Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH:17]([C:18]([OH:20])=[O:19])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=3)=[CH:26][CH:27]=1)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: NC(Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Br)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 6-bromo-2-chloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[4-(5-bromo-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[C:2]#[CH:3]>C(N(CC)C1C=CC=CC=1)C>[O:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:1][CH:2]=[CH:3][C:6]=2[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCOc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)c1ccccc1
Product: C1=Cc2cc(Oc3ccccc3)ccc2OC1
Temperature: 220 °C

Procedure:
4-Phenoxyphenyl propargyl ether (33.7 g, 150 mmol) in 50 mL of N,N-diethylaniline is added to refluxing (220° C.) N,N-diethylanile (300 ml) dropwise over a period of 10 minutes under nitrogen. The mixture is stirred at reflux for 8 hours, cooled and evaporated under high vacuum (bath temp. ~80° C.) to remove solvents. The residue is distilled to give 6-phenoxy-2H-1-benzopyran; b.p. 147°-150° C./0.5 mmHg.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[CH3:21])[C:8]=3[CH:7]=[CH:6][C:5]2=[O:26])[CH2:3][CH2:2]1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:12]=[C:13]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[CH3:21])[C:8]=3[CH:7]=[CH:6][C:5]2=[O:26])[CH2:3][CH2:2]1
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C1CC1
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2C1CC1

Procedure:
The product of Example 54, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.85 (m, 2H), 1.28 (m, 2H), 2.11 (m, 3H), 2.79 (m, 1H), 3.89 (m, 4H), 4.16 (m, 1H), 6.18 (d, 1H, J=9.8), 6.31 (br s, 1H), 6.85-7.14 (m, 4H). LC MS (m/e)=385 (MH+).
Reaction SMILES: C(N(CC)CC)C.[S:8]1C=CC=C1CC(O)=O.CN(C)C=O.[C:22]([NH:25][C:26](=[O:35])[CH:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:24])[CH3:23].[C:36]([OH:39])(=O)[CH3:37]>>[C:22]([NH:25][C:26](=[O:35])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:8][C:36](=[O:39])[CH3:37])(=[O:24])[CH3:23]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(=O)O
Reactant: CC(=O)NC(=O)C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(=O)C(SC(C)=O)c1ccccc1

Procedure:
The triethylamine salt of thiolacetic acid was made by adding 2.23 g. (0.022 mole) of triethylamine to a stirred and ice-cooled solution of 1.67 g. (0.022 mole) of thiolacetic acid in 15 ml. of dimethylformamide. This solution was in turn added dropwise with stirring and ice-cooling to a solution of 4.2 g. (0.02 mole) of the compound prepared in Step B. above in 15 ml. of dimethylformamide, while maintaining the temperature below 10° C. The reaction mixture was stirred an additional hour, and then there was added 1 ml. of acetic acid. The reaction mixture was poured onto ice and a thick yellow oil formed. The mixture was decanted, and the ice was washed with water and again decanted. The yellow oil was taken up in 75 ml. of ether, dried, and evaporated, leaving 2.5 g. of yellow oil. This was chromatographed on a Waters high pressure liquid chromatography apparatus using 25% ethylacetate in hexane as the eluent. A water-white oil weighing 1.9 g. was obtained. A seed was formed by rubbing a little with petroleum ether and the bulk of material precipitated quickly to yield 1.6 g. of material having an m.p. of 96° C.
Reaction SMILES: ClC1C(C2C=CC(Cl)=C(NS(C)(=O)=O)C=2)=NC=C(C(F)(F)F)C=1.[Cl:24][C:25]1[C:26]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([N:43](S(CC)(=O)=O)[S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])[CH:36]=2)=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.[O-]CC.[Na+]>C(O)C>[Cl:24][C:25]1[C:26]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[C:37]([NH:43][S:44]([CH2:47][CH3:48])(=[O:45])=[O:46])[CH:36]=2)=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1
Reactant: CCS(=O)(=O)N(c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1C#N)S(=O)(=O)CC
Agent: CC[O-]
Agent: CS(=O)(=O)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)(=O)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1C#N
Yield: 58.9 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-methylsulfonylaminophenyl)-5-trifluoromethylpyridine, use of 4.2 g of 3-chloro-2-[4-cyano-3-bis(ethylsulfonyl)aminophenyl]-5-trifluoromethylpyridine, about 100 mg of sodium ethoxide and 100 ml of ethanol resulted in 2.0 g (59%) of colorless crystals;
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[C:34]([S:38]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:40])=[O:39])[CH:35]=[N:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-1-(4-Fluorophenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 5-bromopyridine-3-sulfonyl chloride. LCMS (Method D): 533 (M+H)+, Retention time 4.1 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([CH2:18][C@H:19]([NH:30][S:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(=[O:33])=[O:32])[C:20]([N:22]([CH2:26][C:27]([OH:29])=O)[CH:23]2[CH2:25][CH2:24]2)=[O:21])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:45][O:46][NH2:47].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH:23]1([N:22]([CH2:26][C:27](=[O:29])[NH:47][O:46][CH3:45])[C:20]([C@@H:19]([NH:30][S:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(=[O:33])=[O:32])[CH2:18][C:16]([NH:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)=[O:17])=[O:21])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N(CC(=O)O)C2CC2)C1
Reactant: CON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CONC(=O)CN(C(=O)[C@H](CC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)NS(=O)(=O)c1ccc2ccccc2c1)C1CC1
Yield: 53.9 %

Procedure:
500 mg of [[(S)-3-[(S)-1-tert-butoxycarbonyl-piperidin-3-ylmethylcarbamoyl]-2-(naphthalen-2-sulfonylamino)-propionyl]-cyclopropyl-amino]-acetic acid are stirred at room temperature for 20 hours in 10 ml of methylene chloride together with 71 mg of O-methylhydroxylamine hydrochloride, 0.28 ml of N-methyl-morpholine and 376 mg of BOP. The mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and then with water. After drying and evaporation the product is purified over silica gel with ethyl acetate/methanol (9:1). There are obtained 282 mg of tert-butyl (S)-3-[(S)-3-([cyclopropyl-methoxycarbamoylmethyl-carbamoyl)]-3-(naphthalen-2-ylsulfonylamino)-propionylamino-methyl]-piperidine-1-carboxylate, MS (ISP): 646.6 (M+H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(O)(=O)C.O>[OH:3][N:1]=[C:12]([C:11](=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH3:5])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=N[O-]
Reactant: COCCCCC(=O)CC(=O)OC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCCCC(=O)C(=NO)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To an aqueous solution (20 ml) of sodium nitrite (2.20 g) was added dropwise a solution of methyl 7-methoxy-3-oxoheptanoate (5.00 g) obtained in Reference Example 359 in acetic acid (5 ml) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.91 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[Se](=O)=[O:21].O>O1CCOCC1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([CH:1]=[O:21])[CH:7]=2)[CH:9]=[C:10]([O:18][CH3:19])[C:11]=1[O:16][CH3:17]
Reactant: O=[Se]=O
Reactant: COc1cc(-c2cc(C)ncn2)cc(OC)c1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cc(C=O)ncn2)cc(OC)c1OC
Temperature: 105 °C
Reaction time: 8 h

Procedure:
4-Methyl-6-(3,4,5-Trimethoxyphenyl)pyrimidine (920 mg) was dissolved in dioxane (100 mL), to the solution selenium dioxide (784 mg) was added, and the mixture was stirred overnight at 105° C. Water was added to the reaction mixture to conduct extraction with ethyl acetate, and the resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:27]=[C:26]([NH2:28])[N:25]=[C:24]4[NH:29][N:30]=[CH:31][C:23]=34)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]ncc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 54.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (360 mg, 54.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.83 Hz, 3 H), 3.59-3.68 (m, 3 H), 3.83 (s, 3 H), 5.57 (dd, J=13.42, 6.59 Hz, 3 H), 6.46 (d, J=1.46 Hz, 1 H), 6.61 (d, J=2.93 Hz, 1 H), 7.55 (d, J=1.46 Hz, 1 H), 7.72 (d, J=3.42 Hz, 1 H), 7.89 (s, 1 H), 7.95-8.03 (m, 2 H), 12.33 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10,389; found 389.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2].[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O.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:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22]([CH2:46][C:45]5[CH:48]=[CH:49][C:42]([C:41]([F:51])([F:50])[F:40])=[CH:43][CH:44]=5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(B5OC(C)(C)C(C)(C)O5)CC4)cc3)oc12
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)oc12
Reaction time: 0.03 h
Yield: 13.5 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]methyl}benzamide (70 mg, 0.133 mmol, INTERMEDIATE 9), 4-trifluoromethylbenzyl bromide (30 mg, 0.126 mmol), and 2M sodium carbonate (0.15 ml, 0.300 mmol) in toluene (2 ml), water (0.6 ml), and ethanol (0.25 ml) was added tetrakis(triphenylphosphine)palladium(0) (4 mg, 3.46 μmol). The mixture was microwaved at 100° C. in a sealed tube for 30 min, at which point LC/MS analysis showed a new peak at the product molecular weight. The organic phase of the reaction mixture was added directly to a 25 samplet and purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. This product was repurified by reverse-phase HPLC on a Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (9.4 mg, 0.017 mmol, 25.3% yield). Mass spectrum (ESI) 558.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H); 7.93 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.53 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.28 (br t, J=5.5 Hz, 1H), 5.48 (br s, 1H), 3.47 (septet, J=7.0 Hz, 1H), 3.44 (br t, J=6.0 Hz, 2H), 3.32 (s, 1H), 2.24 (m, 1H), 1.80-1.98 (m, 7H), 1.46 (d, J=7.0 Hz, 6H), 1.30-1.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(CBr)OC
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried round bottom flask, add 2-methoxy-4-nitro-phenol (2.45 g, 14.5 mmol) and purge with nitrogen. Add DMF (25 mL) by syringe, followed by K2CO3 (3.0 g, 21.7 mmol) and KI (catalytic) neat. Stir 30 min at room temperature and add 2-bromo-1,1-dimethoxy-ethane (1.9 mL, 15.9 mmol) by syringe. Attach a reflux condenser and stir overnight in a 120° C. oil bath. Quench with water, extract with ether (3×), dry over MgSO4, filter and concentrate under vacuum. Add xylenes and concentrate again under vacuum. Purify by flash chromatography on silica gel using a gradient of EtOAc/hexane (20% to 60%) to give the title compound as a white residue (2.55 g, 68%). Exact mass=257.1, MS (ES+) 258.2 (M+1)+. 1H NMR (CDCl3): δ 7.88 (dd, J=9.1, 2.8 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.13 (d, J=4.9 Hz, 2H), 3.93 (s, 3H), 3.48 (s, 6H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[O:14][CH3:15])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.[Cl-].[Na+].O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:16][C:1]([CH3:2])=[N:4][N:5]=2)=[C:8]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(Br)ccc1C(=O)NNC(C)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)ccc1-c1nnc(C)o1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
N′-Acetyl-4-bromo-2-methoxybenzohydrazide (720 mg, 2.51 mmol) and Burgess' Reagent (896 mg, 3.76 mmol) were dissolved in 10 ml of THF and stirred in the microwave at 120° C. for 30 minutes. The reaction was diluted with brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a yellow oil. Chromatography on silica gel (0-50% EtOAc/DCM) gave a yellow solid (465 mg, 1.73 mmol, 69%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(N3CCOCC3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=563.3 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and morpholine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.[O-]O.C1(C(C)C)C=CC=CC=1.C([O:39]O)(C)(C)C.NC1(O)C2C(=CC=CC=2)CC1>CN1C(=O)CCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12]([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:39])[NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: NC1(O)CCc2ccccc21
Agent: [O-]O
Solvent: CN1CCCC1=O
Solvent: CC(C)c1ccccc1
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2n1

Procedure:
Therefore, for example, according to the method of the invention, an enantioselective oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]imidazo[4,5-b]-pyridine by cumene hydroperoxide or tert-butyl hydroperoxide in presence of Ti(OiPr)4 and of amino-indanol in NMP can advantageously be carried out in order to obtain (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]imidazo[4,5-b]pyridine, that is to say tenatoprazole, the formula of which is represented above.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]([Cl:18])([Cl:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[S:15]Cl.[Cl-].[K+]>C(O)(=O)C.C(OCC)C>[Cl:4][C:5]([Cl:18])([Cl:17])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[S:15][C:1]#[N:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#CSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Temperature: 10 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
At 10° to 15° C., 13 g of potassium cyanide is dissolved in 100 ml of glacial acetic acid. At 10° C., a solution of 61.4 g of 2-trichloromethyl-4-nitrobenzenesulfenic acid chloride in 200 ml of diethyl ether is added to the solution. The mixture is stirred for 2 hours at 10° C. and for 5 hours at room temperature. The precipitated potassium chloride is filtred off, the solvent is distilled off, and the residue is recyrstallized from petroleum ether. There is obtained 53 g (89% of theory) of 2-trichloromethyl-4-nitrophenyl thiocyanate; m.p.: 72° C.
Reaction SMILES: C([Si]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C@H:26]2[C@@H:31]([O:32][CH2:33][O:34][CH3:35])[C@@H:30]([O:36][CH2:37][O:38][CH3:39])[C@H:29]([O:40][CH2:41][O:42][CH3:43])[CH:28]([CH2:44][O:45][CH2:46][O:47][CH3:48])[O:27]2)[CH:23]=[CH:22][C:21]=1[Cl:49])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:49][C:21]1[CH:22]=[CH:23][C:24]([C@H:26]2[C@@H:31]([O:32][CH2:33][O:34][CH3:35])[C@H:30]([O:36][CH2:37][O:38][CH3:39])[C@H:29]([O:40][CH2:41][O:42][CH3:43])[CH:28]([CH2:44][O:45][CH2:46][O:47][CH3:48])[O:27]2)=[CH:25][C:20]=1[CH2:19][OH:18]
Reactant: COCOCC1O[C@@H](c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)[C@@H](OCOC)[C@@H](OCOC)[C@@H]1OCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOCC1O[C@@H](c2ccc(Cl)c(CO)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a stirred solution of the product from step A (1.3 g, 1.8 mmol) in tetrahydrofuran (16 mL) at 0° C. was added dropwise tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran; 2.2 mL, 2.2 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h. Then it was concentrated and the crude material obtained was purified by flash column chromatography (eluent: hexanes/ethyl acetate 100:0 to 75:25) to give compound (2-chloro-5-((2S,3R,4S,5R)-3,4,5-tris(methoxymethoxy)-6-((methoxymethoxy)methyl)tetrahydro-2H-pyran-2-yl)phenyl)methanol (0.81 g, 94%) as a colorless syrup: 1H NMR (CDCl3, 500 MHz) δ 7.54 (br d, J=2.0 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.2, 2.0 Hz, 1H), 4.91 (d, J=6.4 Hz, 1H), 4.89 (d, J=6.3 Hz, 1H), 4.87 (d, J=6.3 Hz, 1H), 4.78-4.76 (m, 3H), 4.65 (s, 2H), 4.47 (d, J=6.5 Hz, 1H), 4.19 (d, J=9.5 Hz, 1H), 4.14-4.10 (m, 2H), 3.92 (dd, J=11.3, 1.6 Hz, 1H), 3.76 (t, J=8.8 Hz, 1H), 3.71 (dd, J=11.2, 5.2 Hz, 1H), 3.63-3.58 (m, 2H), 3.53 (t, J=9.4 Hz, 1H), 3.452 (s, 3H), 3.448 (s, 3H), 3.34 (s, 3H), 2.82 (s, 3H); ESI MS m/z 481 [M+H]+.