Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].O>C1COCC1.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>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
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: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C=O)cc3)cc2)cc1
Yield: 58 %

Procedure:
Under an argon atmosphere, (4-formylphenyl)boronic acid (0.54 g, 3.6 mmol), 4-Bromo-4′-pentyloxy-biphenyl (0.958 g, 3 mmol) 1) (A1), sodium hydrogen carbonate (0.76 g, 9 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.057 g, 0.030 mmol) were dissolved in THF (15 mL) and water (15 mL) and stirred under a reflux condition. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4″-(pentyloxy)-[1,1′:4′,1″-terphenyl]-4-carbaldehyde (A2) was obtained (0.60 g, yield: 58%). The obtained product (A2) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=10.06 (s, 1H, CHO), 7.95-7.97 (d, 2H, phenylene), 7.79-7.81 (d, 2H, phenylene), 7.71-7.66 (m, 4H, phenylene), 7.00-6.98 (s, 2H, phenylene), 4.03-3.99 (t, 2H, —O—CH2—), 1.84-1.81 (t, 2H, —CH2—), 1.47-1.40 (m, 4H, —CH2—), and 0.93-0.97 (t, 3H, —CH3). 13C NMR (CDCl3, 100 MHz) δ=191.7, 159.0, 146.7, 141.0, 137.8, 135.2, 132.4, 130.2, 128.0, 127.2, 114.9, 68.1, 29.0, 28.3, 22.7, and 14.1.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ccncc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccncc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methyl]amino}benzoic acid (211 mg) synthesized above, β-alanine ethyl ester hydrochloride (128 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (233 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (214 mg, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH:28]1[CH2:32][CH2:31][N:30](CC2C=CC=CC=2)[CH2:29]1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4CCNC4)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 26 h
Yield: 49.1 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), 3-amino-1-benzylpyrrolidine (97 mg) and triethylamine (160 mg) were added to pyridine (600 mg), and the mixture was stirred for 26 hours at room temperature and f or 15 hours at 60° C. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Acetic acid (2 ml) and 10% palladium-carbon (25 mg) were added to the resultant residue to conduct hydrogenation for 20 hours at 45° C. and for 21 hours at room temperature. After the catalyst was separated by filtration and washed with acetic acid, the filtrate and washings were concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (115 mg) as a pale brown powder.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (25.0 g, 0.12 mol) and N,N-dimethylethylenediamine (100 mL) are heated at 100° C. in a miniclave for 20 h. The reaction mixture is concentrated in vacuo and the pale yellow crystals that form are collected by filtration, washed with MeOH and dried under vacuum to afford the title compound. [M+H]+ 259.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]3[O:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C:37]=3[CH:50]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[O:42]1[C:36]2[CH:35]=[CH:34][C:33](/[CH:32]=[CH:31]/[C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=7)[NH:15][C:14]6=[O:22])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:50][C:37]=2[CH2:38][NH:39][CH2:40][CH2:41]1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3ccc4c(c3)CNCCO4)n[nH]c2c1
Reaction time: 1 h
Yield: 30 %

Procedure:
The title compound was synthesized according to the method of Example A51B, by using (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (105 mg, 0.27 mmol) and (E)-tert-butyl 7-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (130 mg, 0.32 mmol). The residue from the reaction was dissolved into CH2Cl2 (5 mL) and TFA (0.2 mL) was added and the mixture was stirred for 1 h and concentrated to dryness. Purification by preparative HPLC gave the title compound as a cream solid (40 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=8.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.50-7.39 (m, 3H), 7.16 (d, J=8.2 Hz, 1H), 7.07-7.01 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 5.98 (d, J=7.4 Hz, 1H), 4.45 (s, 2H), 4.39 (br. s, 2H), 3.68 (br. s, 2H), 3.39-3.33 (m, 1H) 2.25-2.16 (m, 2H); MS ESI 449.3 [M+H]+, calcd for [C28H24N4O2+1-1]+ 449.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>CO>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:14][CH:15]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: CO
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NS(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 80 °C
Yield: 54.7 %

Procedure:
To a solution of 2′-Methyl-5′-oxazol-2-yl-biphenyl-4-ylamine (c) (30 mg, 0.12 mmol) in MeOH (2 mL) was added 2,6-difluorobenzene sulfonyl chloride (30 μL, 0.22 mmol). The reaction was heated to 80° C. for 2 hr before the solvent was removed. Column chromatography afforded Compound 1 (28 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].C1(SC2C=CC=CC=2)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(C(C)(C)O)c(F)c1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)C)c(F)c1
Reaction time: 12 h

Procedure:
The solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol in IPAC (500 ml, 451 mmol) and diphenyl sulfide (0.151 ml, 0.901 mmol) were combined in a hydrogenation shaker. The reaction mixture was purged with nitrogen/vacuum cycles, and 5% palladium on carbon (7.67 g, 1.802 mmol) was added, followed by TFA (17.36 ml, 225 mmol). Hydrogenation was conducted at 60° C. under 50 psig pressures for 12 h. The catalyst was removed by filtration through a 1 inch plug of Solka-Floc® powdered cellulose and rinsed with IPAC (49.8 ml). The filtrate was assayed and was found to contain 76 g of the desired product, which corresponds to a quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:19].[Na+].O>O1CCOCC1>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:19])=[O:1]
Reactant: O=C1Cc2cccc(S(=O)c3ccccc3)c2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1S(=O)c1ccccc1
Yield: 42.4 %

Procedure:
A mixture of 2-oxo-7-phenylsulfinylindoline (4.3 g.), sodium hydroxide (1.2 g.), water (10 ml.) and dioxane (10 ml.) was refluxed for 6 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed with a mixture of ethanol and diisopropyl ether to give crystals of 2-(2-amino-3-phenylsulfinylphenyl)acetic acid (1.95 g.).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl.Br[C:9]1[CH:14]=[CH:13][NH+:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(O)C>O>[N:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: Brc1cc[nH+]cc1
Reactant: OC1CCNC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccncc2)C1
Temperature: 150 °C

Procedure:
A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol), 4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine (47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tube reaction vess 1, was purged with nitrogen and sealed. The mixture was heated to 150° C. for 96 hours and cooled. The solvent was evaporated and ethyl acetate (50 mL) was added. After trituration, the organic solvent was decanted off and saved. Methylene chloride (80 mL) and 2 N sodium hydroxide (60 mL) were added to the solid. The mixture was shaken vigorously and was filtered with water and methylene chloride wash to give the title compound as an off-white solid. The organic supernatant and the methylene chloride and water washes were combined. This mixture was extracted with methylene chloride. The organic layer was sodium sulfate dried and concentrated. The residue was triturated with methylene chloride and the solid was filtered. This solid was combined with the solid from above and vacuum dried (100° C. at 133 Pa for 14 hours) to give the title compound as an off-white solid (8.52 g, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(Cl)Cl.CO.CCCCCC>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)[CH3:33]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of 294 mg (1 mmol) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was treated with 40 mg (1 mmol) of 60% NaH/mineral oil and after 1 hours, 0.15 mL (1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 2 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with EtOAc to give (after crystallizing from CH2Cl2/MeOH/hexane, 228 mg (76% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]butanoic acid ethyl ester, mp, 126-133° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:9]([OH:11])=O)[CH2:5][CH2:4]1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:9]([C:6]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[O:11])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)(c2ccccc2)CC1
Yield: 79.5 %

Procedure:
A solution of 1-methyl-4-phenylpiperidine-4-carboxylic acid hydrochloride (1.35 g, 5 mmol), benzyl piperazine 0.88 g (5 mmol), triethylamine 1 ml and EDC 1.91 g (10 mmol) and DMAP (catalytic) in 40 ml dichloromethane was stirred at room temperature overnight, concentrated, added water and extracted with ethyl acetate 2′50 ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 1.5 g of desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[N:2]1.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[CH3:12][N:2]1[CH:3]=[C:4]2[C:9]([C:8]([C:10]#[N:11])=[CH:7][CH:6]=[CH:5]2)=[N:1]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc2cn[nH]c12
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cn1cc2cccc(C#N)c2n1
Temperature: 80 °C

Procedure:
To a solution of 1H-indazole-7-carbonitrile (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:32]2[CH2:31][CH2:30][CH2:29][NH:28][C:27]=2[CH:26]=[N:25]1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:18]4[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=4[F:16])[N:25]=[CH:26][C:27]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)c(F)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1F
Yield: 70 %

Procedure:
The compound was prepared 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The organic layer was concentrated and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide the title compound as a white foamy solid (47 mg, 70%). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.39 (s, 0.8H), 7.64 (s, 0.2H), 7.48 (m, 2H), 7.00 (m, 2H), 5.25 (s, 0.4H), 5.14 (s, 1.6H), 3.92 (m, 0.4H), 3.85 (m, 1.6H), 2.70 (m, 2H), 2.33 (s, 2.4H), 2.32 (s, 0.6H), 2.11 (m, 1.6H), 2.03 (m, 0.4H); MS: (ES) m/z calculated for C19H16ClF5N5O [M+H]+ 460.1, found 460.1.
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: CC(C)(C)OO
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: NC1(O)CCc2ccccc21
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CN1CCCC1=O
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: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5](=[O:17])[C:4]=1[Br:18].C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30].[OH-].[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[Br:18][C:4]1[C:5](=[O:17])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=[CH:8][C:3]=1[NH:2][C:29](=[O:30])[C:28]1[C:27]([F:26])=[CH:35][CH:34]=[CH:33][C:32]=1[F:36]
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) were suspended in acetonitrile (5 mL) followed by dropwise addition of triethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for 10 minutes at room temperature before being cooled to 0° C. 2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and 1N NaOH (10 mL) was added. The reaction was then stirred for 45 minutes at room temperature. The reaction mixture was extracted with ethyl acetate (3×25 mL) and the organic layer washed with 1N NaOH (2×25 mL), H2O (until pH neutral), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (on C-18, acetonitrile/H2O with 0.1% trifluoracetic acid) to afford a white solid (0.19 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.67 (d, J=7.65 Hz, 1H), 7.49 (app tt, J=6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+H C19H12BrF3N2O2 requires 437.0107).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([CH2:23][O:24][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:15]=1)=[O:10])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[C:25]12([O:24][CH2:23][C:12]3[C:11]([C:9]([OH:10])=[O:8])=[CH:15][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: Cc1ccccc1-n1cc(C(=O)OCc2ccccc2)c(COC23CC4CC(CC(C4)C2)C3)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cc(C(=O)O)c(COC23CC4CC(CC(C4)C2)C3)n1

Procedure:
A solution of 3-(adamantan-1-yloxymethyl)-1-o-tolyl-1H-pyrazole-4-carboxylic acid benzyl ester (0.359 g, 0.79 mmol) in MeOH-THF (1:1/24 mL) was hydrogenated over 10% palladium on charcoal (50 mg) for 19 h. The reaction mixture was filtered through a pad of Celite and the filtrate evaporated to afford the product, (0.29 g, 100%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:40](=[O:39])[CH2:41][OH:42])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.