Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:9]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[C:24]([O:27][CH3:31])[CH:23]=[CH:22][CH:21]=3)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3c(O)cccc3cn2)oc2ccccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2cnc(-c3cc(=NOC(C)(C)C)c4ccccc4o3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a ice-water bath cooled solution of 2-(5-hydroxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (80 mg, 0.22 mmol) in dimethylformamide (2.5 ml) was added sodium hydride (60% in mineral oil, 13 mg, 0.33 mmol) under argon and the mixture was stirred at room temperature for 1 hour. The solution was cooled to 0° C. and iodomethane (15 μl, 0.24 mmol) was added. The resulting solution was stirred at room temperature for 20 hours and then hydrolyzed with brine. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and then purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 80/20) to yield 2-(5-methoxy-isoquinolin-3-yl)-chromen-4-one O-tert-butyl oxime (65 mg, 79%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CNc1ccc(F)c(F)c1
Reactant: CC(Br)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)c(F)c1
Yield: 45.8 %

Procedure:
3,4-difluoro-N-methylaniline (161 mg, 1.13 mmol) was reacted with 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.28 mmol) using a procedure similar to the one described in Example 3.00 to give 8-(1-((3,4-difluorophenyl)(methyl)amino)ethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (66.0 mg, 45.6%). Mass Spectrum: M+H+ 515. NMR Spectrum: (DMSOd6) 1.56 (d, 3H), 2.18 (s, 6H), 2.41 (t, 2H), 2.63 (s, 3H), 3.21-3.28 (m, 2H), 3.34-3.41 (m partially hidden by H2O, 4H), 3.41-3.49 (m, 2H), 3.49-3.56 (m, 2H), 5.53 (q, 1H), 5.55 (s, 1H), 6.61 (d, 1H), 6.87 (ddd, 1H), 7.24 (dd, 1H), 8.09 (d, 1H), 8.43 (d, 1H), 8.74 (t, 1H).
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9]>C(O)C.C(O)=O>[CH3:3][S:4]([CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9])=[O:1]
Reactant: OO
Reactant: CSCCNC(N)=O
Solvent: CCO
Solvent: O=CO
Product: CS(=O)CCNC(N)=O
Reaction time: 2 h
Yield: 85 %

Procedure:
There are slowly added 3 ml of H2O2 (110 volumes) to a well agitated solution of 20 moles of 2-methylthio ethylurea in a mixture of ethanol and formic acid. The solution obtained is agitated for 2 hours after which it is concentrated under reduced pressure. The resulting residue is then crystallized in ethylacetate thus providing white crystals melting at 88° C. in a yield of 85%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25](/[CH:27]=[CH:28]/[C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=4)[C:32]([O:34][CH3:35])=[O:33])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=4)[C:32]([O:34][CH3:35])=[O:33])[C:24]([C:39]([F:40])([F:41])[F:42])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(/C=C/c2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
A suspension of (E)-methyl 2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)vinyl)isonicotinate (1128) (110 mg, 0.188 mmol), and 10% Pd/C (20 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure for 16 hours. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound (I129) (70 mg, 63%) as a yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J=5.1, 0.7 Hz, 1H), 8.51 (s, 1H), 7.76 (s, 1H), 7.66 (dd, J=5.1, 1.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.18 (t, J=5.5 Hz, 2H), 4.22 (s, 2H), 3.93 (d, J=3.9 Hz, 3H), 3.43-3.35 (m, 2H), 3.34-3.26 (m, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.63 (d, J=3.5 Hz, 1H), 1.82 (d, J=12.3 Hz, 2H), 1.67-1.54 (m, 2H), 1.48 (d, J=7.1 Hz, 3H). LCMS Method C: rt 6.75 min; m/z 586.1 [M+1]+, 584.2 [M−1]−.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:15]2[C:16]3[C:21]([CH:22]=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:2]=1.C1C(=O)N([Br:36])C(=O)C1>C1COCC1>[Br:36][C:22]1[C:21]2[C:16]([C:15]([C:3]3[CH:2]=[CH:1][C:14]4[CH:13]=[CH:12][C:11]5[C:6]([C:5]=4[CH:4]=3)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[C:28]3[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]3)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3ccc4ccc5ccccc5c4c3)c3ccccc3cc2c1
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3ccc4ccccc4c3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
30 g (80 mmol) of 9-phenanthren-3-ylanthracene are suspended in 300 ml of THF, 14.2 g (80 mmol) of NBS are added, and the mixture is stirred at RT for 2 h with exclusion of light. The solvent is subsequently removed in vacuo, and the residue is boiled in EtOH and recrystallised twice from dioxane, leaving 32.9 g (95%) of bromide as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S(Cl)(=O)=O)#[N:2].[F-:13].[K+].S1(CCCC1)(=O)=O>>[F:13][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccccc1F

Procedure:
20.15 grams(0.l mole) of the product prepared in Example 1 above, 12 grams(0.21 mole) spray-dried potassium fluoride, and 45 milliliters sulfolane were heated under nitrogen to 230°-248° C. for one hour. The product was distilled directly through a 5-inch(12.7 centimeters) vigreaux column to give 6.9 grams 2-fluorobenzonitrile having a boiling point of 91°-92° C. at 27 mm Hg. The infrared spectrum was identical with that of the published spectrum. Based on 2-cyanobenzenesulfonyl chloride, the per cent yield of 2-fluorobenzonitrile was 57. Based on saccharin, the overall yield was 52.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:16][C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1Nc2ccccc2C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2[nH]c3ccccc3c2-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
3-Phenyloxindole (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and heated to 80° C. with stirring in a preheated oil bath. After 20 minutes, 5 ml of acetone and 1 ml of water are then added and the mixture is heated for a further 30 minutes. The hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.59 g of product in an HPLC purity of 98% (29% of theory). A structural elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.67 g of product in an HPLC purity of 40% can be isolated from the filtrate (13% of theory).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:8][CH:9]=3)[N:17]=2)=[CH:33][CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: N/C(=N\O)c1ccc(Oc2ccccn2)cc1
Solvent: c1ccncc1
Product: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccccn5)cc4)no3)cc2)cc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
(Z)-N′-Hydroxy-4-(pyridin-2-yloxy)benzamidine (339 mg, 137 μmol) and 4-benzyloxybenzoyl chloride (24 mg, 106 μmol) were suspended in pyridine (2.0 mL) the solution was refluxed for 21 hours. The reaction mixture was then cooled to room temperature and solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (Hex/EtOAc 2:1) to give the product as a white solid (20 mg, 46%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.16 (2H, s), 6.99 (1H, d, J=8.2 Hz), 7.05 (1H, ddd, J=7.2, 5.0, 0.80 Hz), 7.11 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.34-7.38 (1H, m), 7.40-7.46 (4H, m), 7.73 (1H, ddd, J=8.8, 8.2, 2.0 Hz), 8.16 (2H, d, J=9.0 Hz), 8.20 (2H, d, J=8.6 Hz), 8.24 (1H, dd, J=5.0, 2.0Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 70.4 (CH2), 112.3 (CH), 115.5 (CH), 117.3, 119.3 (CH), 121.4 (CH), 123.5, 127.7 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 130.3 (CH), 136.2, 139.9 (CH), 148.0 (CH), 156.8, 162.5, 163.3, 168.5, 175.7. MS (FAB+): 422 (MH+). HRMS for C26H19N3O3 (MH+): calculated: 422.1505; found 422.1505.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:36])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]2)[CH:14]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:15]3[CH:14]=[C:13]4[C:18]([N:19]5[CH:10]([C:11](=[O:36])[NH:12]4)[CH2:9][NH:8][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:28][CH2:27]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Temperature: 25 °C
Yield: 8.9 %

Procedure:
7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (250 mg, 0.487 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added while stirring at room temperature. The reaction was stirred for 16 h and concentrated to a residue. The residue was dissolved in DMF and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (17.8 mg, 8.8%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.68 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.33 (d, J=11.4 Hz, 1H), 3.97 (dd, J=11.0, 3.4 Hz, 1H), 3.45 (dd, J=12.5, 2.9 Hz, 4H), 3.32-3.36 (m, 4H), 3.16 (d, J=9.6 Hz, 1H), 3.06-3.13 (m, 4H), 2.72-2.87 (m, 3H). [M+H] calc'd for C26H33ClN6O3, 413. found, 413.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28](/[C:30](=[CH:15]/[C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:12]([O:19][CH3:20])[CH:13]=3)/[C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COc1cc(C=O)ccc1OCCCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCO
Yield: 99 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(8-hydroxyoctyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(8-hydroxyoctyl)oxy]-3-methoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 99% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:1][C:2]1[C:9]([O:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc(C=O)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A suspension of 2,3-dihydroxybenzaldehyde (15 g, 109 mmole) in CH2Cl2 (70 ml) was cooled to -10° C. Triethyl amine (5.49 g, 54.3 mmol) was added followed by pivaloyl chloride (6.49 g, 53.9 mmol). The reaction was allowed to stir for 1 hour at -10° C. and then warmed to ambient temperature. The reaction mixture was stirred at ambient temperature overnight, then washed with water, 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give 2-hydroxy-3-pivaloyloxybenzaldehyde: (10.15 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)sc2c1
Yield: 47.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 76 mg (47%) of the title compound as an amorphous solid. mp 102°-107°. FDMS: m/e=424. α[D]589 =+64.29 (c=0.71, chloroform).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[NH3:19]>CO>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3](=[O:2])[NH2:19])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of (S)-azetidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (2.5 g) and 7 M ammonia in MeOH (10 ml) was stood at it for 18 h in a sealed vessel. The RM was then evaporated to give the title compound as a white solid which was used without further purification. MS: M+H 235.1 and M−H 233.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:44])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A solution of triphenylphosphine (281 mg, 1.07 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (190.4 mg, 1.07 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (220 mg, 0.63 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (189 mg, 1.89 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide (79 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C20H23ClN6OS (M+) 430.1343, found 430.1343.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:31])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[C:17]([O:29]C)[C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[C:20]=2[O:23]C)[CH2:15]1)[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH2:1]([NH:3][C:4](=[O:31])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:20](=[O:23])[C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[C:17](=[O:29])[C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNC(=O)OCCCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)OCCCCCCCCC1CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octyl N-ethylcarbamate (1.22 g) in acetonitrile (12 ml) was dropwise added a solution of CAN (3.83 g) in water (12 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=4:1) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (630 mg) as crystals.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]([C:59]1[N:60]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[C:61]2[C:66]([C:67](=[O:79])[C:68]=1[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76](=[O:78])[CH3:77])=[CH:72][CH:71]=1)=[CH:65][CH:64]=[C:63]([CH3:80])[N:62]=2)=[O:58]>CO>[CH3:55][O:56][C:57]([C:59]1[N:60]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[C:61]2[C:66]([C:67](=[O:79])[C:68]=1[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76](=[O:78])[CH2:77][Br:1])=[CH:72][CH:71]=1)=[CH:65][CH:64]=[C:63]([CH3:80])[N:62]=2)=[O:58]
Reactant: COC(=O)c1c(Cc2ccc(C(C)=O)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(C(=O)CBr)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (72 mg, 0.15 mmol) was added to a solution of 3-(4-acetylbenzyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (53 mg, 0.12 mmol) in MeOH (8 mL), and the resulting mixture stirred at RT overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue purified by preparative TLC (EtOAc/hexane, 10/90) to afford 23 of 3-[4-(2-bromoacetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester as an off-white powder. MS=507 [M+H]+; MP=189.0-191.1° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](\[NH:14]OC)/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[H][H]>[Ni].CO>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NOC
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Yield: 100.1 %

Procedure:
A reactor vessel charged with 171 g of (4R,5R)-3-methoxyamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester, 1600 mL of MeOH, and 65 g of Raney nickel (Ra—Ni) catalyst. The methoxyamino ester was reacted with hydrogen at 50 psig to 55 psig. During the hydrogenation, additional Ra—Ni was added at reaction times of 8 hours (20 g), 21 hours (20 g), and 37 hours (8 g). After the reaction was completed (51 hours), the Ra—Ni was filtered off and the filtrate was concentrated under reduced pressure to give 150 g (>99% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D): 0.86 (t, J=4.5 Hz, 3 H), 0.88 (d, J=4.9 Hz, 3 H), 1.05–1.50 (m, 6 H), 1.10 (d, J=7.0 Hz, 3 H), 1.24 (t, J=7.2 Hz, 3 H), 1.87 (m, 1 H), 3.45 (s, 2 H) 4.08 (q, J=7.0 Hz, 2 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)Cl>[Br:27][C:13]1[O:12][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(-c2coc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
tert-butyl 4-{4-[4-(methylsulfanyl)phenyl]-1,3-oxazol-2-yl}piperidine-1-carboxylate (585 mg, 1.56 mmol) was dissolved in dichloromethane (15.6 mL) under argon atmosphere. N-bromosuccinimide (306 mg, 1.72 mmol) was added portionwise as a solid to the stifling solution. The resulting solution stirred at 25° C. for 6 hours. The solution was then diluted with chloroform and washed with aqueous sodium bisulfite. The organics were dried over sodium sulfate and concentrated in vacuo to yield 680 mg of the desired product as yellow oil. LCMS (M+1)=453.40