenzothiophene (Example 84; 75 mg, 0.19 mmol), DMF (2.5 ml), morpholine (16.5 mg, 0.19 mmol), EDAC (44 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (25.65 mg, 0.19 mmol) were stirred together for 18 hours. The solvent was removed under vacuum and the residue partitioned between H2O/EtOAc. The organic layers were washed with water, saturated aqueous NaHCO3 then brine, and then dried, filtered and evaporated to an amorphous solid. NMR: 9.08 (s, 1H)) 8.21 (d, 1H), 7.93 (m, 2H), 7.79 (m, 2H), 7.65 (m, 2H), 4.14 (m, 2H), 3.52 (m, 6H), 3.45 (m, 2H), 2.92 (m, 3H), 1.68 (m, 2H), 1.53 (m, 2H); m/z 456.73.
Reaction SMILES: [F:1][CH:2]1[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([O:15]C(CCCCC)=O)[CH2:4][CH2:5]2.[OH-].[K+].O.Cl>C(OCC)(=O)C.C(O)C>[F:1][CH:2]1[C:7]([F:8])([F:9])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([OH:15])[CH2:4][CH2:5]2
Reactant: CCCCCC(=O)OC12CCC(CCC)(CC1)C(F)(F)C2F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCC12CCC(O)(CC1)C(F)C2(F)F
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,3,3-trifluoro-1-pentylcarbonyloxy-4-n-propylbicyclo[2.2.2]octane (3) (0.12 g), potassium hydroxide (0.11 g), water (0.5 mL) and ethanol (2.0 mL) was stirred at 70° C. for 20 minutes. The mixture was neutralized with hydrochloric acid, added with ethyl acetate (30 mL), and the organic layer was washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was vaporized off under reduced pressure, to thereby obtain a crude product. The crude produce was purified by silica gel column chromatography (hexane/ethyl acetate=3:1), to thereby obtain 2,3,3-trifluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (4) (yield=82 mg, yield ratio=98%) as a colorless clear solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5]1)=[N+]=[N-].CC1CCCO1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(OC)(C)C>[C:9]1([C@@H:7]2[CH2:8][C@H:4]([NH2:1])[CH:5]=[CH:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=N[C@@H]1C=C[C@H](c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Solvent: COC(C)(C)C
Solvent: O
Product: N[C@@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 0.83 h

Procedure:
A solution of Example 48B (530 mg, 2.86 mmol), 2-methyl tetrahydrofuran (9.5 mL), water (1.056 mL), and triphenylphosphine (900 mg, 3.43 mmol) was heated to 70° C. After 50 minutes, LCMS showed complete reaction. The mixture was diluted with MTBE (50 mL) and extracted with 2N HCl (25 mL) and water (25 mL). Aqueous 2N NaOH (30 mL) was added to the aqueous layer, followed by extraction with MTBE (50 mL×3). The final organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound, which was used crude in the next step. MS (DCI) m/z 160 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:12]([N:20]=[C:21]=[S:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:21]([NH:20][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[S:22])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: S=C=NCCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1)NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(1H-indol-5-yl)methylamine (8.5 mg) prepared in Step 1 was dissolved in dimethylformamide (100 μl) and the solution was diluted with dichloromethane (1 ml). To the diluted solution was added phenethylisothiocyanate (40 μl) and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (2/3) to yield 1-(1H-indol-5-ylmethyl)-3-phenethylthiourea (15 mg, 83%).
Reaction SMILES: [F:1][C:2]1[C:7]([Si:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])(OCC)[O:9][CH2:10][CH3:11])=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29].S(Cl)([Cl:32])=O.Cl.[NH+]1C=CC=CC=1>>[F:1][C:2]1[C:7]([SiH:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[O:9][CH2:10][CH2:11][Cl:32])=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29]
Reactant: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Fc1c(F)c(F)c([SiH](OCCCl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reaction time: 16 h

Procedure:
180.93 g (0.400 mol) di(pentafluorophenyl)diethoxysilane, 29 mL (0.400 mol, 47.6 g) thionylchloride and 4.92 g (0.0426 mol) pyridinium hydrochloride are refluxed and stirred for 16 h. Unreacted SOCl2 is evaporated and di(pentafluorophenyl)chloroethoxysilane isolated by vacuum distillation.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]([O:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1)([CH3:10])[CH3:9].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>C(OCC)(=O)C>[CH:8]([O:11][C:12]1[N:16]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[N:15]=[C:14]([NH2:17])[CH:13]=1)([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)Oc1cc(N)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(N)nn1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Sodium hydride (60%, 425 mg, 10.63 mmol) was added to a DMF (mL) solution of 5-isopropoxy-1H-pyrazole-3-amine (1.5 g, 10.63 mmol) at −18 degrees, and the mixture was stirred for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.89 mL, 10.63 mmol) was added dropwise, and stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate, and washed once with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the title compound (462 mg, 16%).
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]1[C:31]([CH:40]=O)=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1.C(OC(C)C)(C)C>[Br:2]/[CH:3]=[CH:40]\[C:31]1[C:30]([CH3:29])=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1
Reactant: Cc1cc2ccccc2nc1C=O
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cc1cc2ccccc2nc1/C=C\Br
Temperature: -75 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a suspension of (bromomethyl)triphenylphosphonium bromide (3.06 g, 7.01 mmol) in 30 mL of THF, potassium tert-butoxide (0.78 g, 7.01 mmol) was added portionwise at −75° C. under argon. After completion of the addition, the mixture was stirred for 1 h a −75° C. Then, a solution of 3-methylquinoline-2-carbaldehyde (1 g, 5.84 mmol) in 20 mL of THF was added. The reaction mixture was stirred for 5 h at −75° C. and then allowed to warm up to room temperature overnight. For work-up, the reaction mixture was diluted with diisopropyl ether (1:1) and the precipitate formed was sucked off. The filtrate was concentrated and triturated in diisopropyl ether. The precipitate was sucked off. The filtrate was purified by column chromatography (normal phase, eluent: cyclohexane/EA) to give 492.5 mg (34%) of the title compound as yellow solid. LC-MS: m/e 248.0 (M+H)+; Rt 1.561 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:3]=1.[CH2:30]([NH2:33])[CH2:31][NH2:32].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:26][C:24]1([CH3:27])[CH2:25][CH:20]([NH:19][C:4]2[N:5]=[C:6]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:7]=[C:2]([NH:32][CH2:31][CH2:30][NH:33][C:2]3[N:3]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:5]=[C:6]([NH:8][CH:9]4[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]4)[N:7]=3)[N:3]=2)[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23]1
Reactant: NCCN
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(Nc2nc(NCCNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
42.3 (0.1 mole) of 2-chloro-4,6-bis(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine (prepared according to example 2A), 3 g (0.05 moles) of ethylenediamine, 4 g of sodium hydroxide and 150 ml of xylene were boiled for 16 hours under stirring.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CSc1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of acetic anhydride (170 mL), 4-(methylthio)benzaldehyde (20.93 g, 137 mmol), 2-chlorophenylacetic acid (23.43 g, 137 mmol), and triethylamine (14.97 g, 147 mmol) was heated to reflux for 2 hours. The reaction was cooled to 90° C., and water (180 mL) was added through an addition funnel. A yellow solid that separated from the solution was isolated by filtration and air dried to afford the desired acid. The acid was recrystallized from a mixture of ethyl acetate and isooctane to afford 24.62 g (59%): mp 159°-164° C. 1H NMR (CDCl3) 300 MHz 7.97 (s, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.17-7.35 (m, 3H), 7.02 (d, J=8.7 Hz 2H), 6.97 (d, J=8.7 Hz, 2H), 2.43 (s, 3H). High resolution mass spectrum Calc'd. for C16H13ClO2S: 304.0325. Found: 304.0334.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(Cc2ccccc2)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Temperature: 0 °C
Yield: 63 %

Procedure:
To 2-benzyl-5-(2-nitro-ethyl)-pyridine (260 mg, 1.1 mmol) described in Manufacturing Example 210-1-6 and methanol (5 mL) was added lithium methoxide (81 mg, 2.1 mmol), which was concentrated under a reduced pressure. Titanium(IV) tetrachloride (0.38 mL, 3.4 mmol) was added dropwise at −76° C. to a suspension of the residue in methylene chloride (5 mL) and tetrahydrofuran (2.5 mL), which was stirred for 20 minutes at room temperature. This reaction solution was added to ice water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again (four times). The organic layers were combined, washed with aqueous sodium chloride (one time), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and tetrahydrofuran was added to the residue. The insolubles thus produced were filtered out. The filtrate was concentrated under a reduced pressure to obtain the title compound (180 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[N:8](COC(=O)[C@H](C3C=CC=CC=3)O)[C:7]=2[CH:36]=1.[OH-].[Na+].C(OC)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:36]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(COC(=O)[C@@H](O)c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 81 %

Procedure:
0.76 g (1.5 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(S)-mandeloyloxymethyl]-1H-benzimidazole was dissolved in 50 ml methanol. A solution of 0.12 mg (3.0 mmol) sodium hydroxid in 1.5 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 25 ml water and 25 ml dichloromethane. The organic solution was extracted with 25 ml water and to the combined aqueous solutions was added 200 μl (3.2 mmol) methyl formate. After 15 minutes the mixture was extracted with 3×25 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.42 g (81%) of the title compound as a colourless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 98%. [α]D20 =+157° (c=0.5%, chloroform).