Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:33])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: CCOc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-ethoxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.275 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Produce was separated by solvent evaporation Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-ethoxybenzotriazole was 6.6 g (85%)
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:6]([NH2:3])([CH3:7])[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1
Reactant: Cc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(C)(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of o-tolylacetic acid (50.0 g, 0.33 mol) in tetrahydrofuran (400 ml) and hexamethylphosphoric triamide (116 ml, 0.668 mol) at 0° C. was added n-butyllithium (416 ml of 1.6M hexane solution, 0.666 mol). The solution was warmed to ambient temperature and stirred for 0.5 hour. The solution was cooled to -78° C. and iodomethane (20.7 ml, 0.33 mol) was added and the reaction allowed to warmto room temperature and stirred for 45 minutes. The reaction mixture was cooled to 0° C. and n-butyllithium (208 ml of 1.6M hexane solution,0.333 mol) was added. The reaction was warmed to ambient temperature for 10minutes, recooled to 0° C. and benzyl bromide (40.4 ml, 0.333 mol) was added. The reaction mixture was warmed to ambient temperature and stirred at that temperature overnight. The reaction was poured into 1N HCland extracted with ethyl acetate. The organic solution was washed with water (2×) saturated sodium chloride, and dried over magnesium sulphate. Removal of the solvent gave 111 g of an oil. To a solution of the above oil (111 g) in toluene (600 ml) were added triethylamine (51 ml,0.36 mol) and diphenylphosphoryl azide (82.5 ml, 0.38 mol) and the solutionwas heated to reflux under nitrogen for 2 hours. Benzyl alcohol (138 ml, 1.3 mol) was added and the solution was refluxued overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate (300 ml), washed with 1N HCl (2×), 5% sodium hydroxide (2×), saturated sodium chloride, dried over magnesium sulphate, and the solvent removed toprovide 300 g of an oil. The above oil (300 g) was dissolved in methanol (1.81) and 3N HCl (200 ml) and hydrogenated at 40 psi of hydrogen over 10%Pd/C (17.4 g) for 2 hours. The catalyst was removed by filtration and the solvents evaporated. The residue was dissolved in chloroform (300 ml) and washed with 1N sodium carbonate (2×300ml), saturated sodium chlorideand dried over magnesium sulphate. Removal of solvent gave an oil which waspurified by silica gel chromatography, elution with ammoniated 25% ethyl acetate-hexane, to provide 14.5 g of 2-(2-methylphenyl)-1-phenyl-2-propylamine as an oil. The above oil (0.5 g)was treated with fumaric acid in ethyl acetate/isopropanol to provide 0.35 g of the title compound, mp 180°-182° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[O:64]1[C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=[N:65]1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH:48]4[CH2:53][CH2:52][N:51]([C:69]([C:68]5[O:64][N:65]=[CH:66][CH:67]=5)=[O:70])[CH2:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and isoxazole-5-carboxylic acid (0.110 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine as a white solid (0.045 g). 1H NMR Spectrum: (DMSO d6 373K) 1.86 (m, 2H), 2.10 (m, 2H), 3.59 (m, 2H), 3.88 (m, 2H), 3.98 (s, 3H), 4.92 (m, 1H), 6.87 (s, 1H), 7.26 (m, 1H), 7.38 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 498.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C)c2)c1C

Procedure:
m-Toluidine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 103° C.-104.5° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]([OH:24])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC(Cl)=C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[C:12]([C:13](=[O:24])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=C(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Reaction time: 4 h

Procedure:
The mixture of 36,1 g of 1-benzyl-5-(4-(4-fluorophenyl)-1-hydroxybutyl]-1H-imidazole and 53 g manganese dioxide in 550 ml of tetrachloroethylene is refluxed stirring for four hours. The reaction mixture is filtered through siliceous earth and the flitrate is evaporated to dryness. The product is crystallized from acetone as hydrochloride salt.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
To a solution of methyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoate (42.2 g, 179.5 mmol) in THF-methanol (3:1, 535 mL) is added 2 M aqueous sodium hydroxide solution (135 mL, 269.3 mmol). The solution is stirred at 23° C. for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid as an oil (33.0 g, 83% yield).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[CH2:20][C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][C:13]2=[O:23])[CH2:3]1.Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1>>[O:22]=[C:21]1[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:4]2[CH2:5][CH2:6][N:7]([C:25]3[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:2]([CH3:1])[CH2:3]2)[C:13](=[O:23])[CH2:14][C:15]2([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:20]1
Reactant: CC1CN(CCCCN2C(=O)CC3(CCCC3)CC2=O)CCN1
Reactant: N#Cc1cccnc1Cl
Product: CC1CN(CCCCN2C(=O)CC3(CCCC3)CC2=O)CCN1c1ncccc1C#N

Procedure:
The product of Procedure 6 is allowed to react with 2-chloro-3-cyanopyridine as described in Procedures 2 and 5 to yield this substance.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCO)c(C)c1
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-benzoate (3.03 g, 18.2 mmol) in DMF (9 mL) was added 3-bromopropan-1-ol (3.80 g, 2.4 mL, 27.4 mmol) and cesium carbonate (17.8 g, 54.7 mmol) and the reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then partitioned between water (250 mL) and ethyl acetate (2×100 ml). The organic layers were combined, washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield a crude oil that was purified by silica gel column chromatography eluting with EtOAc/hexanes (10-100%) to give methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (1.87 g, 46%) as a white solid. ESI-MS m/z calc. 224.0. found 225.0 (M+1)+; Retention time: 1.27 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.94-7.77 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.98-3.82 (m, 5H), 2.24 (s, 3H), 2.10 (p, J=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[CH3:18])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:19](OC)(OC)OC.C([O-])(=O)C.[NH4+]>CO>[CH3:18][N:14]1[CH2:13][C@@H:12]2[CH2:17][C@H:15]1[CH2:16][N:11]2[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:19][NH:6][C:4]2=[O:5]
Reactant: COC(OC)OC
Reactant: CN1C[C@@H]2C[C@H]1CN2c1ccc(N)c(C(N)=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc2nc[nH]c(=O)c2c1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution 2-amino-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide (Intermediate 31D) (1 g, 3.83 mmol) in methanol (15 ml) was added trimethyl orthoformate (812 mg, 7.66 mmol) and ammonium acetate (0.60 g, 7.66 mmol). The vessel was sealed and the reaction heated at 120° C. for 4 hours. The methanol was then removed and the product chromatographed on silica elueting with 5% methanol in dichloromethane to afford 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-4(3H)-one (0.60 g, 2.33 mmol) as an off-white solid.
Reaction SMILES: C(N[C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH2:13][OH:14])[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)C.[CH2:17]([N:19](C(C)C)C(C)C)[CH3:18].Cl[C:27]([O:29][CH3:30])=[O:28].CO.C(Cl)Cl>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[NH:19][CH2:17][CH2:18][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH2:13][OH:14])[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1
Reactant: COC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)NCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (100.00 mg; 0.40 mmol; 1.00 eq.) in dry THF (12 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.09 ml; 0.52 mmol; 1.30 eq.). The mixture was cooled to 0° C. then methyl chloroformate (0.05 ml, 0.60 mmol, 1.50 eq.) was added dropwise. The reaction was stirred at room temperature for 2 h. The desired product was isolated by flash chromatography (KPNH column, 10 to 100% MeOH/DCM) to afford methyl [(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate (19.6 mg, 16%) as a white solid (once lyophilized).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)[C@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.30 g), N,N-dimethylformamide (4.0 mL), potassium carbonate (0.13 g) and (S)-2-chloropropionic acid methyl ester (0.11 g) was stirred at 45° C. for 3 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 6:4 by volume) to afford title compound as a pale peach solid, 0.17 g.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1.CC1(C)[O:23][CH:22]2[CH:18]([C@@H:19]([CH2:33]O)[O:20][C@H:21]2[N:24]2[C:30](=[O:31])[NH:29][C:27](=[O:28])[C:26]([F:32])=[CH:25]2)[O:17]1>N1C=CC=CC=1>[O:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:33][C@H:19]2[O:20][C@@H:21]([N:24]3[CH:25]=[C:26]([F:32])[C:27](=[O:28])[NH:29][C:30]3=[O:31])[C@H:22]([OH:23])[C@@H:18]2[OH:17])=[O:13])[CH2:6][CH2:7]1
Reactant: O=C(O)CCCCN1CCOCC1
Reactant: CC1(C)OC2C(O1)[C@@H](CO)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(CCCCN1CCOCC1)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.96 g (13.2 m-mol) of 5-morpholinopentanoic acid hydrochloride in pyridine (30 ml) was added 4.2 g (13.9 m-mol) of TPS, and the mixture was stirred for 15 minutes at room temperature. To this solution was added 2.00 g (6.62 m-mol) of 2',3'-O-isopropylidene-5-fluorouridine, and the mixture was stirred for 18 hours at room temperature. The reaction liquid was concentrated under reduced pressure and the residue was distributed in chloroform (50 ml) and an 8% aqueous solution of potassium carbonate (50 ml). The aqueous phase was extracted with chloroform (50 ml ×5) and the extracts were combined with the chloroform phase previously obtained. The chloroform phase was dried with Na2SO4 and concentrated and the residue was subjected to a separation-purification treatment by way of silica gel column chromatography (column size: 5×8 cm, developing solvents: chloroform and chloroform containing 2% methanol) whereby 1.17 g of 5'-O-(5-morpholinopentanoyl)-2',3'-O-isopropylidene-5-fluorouridine was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].I[CH3:21]>C1COCC1>[Cl:3][C:4]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH3:21])=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cc(CCO)ccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in oil, 2 eq.) in anhydrous THF (0.23 M) was added tert-butyl 2-chloro-5-(2-hydroxyethyl)benzoate from the previous step (1 eq.). The reaction mixture was heated at reflux for 30 min before iodomethane (7.9 eq.) was added. After carefully quenching with sat. aq. NaHCO3, the resulting mixture was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→85:15 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][OH:13])[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][O:13][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@@]2(CO)C[C@H]2N1C(=O)OC(C)(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@]2(COC3CCCCO3)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1R,3S,5S)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol), 3,4-dihydro-2H-pyran (176 μL, 1.93 mmol) and TsOH.H2O (33 mg, 0.17 mmol) in CH2Cl2 (6 mL) was stirred 3 h at RT. Then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). Colorless oil. TLC, Rf (EtOAc)=0.85; MS (UPLC/MS): 370.4 [M+H]+, 387.4 [M+H2O]+; tR (HPLC conditions f): 2.28 min.
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[C:16]2[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8])(=[O:5])[CH3:4].N1C2C(=CC=CC=2)C=CC1=[O:28].Cl>O>[I:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:6][C:3](=[O:5])[CH:4]=[C:9]2[C:7]([OH:28])=[O:8]
Reactant: CC(=O)N1C(=O)C(=O)c2cc(I)ccc21
Reactant: O=c1ccc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c2ccc(I)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of sodium hydroxide (0.77 g, 19.3 mmol) in water (46.5 mL), was added N-acetyl-5-iodoisatine (107) (2.50 g, 7.86 mmol) (Aeschlimann, J. A. The relative stability of the quinolone and indolinone rings. J. Chem. Soc. 1926, 2908). The mixture was refluxed for 3 h. After cooling to room temperature and then 0° C., a 6 N aqueous hydrochloric acid solution was added (pH=1). The precipitate was filtered and suspended in a saturated aqueous sodium bicarbonate solution (10 mL). The remaining precipitate was filtered and the filtrate was extracted with dichloromethane (6×50 mL). The aqueous layer was acidified up to pH=1 with a 6 N aqueous hydrochloric acid solution and left 1 h at 0° C. The precipitate formed was filtered and dried under vacuum at 35° C. to give compound 108 (0.90 g, 2.86 mmol) as an ocher solid. Yield 36%; mp 361-363° C.; IR (KBr) ν 1219, 1636, 1701, 2800-3150, 3200-3500 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 6.92 (s, 1H), 7.18 (d, 1H, J=8.7 Hz), 7.84 (dd, 1H, J=1.8, 8.7 Hz), 8.57 (d, 1H, J=1.8 Hz), 12.17 (s, 1H), 14.00 (m, 1H); ESI-MS m/z 313.7 [M−H].
Reaction SMILES: [CH2:1]([C:11]1[C:16](N)=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+:18]([C:21]1C=C(S(O)(=O)=O)C=[CH:25][CH:26]=1)([O-])=O.S(=O)(=O)(O)O.B(O)(O)O>OCC(CO)O.[Fe]=S.O>[CH2:1]([C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[N:18]=[CH:21][CH:26]=[CH:25]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccccc1N
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: S=[Fe]
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: O
Solvent: OCC(O)CO
Product: CCCCCCCCCCc1ccc2ncccc2c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 30.2 %

Procedure:
12.5 g of 6-decylaniline, 5.0 g of 3-nitrobenzenesulfonic acid, 1.5 g of iron (II) sulfide, 10 ml of sulfuric acid, and 2.8 g of boric acid were dissolved in 13 ml of glycerin (glycerol), followed by stirring for 6 hours at 140° C. After the reaction, the reaction mixture was poured into water and alkalinized by adding thereto an appropriately amount of sodium hydroxide aqueous solution, followed by extraction with diethyl ether. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography to obtain 2.0 g of 6-decylquinoline.