Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:20]S(C)(=O)=O)[CH:10]=[CH:9]3)[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=1)[S:5]2.[OH-].[K+].[Cl-:42].[NH4+]>CO>[ClH:42].[F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:20])[CH:10]=[CH:9]3)[CH:6]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:29][CH:30]=1)[S:5]2
Reactant: [Cl-]
Reactant: CS(=O)(=O)Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1SC3c1ccc(OCCN2CCCCC2)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1SC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
Dissolve methanesulfonic acid 8-fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-yl ester (7.5 g, 13.3 mmol) in methanol (130 mL), add potassium hydroxide (7.5 g, 133 mmol) and stir at room temperature over night. Pour the reaction into saturated aqueous ammonium chloride and extract with methylene chloride. Dry organic layer with sodium sulfate, filter and concentrate in mow. Dissolve the resultant residue in methylene chloride (50 mL) and add 2M HCl in ether (10 mL). Remove the solvent in vacuo and redissolve in methylene chloride (10 mL). Add slowly to vigorously stirred ether. Collect the resulting precipitate and place in a 50° C. vacuum oven overnight to yield 5.7 g (82%) of the title compound. HPLC Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 30 to 95% B, Purity@254 nm)=2.06 min (100%); mass spectrum (ion spray): m/z=486.3 (M−Cl). Chiral HPLC: 84% ee.
Reaction SMILES: Cl[C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[CH3:13][S:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[N:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1.CCN(C(C)C)C(C)C.[NH2:40][CH:41]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]1>ClCCl>[CH3:13][S:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:2](=[O:5])[NH:40][CH:41]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]3)=[CH:21][CH:22]=2)[N:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)NC3CCN(C(=O)OC(C)(C)C)C3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of bis(trichloromethyl)carbonate (200 mg, 0.67 mmol) in dichloromethane (3 mL). To the resulting mixture was then added a mixture of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) and DIEA (560 mg, 4.33 mmol, 2.21 equiv) in dichloromethane (2 mL) dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred for 3 h at 15° C. The resulting mixture was added to a solution of tert-butyl 3-aminopyrrolidine-1-carboxylate (440 mg, 2.37 mmol, 1.21 equiv) in dichloromethane (3 mL) dropwise with stirring at 15° C. in 15 min. The resulting solution stirred for an additional 4 h at 15° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4˜1:3) to yield tert-butyl 3-(3-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)ureido)pyrrolidine-1-carboxylate as a white solid. MS: 468 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](O)[CH3:15]>Cl>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1])[CH3:15]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
10.0 g (55 mmol) of 2-hydroxy-3-nitrobenzoic acid was dissolved in 100 mL of ethanol 2 mL of concentrated hydrochloric acid was added dropwise thereto and stirred for 24 hr under heat-reflux. The mixture was cooled to room temperature and concentrated under reduced pressure, followed by dilution with ethyl acetate. The diluted solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (10.0 g, yield: 86%).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:11]([O-])(=[O:13])[CH3:12].[Na+]>C(OC(=O)C)(=O)C>[OH:10][C:7]1[C:8]([C:11](=[O:13])[CH3:12])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: CC(=O)[O-]
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cc2c(cc1O)OCO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of sesamol (5.6 g, 40 mmol) in acetic anhydride (20 mL) was cooled to 0° C. under an argon atmosphere. The solution was slowly added with boron trifluoride/diethyl ether complex (10 mL), and then the mixture was stirred at 90° C. for 2 hours. The reaction mixture was added to saturated aqueous sodium acetate (50 mL), and the mixture was stirred at room temperature. The solid formed was removed by filtration, and then the reaction mixture was extracted with ethyl acetate, and the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residual solid was suspended in methanol, thereby washed, then collected by filtration and dried to obtain 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)ethanone (5.9 g, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N:11]=O)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O

Procedure:
2,6-di tert.butyl-4-aminophenol was prepared by hydrogenating a mixture of 23.5 grams of 2,6-di tert.butyl-4-nitrosophenol, 2 grams of 5% Palladium on carbon, and 200 milliliters of absolute ethanol in a Parr Pressure Reaction Apparatus. The reduction was accomplished in 1 hour at a maximum hydrogen pressure of 50 psi and a maximum temperature of 50° C. The resulting solution of 2,6-di tert.butyl-4-aminophenol was removed from the Pressure Apparatus and filtered to remove the catalyst.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][CH2:4][NH2:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].[NH:33]([C:37]1[S:38][CH:39]=[C:40]([CH2:42][S:43][CH2:44][CH2:45][NH2:46])[N:41]=1)[C:34]([NH2:36])=[NH:35]>C(OCC)(=O)C.CO>[NH:33]([C:37]1[S:38][CH:39]=[C:40]([CH2:42][S:43][CH2:44][CH2:45][NH:46][C:21]([NH:5][CH2:4][CH2:3][N:2]([CH2:6][CH2:7][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:1])=[O:22])[N:41]=1)[C:34]([NH2:36])=[NH:35]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CN(CCN)CCC(c1ccccc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 1 g (3.7 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 1.15 g (5 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int. [%])=527 ([M+H]+ 3), 196 (100).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:20]\2=[O:21])=[CH:12][N:11]=[CH:10]1)=[O:7])[CH3:4].ClCCl>C(O)C>[CH2:3]([O:5][C:6]([CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:19][CH:20]\2[OH:21])=[CH:12][N:11]=[CH:10]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
Sodium borohydride (0.06 g) was added to a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (1.5 g) in a mixed solvent of dichloromethane (10 ml) and ethanol (10 ml) at 0° C. After the mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 1.5 hour, it was partitioned between water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using dichloromethane and methanol (19:1) as an eluent to give the title compound (560 mg, yield: 37%) as a yellow amorphous solid.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1N=C(N)[S:61][N:60]=1>ClCCl>[F:55][C:56]([F:66])([F:65])[CH2:57][CH2:58][C:59]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:61][N:60]=1
Reactant: Nc1nc(CCC(F)(F)F)ns1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nc(CCC(F)(F)F)ns1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 68 mg, 0.21 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol). The resulting solution was stirred for 5 min before 3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.25 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-yl]-amide (52 mg, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C21H22ClF3N4O3S [M+H]+ 503.1126, observed 503.1127; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.48 (br. s., 1H), 1.55-1.77 (m, 1H), 1.77-1.97 (m, 1H), 2.66-2.90 (m, 2H), 3.05 (t, J=6.9 Hz, 2H), 4.30 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 4.93-5.07 (m, 1H), 7.37 (td, J=8.0, 1.5 Hz, 1H), 7.47 (td, J=8.0, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 13.38 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1F)[C:11]([O:13][CH3:14])=[O:12].[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[N:23]1[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC1CCNCC1
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(C)CC2)c(F)c1
Temperature: 60 °C

Procedure:
0.076 g of potassium carbonate was added to a solution of 0.086 g of methyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of DMF. The reaction was heated at 60° C. for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:24][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1)[CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C(C)O)c2nn(COCC[Si](C)(C)C)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(C)Br)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (712 mg, 2.21 mmol) and carbon tetrabromide (1.10 g, 3.31 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (869 mg, 3.31 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5% 30% EtOAc/Hex) to give 240 mg (28.2%) as colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.95 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 5.84 (q, J=6.0 Hz, 1H), 5.67 (s, 2H), 3.8 (s, 3H), 3.62 (m, 2H), 2.94(d, J=6.0 Hz, 2H), 0.9 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
2,4,5-Trifluorobenzoyl chloride (540 mg, 2.78 mmol) was added to a stirred solution of 2-methylaminoethanol (0.185 mL, 3.06 mmol) in DCM (5 mL) and 10% aqueous sodium hydroxide solution (5 mL) at 0° C. After addition was complete the icebath was removed and the reaction was allowed to warm up to RT and stirred for 3 hours. The phases were then separated and the aqueous phase extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to give the desired compound as a colourless oil (686 mg). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[CH3:10]C([N-]C(C)C)C.IC.C(=O)([O-])O.[Na+]>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH3:10]
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: Cc1c(Cl)cncc1Cl
Reaction time: 0.08 h
Yield: 53 %

Procedure:
3,5-Dichloropyridine (2.04 g, 13.5 mmol) in THF (5 ml) was added dropwise to a solution of LDA [prepared from diisopropylamine (1.9 ml, 13.5 mmol) and n-butyllithium (1.6 M, 8.4 ml, 13.5 mmol)] in THF (25 ml) at -70° C. After stirring at this temperature for 5 min, iodomethane (0.85 ml, 13.5 mmol) was added and the reaction mixture stirred for a further 1.5 h at -70° C. Saturated sodium hydrogen carbonate solution (20 ml) and dichloromethane (20 ml) was added and the organic phase separated, dried (MgSO4), and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O-hexane,1:3) to afford the title compound (1.16 g) as a pale yellow solid. δH (CDCl3) 2.46 (3 H, s, Me), and 8.36 (2 H, s, pyridine H2, H6).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([S:15][C:16]2[C:17]([CH3:25])=[N:18][N:19]([CH2:22][CH2:23][OH:24])[C:20]=2[CH3:21])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[OH2:26]>CO>[Cl:14][C:12]1[CH:11]=[C:10]([S:15]([C:16]2[C:17]([CH3:25])=[N:18][N:19]([CH2:22][CH2:23][OH:24])[C:20]=2[CH3:21])(=[O:1])=[O:26])[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: Cc1nn(CCO)c(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [K+]
Solvent: CO
Product: Cc1nn(CCO)c(C)c1S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
A solution of Oxone (Trade Mark) (581 mg, 0.946 mmol) in water was added to a stirred suspension of the sulphide of Example 21 (200 mg, 0.63 mmol) in methanol (2.5 ml) at 0° C. producing a viscous white suspension. The cooling bath was removed and further methanol (2.5 ml) was added to aid dissolution and stirring. The mixture was stirred at room temperature for 2½ hours and at 50° C. for 24 hours. After cooling the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (25 ml). The organic layer was washed with brine (25 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a white solid (195 mg). The crude product was pre-absorbed on silica gel and purified by flash chromatography on silica gel eluting with methanol:dichloromethane (2:98, by volume) to provide the title compound (175 mg) as a white solid, m.p. 199–200° C.
Reaction SMILES: O.[N:2]1(C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H][H].CO>CCOC(C)=O.[Pd]>[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCNCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a 3 L florentine under nitrogen was charged Pd on C, wet, Degussa (10% Pd, 50% WATER) (8.120 g, 76.30 mmol) then EtOAc (1.706 L). The mixture was degassed via N2/vacuum cycles (3×), then a solution of O1-benzyl O4-tert-butyl piperidine-1,4-dicarboxylate 21 (243.7 g, 763.0 mmol) in EtOAc (243.7 mL) was added. Mixture was stirred under a hydrogen atmosphere overnight. Hydrogen was replenished and mixture was stirred for a further 3.5 h. Methanol (60 mL) was added to aid dissolution of precipitate then filtered through celite, washing through with methanol. Filtrate concentrated in vacuo to leave a brown oil with a slight suspension of a white solid, 138.6 g. Solid removed by filtration, and washed with minimal EtOAc. Filtrate was concentrated in vacuo to leave desired product as a light brown oil (129 g, 91%). 1H NMR (500 MHz, DMSO-d6) δ 2.88 (dt, 2H), 2.44 (td, 2H), 2.23 (tt, 1H), 1.69-1.64 (m, 2H) and 1.41-1.33 (m, 11H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]4[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH2:58])[C:52]=4[N+:59]([O-])=O)[CH2:47][CH2:46]3)[C:38]=2[O:37][CH2:36]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:70][O:71][C:72]1[CH:77]=[CH:76][C:75]([CH:78]=O)=[CH:74][CH:73]=1>C(O)C.CN(C=O)C>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]4[C:56]([Br:57])=[CH:55][N:54]=[C:53]5[NH:58][C:78]([C:75]6[CH:76]=[CH:77][C:72]([O:71][CH3:70])=[CH:73][CH:74]=6)=[N:59][C:52]=45)[CH2:47][CH2:46]3)[C:38]=2[O:37][CH2:36]1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccc4c3OCO4)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccc6c5OCO6)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 61.9 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 4-(4-(benzo[d][1,3]dioxol-4-ylmethyl)piperazin-1-yl)-5-bromo-3-nitropyridin-2-amine (30 mg, 0.068 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.21 mmol, 0.21 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.075 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (22 mg, 63%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, NCH2), 3.65 (t, J=4.3 Hz, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 6.02 (s, 2H, OCH2), 6.83 (d, J=4.2 Hz, 2H, benzo[d][1,3]dioxyl H-4 & H-6), 6.90 (app. q, J=4.4 Hz, 1H, benzo[d][1,3]dioxyl H-5), 7.09 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 8.14 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.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>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2'-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine)palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to give 9.8 g (47 mmol, 71%) of product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): δ 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[CH3:17][CH:16]([NH:19][CH2:12][C@H:11]([OH:13])[CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([CH2:4][C:1]([NH2:2])=[O:3])=[CH:6][CH:7]=1)[CH3:18]
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Temperature: 10 °C
Reaction time: 7 h
Yield: 70.2 %

Procedure:
P-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. Then, crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane (1.43 g) was dissolved in methanol (8 ml). The solution was dropped in isopropylamine (6.8 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 7 hours. After the reaction, the mixture was condensed in vacuo until crystals beginning to separate, cooled, filtrated by suction and dried in vacuo to give crude (S)-atenolol (1.29 g). The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.).