Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:19]([NH:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[O:23])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cscc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cscc1C(=O)OC

Procedure:
A mixture of 50.0 g (0.258 mol) of methyl 4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g (0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethyl chlorocarbonate was refluxed for 5 hours. The insoluble matter was filtered off, the filtrate was evaporated down in vacuo and the residue was crystallised from petroleum ether. 59.0 g (99.8% of theory) of colourless crystals of melting point 52° C. were obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([Cl:24])=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)C.[Li+].[OH-].Cl>C1COCC1.CCO>[Cl:24][C:18]1[C:17]([CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:10]3[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][S:8][C:9]=3[CH:14]=2)=[CH:22][N:21]=[C:20]([CH3:23])[N:19]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3cnc(C)nc3Cl)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ncc(COc2ccc3c(CC(=O)O)csc3c2)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.8 %

Procedure:
To a mixture of ethyl(6-((4-chloro-2-methylpyrimidin-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (70 mg) in THF (3 mL) and EtOH (2 mL) was added 4N LiOH (0.186 mL) at room temperature. The mixture was stirred at room temperature for 5 h. The mixture was neutralized with 1N HCl at room temperature and concentrated in vacuo. Water and saturated aqueous NH4Cl were poured into the residue and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18, water/CH3CN (including 0.1% TFA)). The fraction including Example 72 was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from EtOAc-hexane to give (6-((4-chloro-2-methylpyrimidin-5-yl)methoxy)-1-benzothiophen-3-yl)acetic acid (Example 72, 18 mg). The fraction including Example 73 was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from EtOAc-hexane to give (6-((4-ethoxy-2-methylpyrimidin-5-yl)methoxy)-1-benzothiophen-3-yl)acetic acid (Example 73, 12.8 mg).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO.O1CCCC1>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Reaction time: 5 h
Yield: 47.5 %

Procedure:
Add magnesium chloride (27.7 g, 0.29 mol) to 2-methoxyethanol (400 mL) and heat the mixture to reflux. Add a solution of 3-(3,4-Dihydro-2H-quinolin-1-yl)2-oxopropion-ic acid ethyl ester (0.29 mol) in 2-methoxyethanol (100 mL) and tetrahydrofuran (40 mL) slowly to the MgCl2 mixture over 1 hour. Upon completion of addition, stir the mixture for 5 hours at reflux, and then concentrate under reduced pressure. Treat the concentrated crude mixture with 2N hydrochloric acid (500 mL) and extract with dichloromethane (3×400 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 20% ethyl acetate/hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as an orange solid (31.6 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2scnc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2scnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5,7-dichlorothiazolo[4,5-d]pyrimidine 42, morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:17][CH:18]([C:19](=[O:29])[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([CH:21]([NH:20][C:19]([CH:18]2[CH2:17][N:16]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:13]3[CH2:14][CH2:15][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)[CH:12]23)=[O:29])[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(N)C3CCCCC3)C12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of 30 (81 mg, 0.14 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 1 h, the reaction mixture was warmed to ambient temperature. After 30 min, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, and brine. The aqueous layers were back-extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford 31 (60 mg) as an off-white foam. 1H NMR (CDCl3, 300 MHz): δ7.42-7.27 (m, 5H), 5.10-5.01 (m, 1H), 4.57 (d, J=4.5 Hz, 1H), 4.22 (m, 1H), 3.86 (d, J=11.1 Hz, 1H), 3.78 (m, 1H), 3.64-3.46 (m, 2H), 3.19 (m, 1H), 2.96 (s, 3H), 2.62-2.56 (m, 1H), 1.77-1.67 (m, 6H), 1.53 (d, J=6.9 Hz, 3H), 1.19-1.15 (m, 6H) ppm. Mass spectrum, m/z [477.5] (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)OCCCCO
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCOC(=O)C1CCC(CCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 4-hydroxybutyl acrylate (8.0 g, 57.0 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (100 ml) in a flask equipped with Dean-Stark apparatus. The reaction is shown to be complete by GCMS after 1 hour. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant. Evaporation of the appropriate fractions gives a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24](=[O:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)CCl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
First, 8.64 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 4.98 g of potassium carbonate, 3.36 g of chloroacetone, and 50 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was filtered. The filtrate was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 10.12 g (yield, 98%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy-acetone, m.p., 83.8° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1.N([O-])=O.[Na+].[ClH:31]>C(O)C.O.[Cu]Cl>[Cl:31][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1[C@@H](NC(C)=O)CC2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(Cl)cc1[C@@H](NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of N-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (0.712 g; 2 mmol) in ethanol (3.75 ml) and 36% hydrochloric acid (1.57 ml) was slowly added into a mixture of ice (6 ml) and 36% hydrochloric acid (1.57 ml). At 0° C. a solution of sodium nitrite (0.14 g; 2 mmol) in water (0.25 ml) was added. The mixture was stirred at 0° C. for 1 hour and then transferred into a separate flask containing a solution of copper(I) chloride (0.218 g; 2.2 mmol) in water (0.35 ml) and 36% hydrochloric acid (0.4 ml). The resulting mixture was stirred at 30° C. for 30 minutes and extracted with toluene/ethyl acetate (50/50). The organic phase was washed with water, dilute sodium hydroxide, and saturated sodium chloride solution, then dried and the volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give N-[(5S)-3-chloro-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][CH2:21][CH2:22][Cl:23])[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1c2ccc(Br)cc2ccn1CCCCl
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (Example 1b) (2 g) dissolved in NMP (20 mL) was treated with potassium carbonate (1.974 g) and 1-bromo-3-chloropropane (8.83 ml) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h. The cooled reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was dried (MgSO4), and evaporated. The residue was purified (SiO2 chromatography, elution with a mixture of DCM and isohexane) to give the subtitle compound (1.70 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1.C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:29]=[CH:28][N:27]=1)CCC>>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([N:5]([CH2:6][C:7]3[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=3)[CH2:4][CH2:3][O:2][CH3:1])[N:31]=2)=[CH:37][CH:36]=1
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(Cl)cc3)n2)cc1C

Procedure:
Prepared from ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the synthetic procedure described for Intermediate 45. Purification by Biotage™ chromatography (silica, 90 g) eluted with 100:15 to 100:25 cyclohexane:EtOAc afforded the title compound as a colourless gum (165 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][NH:47][CH:44]([CH3:46])[CH3:45])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 16.5 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.444 g, 0.725 mmol) and isopropylamine (2.0 mL, 23 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 3 hours. More isopropylamine (2.0 mL, 23 mmol) was then added, and the reaction mixture was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-isopropyl-amine as a yellow semi-solid (0.290 g, 80.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a buff foam (0.273 g); Mass Spectrum (+EI, [M+H]+) m/z 500.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][N:6]1[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:16])([CH3:1])[C:7]1=[O:8]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
At 0° C., a solution of 2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (35.8 g, 0.161 mol) and 1-methoxy-3-(p-toluenesulfonyloxy)propane (47.6 g, 0.195 mol) in DMF (720 ml) is treated with Kl (5.49 g, 33.1 mmol). After adding 60% of NaH (7.80 g, 0.195 mol) over 10 min, the mixture is stirred at 0° C. for 30 min, warmed to 60° C., stirred for 14 h, and treated with H2O (3500 ml). After the extraction of the mixture with EtOAc (3×400 ml) and Et2O (3×400 ml), the combined org. layer is washed with H2O (2×250 ml), dried (Na2SO4), and evaporated. A SiO2 flash chromatography (2000 g, hexane/EtOAc 5:2) gives 4-(3-methoxy-propyl)-2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (39.0 g, 82%) as yellow oil. Rf (hexane/EtOAc 5:2) 0.45. 1H-NMR (400 MHz, CDCl3) 1.55 (s), 1.91-2.02 (m, 2 H), 3.36 (s), 3.43 (t, J=6.0), 4.07 (t, J=6.0), 7.04 (d, J=9.0), 7.93 (dd, J=9.0, 0.4), 8.09 (d, J=0.4). 13C-NMR (100 MHz, CDCl3) 167.6 (s), 148.9 (s), 143.0 (s), 129.5 (s), 119.8 (d), 117.7 (d), 110.4 (d), 78.9 (s), 69.4 (t), 58.7 (q), 39.7 (t), 27.5 (t), 23.7 (2q).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:18])[CH2:5][C:6]1([NH:12]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:18])[CH2:5][C:6]1([NH:12]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CC2(CCCCC2)Nc2cc(O)cc(O)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(O)c2c(c1)NC1(CCCCC1)CC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A mixture of 5,7-dihydroxyspiro[1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-4-one (prepared in Preparation 81) (0.247 g, 1.0 mmol), ethyl bromoacetate (0.184 g, 1.10 mmol), anhydrous potassium carbonate (0.207 g, 1.5 mmol), and dry acetonitrile (4 ml) is stirred at room temperature for 4 hours. The solvent is removed under reduced pressure and the residue is extracted with ethyl acetate and water. The ethyl acetate layer is separated, washed with water, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of acetone and dichloromethane (1:10) to obtain a crude product. Recrystallization from a mixture of diethyl ether and hexane gives ethyl 2-{(5-hydroxy-4-oxospiro [1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-7-yl)oxy}acetate (0.265 g, 79%, m.p.=134°-135° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[N:31][OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(CC2C(=NO)CCc3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-one (600 mg, 1.55 mmol), hydroxylamine hydrochloride (160 mg, 2.32 mmol) and sodium acetate (254 mg, 3.10 mmol) in 6 mL EtOH/H2O (2:1) is refluxed for 2 h. The solution is cooled to RT and extracted with CH2Cl2. The organic layer is washed with water, brined and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography with CH2Cl2 to give the title compound as a yellow liquid. (M+1)+=403.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:30])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][C@@H:17]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:16]2)=[N:5][CH:4]=1.Cl.O1CCOCC1.C(=O)([O-])[O-]>C(Cl)Cl>[NH2:22][CH2:21][C@@H:17]1[O:18][CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:30])[CH2:16]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CNC(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CN)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl [((2S)-4-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-2-morpholinyl)methyl]carbamate (0.46 g, 1.10 mmol) in CH2Cl2 (10 mL) was added HCl in 1,4-dioxane (1.10 mL, 4.40 mmol) and the resulting solution stirred at ambient temperature for 16 h. After concentration under reduced pressure, the free base was formed by treating with excess MP carbonate to yield a yellow oil. (0.300 g, 85%).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[SH:27][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)COc1cccc2c1CCCC2O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1cccc2c1CCCC2S
Yield: 104.2 %

Procedure:
A solution of 1-hydroxy-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.42 g) and Lawesson's reagent (0.40 g) in toluene (4 ml) was refluxed under N2 atmosphere for 1 hour. The reaction mixture was purified by chromatography on silica gel to give 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g). A solution of 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.32 g) and potassium carbonate (0.14 g) in DMF (5 ml) was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylthio]-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.29 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH3:21].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g, 4.5 mmole), 1-bromo-2-methoxyethane (0.7 g, 5 mmole) and K2CO3 (1.3 g, 9 mmole) in DMF (10 mL) was heated at 85° C. for 20 hr, diluted by ethyl acetate, washed by water, dried over MgSO4, filtered, concentrated under vacuum, purified by ISCO (silica gel, elute: 10% ethyl acetate in hexane) to give liquid product (316 mg, 25% yield). MS (ESI) m/z: Calc. 278.2 (M+). Found: 279.3 (M++1).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][O:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O>[O:23]1[CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[CH:21]=[N:22]1
Reactant: O=C(NCCOc1ccc(-c2cnoc2)cc1)OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NCCOc1ccc(-c2cnoc2)cc1
Temperature: 35 °C
Yield: 35.2 %

Procedure:
[2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester (1.00 g, 2.81 mmol) was dissolved in methylene chloride (14 ml) and methanesulfonic acid (2.73 ml, 42.2 mmol) was added. The resulting mixture was heated to about 35° C. for about two hours, and was then diluted with methylene chloride and water. The pH of the mixture was adjusted to about 12 with 5N sodium hydroxide, and the mixture was extracted with methylene chloride. The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography (20% methanol/methylene chloride) to afford 202 mg (53% yield) of the desired amine. LRMS ([M+H]+)=205.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH2:3]1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][CH:13]1[CH2:12][O:16][CH:10]([C:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=2)[O:11]1
Reactant: CC1CC=C(C=O)C(C)(C)C1
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC=C(C2OCC(C)O2)C(C)(C)C1
Yield: 65.1 %

Procedure:
4,6,6-Trimethyl-1-cyclohexen-1-carbaldehyde (2 g, 13 mmole), 1,2-propanediol (4 g, 53 mmole) and p-toluenesulfonic acid (50 mg) were refluxed in 20 ml of toluene, with water separation in a Dean-Stark apparatus, during 6 h. The resulting solution was washed with a NaHCO3 solution and the crude product distilled at a bath temperature of 80°/0.5 hPa, to obtain 1.78 g of the desired product in the form of a mixture of isomers.