Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@:19]3([CH3:30])[O:23][C:22]4=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]4[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:33]N(C=O)C.[H-].[Na+].CI>O>[CH3:33][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C@:19]2([CH3:30])[O:23][C:22]3=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]3[CH2:20]2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CN(C)C=O
Reactant: C[C@]1(CN2CCN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(C(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid (4-trifluoromethylphenyl)amide prepared in Example 477 (200 mg, 0.44 mmol), DMF (4 ml), and sodium hydride (26 mg, 0.66 mmol) was stirred at room temperature for 1.5 hours. To the mixture, methyl iodide (0.5 ml, 0.76 mmol) was added followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid N-methyl-N-(4-trifluoromethylphenyl)amide (35 mg, yield 17%) as a white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C(C)C)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C(C)C)nc2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[methyl(1-methylethyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (363 mg) in DMF (5 mL) was added potassium tert-butoxide (124 mg) at 0° C., and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10-*50% ethyl acetate/hexane) to give the title compound (270 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][O:10][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=c1ccc(Br)cn1CCO
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (3000 mg, 13.7 mmol) in DMF (25 mL) was added sodium hydride (60% dispersion in mineral oil, 632.6 mg, 27.5 μmol) portionwise. After stirred for 30 min at 23° C., additional DMF (20 mL) was added to the thick suspension. To this was added 4-chloro-7-methoxyquinoline (2664 mg, 13.7 mmol). Upon completion, the reaction was quenched with 5% NaHCO3 (100 mL), and the aqueous was extracted with CH2Cl2 (4×75 mL). The combined organics were dried over MgSO4, concentrated from toluene, and purified on 80 grams of silica eluting with 30-80% of 5% MeOH/CH2Cl2. The product was isolated as a white solid. MS (ESI pos. ion) m/z (MH+): 375/377. Calc'd exact mass for C17H15BrN2O3: 374. 13C NMR (101 MHz, CDCl3) δ ppm 48.66, 54.80, 64.75, 97.11, 98.75, 106.69, 114.92, 118.10, 121.48, 121.78, 137.81, 142.38, 150.57, 151.00, 159.87, 160.24, 160.40
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)=[O:5].[H-].[Na+]>N1C=CC=CC=1>[CH:14]1([N:13]2[C:2]3[N:20]=[CH:19][CH:18]=[CH:17][C:3]=3[C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:16][CH2:15]1
Reactant: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2N(C2CC2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Title compound 382 (0.7 g, 2.4 mmol), sodium hydride (0.292 g, 7.3 mmol) and pyridine (20 mL) were stirred together at 80° C. for 5 hours then at room temperature over week-end. The reaction mixture was then poured into an ice-water mixture and stirred for 1 hour. The beige solid was filtered and the filtrate was extracted with ethyl acetate (2 times). The combined organic extracts were dried and concentrated. The residue was purified by flash chromatography (10-70% ethyl acetate in hexanes). The 2 solids were mixed together to afford title compound 383 (0.51 g, 85%) as a beige solid. MS (m/z): 251.9 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Na].C(O)C.[Cl:16][CH:17]=[CH:18][CH2:19]Cl>O>[Cl:16][CH:17]=[CH:18][CH2:19][N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: ClC=CCCl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(CC=CCl)nc1C

Procedure:
Ethyl 3-methylpyrazole-4-carboxylate (5.0 g) was added to sodium alcoholate prepared from 0.75 g of metallic sodium and 30 ml of ethanol. To the homogeneous mixture was added 3.6 g of 1,3-dichloropropene, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was discharged into water and extracted with ethyl acetate. The extract was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 2.5 g (34%) of a Z isomer of ethyl 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylate and 1.5 g (20 %) of its E isomer. The Z isomer (2.5 g) was stirred under heat for 4 hours together with a mixture of 25 ml of ethanol, 2.5 g of sodium hydroxide and 25 ml of water. After the reaction, the reaction mixture was cooled to room temperature, and with cooling, concentrated hydrochloric acid was added to adjust its pH to 4 to 5. The precipitated crystals were collected by filtration and dried. Recrystallization from water gave 0.3 g (yield 14%) of the Z isomer of 1-(gamma-chloroallyl)-3-methylpyrazole-4-carboxylic acid. m.p. 96°-100° C.
Reaction SMILES: C([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)(=O)C.CC(C)([O-])C.[K+].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].O>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([S:31]([NH:4][C:5]1[C:15]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CC(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
2.95 g of 7-acetylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 30 ml of N,N-dimethylformamide. 1.35 g of potassium tert-butoxide was added with ice-cooling. The mixture was stirred for 30 minutes at the same temperature. Then, 1.55 g of ethanesulfonyl chloride was added thereto dropwise. The mixture was stirred for 1 hour at 20°-25° C. 200 ml of water and 200 ml of ethyl acetate were added. The organic layer was separated. The solvent was removed by distillation under reduced pressure. The resulting crystal was mixed with 20 ml of a 1N aqueous sodium hydroxide solution and 10 ml of ethanol. The mixture was refluxed for 2 hours. 100 ml of water and 100 ml of ethyl acetate were added thereto. The mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated. The layer was washed with water and a saturated aqueous NaCl solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a mixture of 5:1 toluene and ethyl acetate) to obtain 0.75 g (yield: 21.7%) of 7-ethylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[OH-:18].[Na+]>S(=O)(=O)(O)O.O>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: [OH-]
Reactant: CCN(CC)CC#CCCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCC(=O)CCCc1ccccc1

Procedure:
Add to a solution of 1-diethylamino-6-phenylhex-2-yne (27.1 g) in concentrated sulphuric acid (7.6 cc) diluted with water (77 cc) at 70° mercuric sulphate (1.6 g), and keep the solution under nitrogen for 1 hour; cool, make basic with sodium hydroxide solution, and filter through glass wool to remove mercuric oxide. Extract the product with ether and evaporate the washed and dried ethereal solution, leaving crude 1-diethylamino-6-phenylhexan-3-one. Distil under reduced pressure with this ketoamine undergoing partial elimination of diethylamine, to obtain a mixture of the ketoamine, and 6-phenylhex-1-en-3-one (18.9 g), b.p. 96°/0.003 mm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[OH:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[OH:45].C(=O)([O-])O.[Na+].Cl>O1CCOCC1.O>[OH:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[OH:45])[CH2:46][CH2:47][NH:48][C:10](=[O:12])[CH:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[OH:13]
Reactant: O=C(O)C(O)c1ccc(O)c(O)c1
Reactant: NCCc1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCc1ccc(O)c(O)c1)C(O)c1ccc(O)c(O)c1
Reaction time: 16 h

Procedure:
2-(3,4-Dihydroxyphenyl)-2-hydroxyacetic acid (300 mg, 1.63 mmol) and N-hydroxysuccinimide (188 mg, 1.63 mmol) were dissolved in 1,4-dioxane (20 ml) under nitrogen, and N,N′-dicyclohexylcarbodiimide (336 mg, 1.63 mmol) was added to the mixture at room temperature, which was stirred at this temperature for 16 h. The by-product which precipitated out was filtered off, and the filtrate was added to a solution of 2-(3,4-dihydroxyphenyl)ethylamine hydrochloride (309 mg, 1.63 mmol) in water (20 ml). Sodium hydrogencarbonate (151 mg, 1.8 mmol) was also added, and the reaction mixture was stirred under nitrogen at 50° C. for 1.5 h. The mixture was rendered acidic using 5% strength hydrochloric acid and extracted 3 times with ethyl acetate (a total of 90 ml). The organic phase was washed with saturated NaCl solution, dried over Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure. The product was purified by chromatography on silica gel using the eluent ethyl acetate. The yield was 266 mg of a colorless syrup (51% of theory based on the acid used).
Reaction SMILES: [N-:1]=[C:2]=[S:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][O:27][C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CC(C)=O.C(Cl)Cl>[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][O:27][C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][N:34]([C:2](=[S:3])[NH2:1])[CH2:35]4)=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: [N-]=C=S
Reactant: c1cc(N2CCC(COc3ccc4c(c3)CNCC4)CC2)ccn1
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution of ammonium isothiocyanate (220 mg) in acetone (4.5 ml) was dropwise added benzoyl chloride (0.32 ml) at room temperature, and the mixture was stirred at 75° C. for 10 min. Then, a mixture of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (850 mg) in acetone (4.5 ml) and methylene chloride (4.5 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. To the obtained residue was added conc. hydrochloric acid (10 ml), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, water was added and the mixture was washed successively with ethyl acetate and chloroform. The aqueous layer was concentrated and the resultant residue was dissolved in water and ethanol, and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1-20:1) and dried under reduced pressure to give the title compound (450 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C:15](=[O:17])O[C:13](=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([C@H:26]([C@@H:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([NH:39][NH2:40])=[O:38])[CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:19]([O:23][C:24]([C@H:26]([C@@H:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([NH:39][N:40]1[C:13](=[O:18])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][C:15]1=[O:17])=[O:38])[CH2:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CC(=O)O1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C(=O)OCc2ccccc2)CC1=O)[C@H](CC=Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of 0.7 g of 2,6-dioxo-4-morpholine carboxylic acid benzyl ester in 20 ml of dichloromethane was treated with 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide (prepared as described in Example 1). The mixture was stirred for 1 hour at room temperature and then treated with 0.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for a further 3 hours at room temperature and then washed in sequence with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying of the organic phase over anhydrous magnesium sulphate and evaporation gave a residue which was purified by column chromatography on silica gel using ethyl acetate/ hexane (3:7) for the elution to give 1.16 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(4-benzyloxycarbonyl-2,6-dioxo-1-piperazinyl)valeramide in the form of a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:15]([CH3:23])=[CH:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[C:1]([C:9]1[CH:10]=[C:11]([C:15]([CH3:23])=[CH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC=C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=CCC(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 88.6 %

Procedure:
A mixture of 5.35 g of the said ester in 50 ml of methanol and 20 ml of 2N sodium hydroxide were refluxed for 2 hours and then the methanol was distilled off. The mixture was added to water, treated with activated carbon and filtered. The filtrate was acidified with 3 ml of concentrated hydrochloric acid and was extracted with ether. The ether extract was washed with water until the wash water was neutral, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 4.31 g of 4-(m-benzoyl-phenyl)-4-methyl-3-butenoic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>CN(C)C=O>[Br:22][C:13]1[CH:14]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(Cc2ccccc2)cc1Br

Procedure:
The commercially available 4-benzyl aniline can be selectively brominated at the ortho position using n-bromosuccinimide in dimethylformamide to give the desired 2-bromo-4-benzyl aniline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15])[N:5]=2.C1COCC1.O.[OH-].[Li+].Cl>O.CO>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15])[N:5]=2
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(N)sc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2ccc(-c3cccc(C(=O)O)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a solution of ethyl 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate (400 mg, 1.34 mmol) in a mixture of water (2.0 mL), THF (2.0 mL) and methanol (2.0 mL) was added lithium hydroxide monohydrate (281 mg, 11.85 mmol). The reaction mixture was stirred at room temperature for 16 h and was neutralized with 1N aqueous HCl until pH=6 (monitored with pH paper). The organic solvent was removed in vacuo and the resulting brown solid was collected and dried to give 310 mg (85% yield) of 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoic acid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>ClCCl>[C:1]([O:9][C@@H:10]1[C:11](=[O:12])[C@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:24]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3,5-tri-O-benzoyl-α-D-ribofuranose (10.0 g, 21.62 mmol, 1.0 equiv.) is dissolved in dichloromethane (60 ml) and cooled under ice. Trichloroisocyanuric acid (5.52 g, 23.80 mmol, 1.1 equiv.) is added, followed by addition of catalytic amount of TEMPO. The ice bath is removed and the mixture is stirred at room temperature for 1 hour then filtered on Celite®. The organic phase is washed with saturated aqueous Na2CO3 solution, followed by 1N HCl and brine. The organic layer is dried (MgSO4) and the solvent is evaporated to give (2R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-dihydrofuran-3-one as a white foam. 1H-NMR (400 MHz, CDCl3): δ 8.13-8.01 (m, 6H), 7.65-7.37 (m, 9H), 6.20 (d, 1H, J=1.2 Hz), 5.88 (dd, 1H, J=1.2 Hz, 8.8 Hz), 5.05 (m, 1H, J=1.2 Hz, 4 Hz, 8.8 Hz), 4.84 (dd, 1H, J=4 Hz, 12.4 Hz), 4.65 (dd, 1H, J=4 Hz, 12.4 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:13]=1[CH:14]=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH:14]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-chlorophenylhydrazine hydrochloride (5.24 g, 29.27 mmol), 2-fluoro-5-iodobenzaldehyde (7.5 g, 30.00 mmol) and cesium carbonate (22.8 g, 69.98 mmol) was suspended in NMP (120 mL) and stirred at ambient temperature for 45 min. The temperature was raised to +160° C. and the reaction mixture was stirred for 1 h, the now black suspension was allowed to reach r.t. Water was added, the slurry was extracted with EtOAc (500 mL. The organic phase was washed with brine (2×). The brine fractions and waterphase was combined and backextracted once with EtOAc. This second EtOAc phase was washed with brine (2×) before combined with the previous EtOAc phase. The organic phases were dried over Na2SO4, filtered and evaporated. The black residue were dissolved in DCM/Heptane (=1/1) and filtered through a silica column, and the column was then further eluted with DCM/Heptane (=1/1) solvent mixture. The fractions containing product was evaporated, residue was dissolved in EtOAc and Heptane was added, evaporation and diluting with Heptane afforded a slurry, the solid material was collected by filtration and washed with Heptane. Yield 2.82 g (27%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.CCOC(C)=O>[Si:22]([O:12][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]1=2)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCCc2nc(Cl)ccc21
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (500 mg, 2.72 mmol) in DMF (10 mL) was treated with imidazole (260 mg, 3.81 mmol). After complete dissolution TBDMS-Cl was added and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and was washed with brine (5×). The organic layer was collected, dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 760 mg. Yield 94%.