Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:18])=[O:17])[CH3:3].CO[C:21]([CH3:23])=[CH2:22]>C(O)(=O)C>[CH3:3][C:2]1([CH3:1])[N:4]([CH:21]([CH3:23])[CH3:22])[C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16](=[O:17])[NH:18]1
Reactant: CC(C)Nc1cc(-c2ccncc2)sc1C(N)=O
Reactant: C=C(C)OC
Solvent: CC(=O)O
Product: CC(C)N1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 35 °C
Yield: 52 %

Procedure:
A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.225 g, 0.858 mmol), ammonium chloride (0.459 g, 8.58 mmol) and triethylamine (1.21 mL, 8.58 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. To the resulting mixture was added 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (0.493 g, 2.57 mmol), and 1-hydroxybenzotriazole (0.347 g, 2.57 mmol) and the reaction was stirred at room temperature for 65 h. Then, the reaction mixture was diluted with sat. NaHCO3 (120 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give crude 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.225 g) as an orange solid. A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.105 g) and 2-methoxypropene (1.53 mL, 16.0 mmol) in acetic acid (1.5 mL) was heated at 35° C. overnight. Then, the reaction mixture was cooled to room temperature and concentrated. The obtained residue was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (1 g) and silica gel (5 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 95:5 ethyl acetate /methanol) to give the title compound (0.063 g, 2 step yield 52%) as an orange solid:
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]2[C@:12]([OH:18])([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](OCC)(OCC)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C([N:48]1[C@@H:57]2[C@:52](O)([CH2:53][CH2:54][CH2:55][CH2:56]2)C(=O)CC1)C1C=CC=CC=1.NC1C=CC=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CC(O)=O.ClCCCl.CCO>[CH2:1]([N:8]1[C@H:17]2[C@:12]([OH:18])([CH2:13][CH2:14][CH2:15][CH2:16]2)[C@H:11]([NH:48][C:57]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)[C@@H]2CCCC[C@@]21O
Reactant: O=C1CCN(Cc2ccccc2)[C@H]2CCCC[C@]12O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: O[C@]12CCCC[C@H]1N(Cc1ccccc1)CC[C@H]2Nc1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To (4aR,8aR)-1-benzyl-4,4-diethoxyoctahydroquinolin-4a(2H)-ol (200 mg, 0.600 mmol) in toluene (12.000 ml) at room temperature was added water (0.162 ml, 9.00 mmol) followed by camphorsulfonic acid (153 mg, 0.660 mmol). The reaction mixture was heated to reflux for 3 hrs. The reaction mixture was diluted with aqueous potassium carbonate (saturated, 30 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered and the solvent was evaporated under reduced pressure. A mixture of (4aR,8aS)-1-benzyl-4a-hydroxyoctahydroquinolin-4(1H)-one (0.500 g, 1.93 mmol) and aniline (0.528 mL, 5.78 mmol) in 4% CH3COOH in DCE (10 mL) was stirred for 4 hr at 80° C. The reaction was then cooled to rt and NaBH4 (0.438 g, 11.6 mmol) was then added followed by the addition of EtOH (10 mL). The mixture was then stirred overnight at rt. The mixture was then quenched with sat'd. aq. NH4Cl. It was then basified with 2M Na2CO3 and extracted 3× with EtOAc. The combined organics were dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound. 1H-NMR (500 MHz, CDCl3) δ 7.29-7.35 (m, 4H), 7.23-7.30 (m, 1H), 7.17 (t, 2H, J=8.3 Hz), 6.76-6.84 (m, 3H), 4.10 (d, 1H, J=8.0 Hz), 3.96 (d, 1H, J=13.2 Hz), 3.03 (d, 1H, J=13.2 Hz), 2.97 (s, 1H), 2.86 (t, 1H, J=7.8 Hz), 2.37 (d, 1H, J=6.8 Hz), 1.41-2.24 (m, 10H). HRMS (ES) m/z M±H calc'd: 337.2274. found: 337.2275.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[OH:39].Br[CH2:41][CH2:42][O:43][CH3:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:41][CH2:42][O:43][CH3:44]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(O)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 3-(4-fluoro-3-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 7AU (2 g, 3.88 mmol) in DMF (25 mL) was added CsCO3 1.9 g, 5.82 mmol) and bromoethylmethyl ether (474 μL, 5.04 mmol). The resulting mixture was stirred at rt for overnight then diluted with EtOAc (300 mL), which was washed with brine, dried (MgSO4) and concentrated. Chromatograph on silica gel (2:1, hexanes/EtOAc) gave 3-[4-fluoro-3-(2-methoxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 8AU (1.8 g) as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:12]([O:13]C(C)C)=[CH:11][C:10]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]2[O:28][CH3:29])=[C:9]([F:30])[CH:8]=1>C(Cl)Cl>[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[N:19]=[C:18]2[O:28][CH3:29])=[C:9]([F:30])[CH:8]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
3.70 ml of concentrated sulphuric acid are added dropwise during 1 minute to a solution of 3.80 g of 1-(4-chloro-2-fluoro-5-isopropoxyphenyl) -2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone (see Example 4, 2nd part) in 10 ml of methylene chloride while stirring and cooling at room temperature. The reaction mixture is stirred at room temperature for 3 hours and poured on to 15 g of ice. The organic phase is separated and the aqueous phase is extracted twice with 5 ml of methylene chloride each time and the combined organic phases are washed twice with 10 ml of water each time. The methylene chloride solution is subsequently dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 147°-149° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)s1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)s4)nc23)CC1
Yield: 73.9 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.29 gm (1.56 mMol) 5-chloro-2-thiophenecarbonyl chloride, 0.36 gm (75%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:23][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:24])([CH3:25])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(F)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 43.4 %

Procedure:
A mixture of 2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.0 g, 6.1 mmol), lithium hydroxide hydrate (2.57 g, 61 mmol), water (5 mL) in methanol (10 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.84 g, 44%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C18H17F2NO2 (M+H)+: 318.3, observed: 318.2.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[N:15]([CH3:18])[CH:16]=[N:17][C:7]=2[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[CH2:1]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:9]=2[C:8]2[N:15]([CH3:18])[CH:16]=[N:17][C:7]=2[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCn1c(=O)c2ncn(C)c2c2ccccc21
Agent: O=S(=O)(O)O
Product: CCCCn1c(=O)c2ncn(C)c2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.39 mmol) of Compound 1 obtained in Example 1 in 0.13 ml of sulfuric acid was added dropwise to an acid mixture consisting of 0.045 ml of 61% nitric acid and 0.35 ml of 96% sulfuric acid with ice cooling, followed by stirring for 30 minutes. After neutralization with an aqueous 50% sodium hydroxide, the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=10/1) to afford 13 mg of Compound 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[C:12](=O)[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.O.[NH2:20][NH2:21].C(O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH:13]([NH:14][C:15]2=[O:16])[C:12](=[N:20][NH2:21])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: COc1cccc(C23CCC(=O)C(C2)NC3=O)c1
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(C23CCC(=NN)C(C2)NC3=O)c1
Yield: 94.2 %

Procedure:
A mixture of 21.73 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione, 4.9 g of hydrazine hydrate and 170 ml of ethanol is refluxed for 1 hour. After cooling, the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is dispersed in benzene and then filtered to give 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone as crude crystals. A mixture of 21.64 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-4,7-dione-4-hydrazone, 17.1 g of potassium tert.-butoxide and 400 ml of toluene is refluxed for 2 hours under heating. After cooling, water is added to the mixture, and the aqueous mixture is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of ethylacetate and n-hexane. 17.54 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-7-one are obtained. M.p. 109° - 111°C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])/[C:9]1=[O:24])=O)(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28](/[CH:32]=[N:33]/[CH2:34][Si](C)(C)C)[CH:29]=[CH:30][CH:31]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:24])[C:10]3([CH:18]([CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:34][NH:33][CH:32]3[C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[C:11]2=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1
Reactant: CC(C)(C)C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 4 (2.4 g, 6.9 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 14 (3 g, 13 mmol), acetic acid (0.6 g, 10 mmol) and H2O (0.2 g, 11 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (50-75% EtOAc in hexanes) to give rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.8 g, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 681.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[N:9][CH:10]=1)=[O:4].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH:8]=[N:9][CH:10]=1)=[O:4]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
Assay Found: C 60.61; H 3.93; N 10.78% C13H10N2O4 requires C 60.47; H 3.90; N 10.85%; from 3-bromo-5-pyridinecarboxylic acid methyl ester (1.00 g) and 3-nitrophenylboronic acid (785 mg) tetrakis(triphenylphosphine)palladium(0) (164 mg).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:10]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:30][C:31]3[NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[N:32]=3)[C:24]=2[CH3:40])[O:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][O:11]1)[CH3:9].ClC1C=CC=C(C(OO)=[O:49])C=1>CO>[CH2:8]([C:10]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:30]([C:31]3[NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[N:32]=3)=[O:49])[C:24]=2[CH3:40])[O:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][O:11]1)[CH3:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a toluene (10.8 ml) and methanol (1.2 ml) solution of the 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (380 mg, 0.81 mmol) obtained in the step (4h), a toluene (2.7 ml) and methanol (0.3 ml) solution of 3-chloroperbenzoic acid (192 mg, 0.73 mmol as the content was regarded as 65%) was added dropwise at −70 to −60° C. for 10 minutes in a nitrogen atmosphere. The mixture was stirred for one hour in the same conditions. The reaction was terminated by adding a saturated aqueous solution (15 ml) of sodium hydrogen carbonate at the same temperature. The mixture was extracted with chloroform (50 ml) twice and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (NH silica gel: elusion solvent: ethyl acetate/methanol=1/0-4/1 gradient) and desired fractions were concentrated. The obtained foamy product was re-precipitated with chloroform and diethyl ether and filtered. The operation was repeated four times and the obtained solid was washed with diethyl ether and then dried to obtain the title compound (188 mg, 47.9% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc(C)[nH]1
Product: CCOC(=O)c1nc(Br)c(C)[nH]1
Yield: 94 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-methyl-1H-imidazole-2-carboxylate obtained by the method described in Example (5a) (0.30 g, 1.95 mmol) and NBS (0.35 g, 1.96 mmol), to obtain 0.43 g of the title compound as a white solid (94%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[C:6]2[C:4]([OH:3])=[O:5])=[CH:26][CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(N)cc1
Product: O=C(O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(Nc2ccccc2)cc1

Procedure:
The title compound was prepared from 1-(4-amino-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and phenylboronic acid followed the procedure of Example 16 as a light green solid: 1H NMR (DMSO-d6) δ 5.70 (s, 2H), 6.78 (td, J=7.4, 1.0 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 7.01 (dd, J=8.5, 1.0 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.16 (t, J=3.5 Hz, 1H), 7.17 (dd, J=5.2, 1.6 Hz, 2H), 7.21 (dd, J=6.9, 2.1 Hz, 2H), 7.33-7.37 (m, 1H), 7.61 (dd, J=5.1, 1.3 Hz, 1H), 7.66 (t, J=8.7 Hz, 2H), 8.12 (br s, 1H), 13.34 (br s, 1H); MS (ESI) m/z 425 (MH+); MS (ESI) m/z 423 ([M−H]−); HRMS calcd for C26H21N2O2S: 425.1321; found (ESI+): 425.1319.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=1.Cl>CN(C=O)C>[O:6]=[C:2]1[N:3]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=2)[CH2:4][CH2:5][O:1]1
Reactant: O=C1NCCO1
Reactant: OB(O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of oxazolidin-2-one (243 mg) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 140 mg) in small portions under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, to the reaction mixture was added (4-(bromomethyl)phenyl)boronic acid (500 mg), and the mixture was stirred for 60 hr. To the reaction mixture was added ice water, and the aqueous layer was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether and ethyl acetate to give the title compound (273 mg).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:2])=[O:13])[S:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1cc(Br)cs1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chromium(VI) oxide (20 g), and concentrated sulfuric acid (32 g) were dissolved in water (50 mL) and when dissolution was complete, the volume was made up to 100 mL with water. 55 mL of the resulting solution was added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 mL) stirred at 0° C. After 2 h, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water, then extracted with aqueous sodium hydroxide. The alkaline mixture was acidified by cautious addition of concentrated hydrochloric acid then extracted with chloroform. The organic layer was then dried(Mg2SO4), filtered, and evaporated. The resulting solid was recrystallised from diethyl ether/hexane to give a colourless solid; MS (ES+) 207, 209 (MH+).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][C:15]1=[O:22].CI>COCCOC>[CH3:13][C:14]1([CH3:23])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH:16]([CH3:1])[C:15]1=[O:22]
Reactant: CC1(C)CCC(C)(C)C(=O)C1
Reactant: [Li]CCCC
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CC1C(=O)C(C)(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
106.9 ml of n-butyl lithium (2 molar in hexane) are added dropwise while cooling with ice to a solution of 21.6 g of diisopropylamine in 340 ml of ethylene glycol dimethyl ether. After stirring for 30 minutes at 0° C., a solution of 23.2 g of 2,2,5,5-tetramethylcyclohexanone in 100 ml of ethylene glycol dimethyl ether is added while cooling with ice. The mixture is stirred at room temperature for a further 45 minutes, again cooled to 0° C. and 213.9 g of methyl iodide are added thereto rapidly. The mixture is stirred at 50° C. for 45 minutes, cooled, poured on to ice and extracted with ether. After washing the organic phase with 5% hydrochloric acid and diluted sodium hydrogen carbonate solution, it is dried over sodium sulphate and evaporated. Distillation of the crude product on a spinning band column gives 13.7 g of 2,2,5,5,6-pentamethylcyclohexanone as a colourless liquid of boiling point 86°-94° C./16 mm Hg.