Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][NH:74][C@H:75]([CH3:82])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:24]([N:74]([CH3:73])[C@@H:75]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[CH3:82])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN[C@H](C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccccc1)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol), DiPEA (7.1 mL; 40 mmol) and acetonitrile:CH2Cl2 (1:1; 100 mL) followed by (R)-(+)-N,α-dimethylbenzylamine (2.0 mL; 13 mmol), then stirred overnight. After work up the crude product was purified by chromatography on silica gel with EtOAc to provide 6.0 g (91%) of the sub-title compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:4]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:9]1[C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:4]=[C:3]1[CH2:1][CH3:2]
Reactant: ClCCCCBr
Reactant: CCC1=COc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1=COc2ccccc2C(=O)N1CCCCCl
Reaction time: 0.5 h

Procedure:
430 mg of 4,5-dihydro-3-ethyl-1,4-benzoxazepin-5-one was dissolved in 10 ml of dimethylformamide, then 110 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 480 mg (1.2 equivalents) of 1-bromo-4-chlorobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH:27]1([O:33][C:34]([O:36][CH:37](Cl)[CH3:38])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:26])[C@@H:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:38][CH2:37][O:36][C:34]([O:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:35])=[O:13])(=[O:6])=[O:7]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Yield: 74.7 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.4 g, 1.0 mmol) dissolved in 5 mL of anhydrous toluene was reacted with 0.67 g (4.0 mmol) of 1-chloroethyl cyclohexyloxyformate in the presence of 0.55 g (2.0 mmol) of silver carbonate (Ag2CO3). After work-up, the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:4) as eluent to provide 0.41 g (71% yield) of the title compound (43a). Rf=0.40 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.25-1.58 (br. m, 9H), 1.73-1.78 (br. m, 2H), 1.88-1.95 (br. m, 2H), 2.24-2.31 (m, 2H), 3.20-3.25 (m, 2H), 3.63-3.66 (m, 2H), 3.84-3.85 (2s, 1H), 3.94-3.97 (2d, J=9.2, 8.8 Hz, 1H), 4.19-4.23 (2d, J=9.2, 8.8 Hz, 1H), 4.33-4.38 (2d, J=11.2, 11.6 Hz, 1H), 4.55-4.70 (m, 2H), 6.81-6.87 (m, 1H), 7.31-7.37 (m, 5H) ppm. MS (ESI) m/z 571.05 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([C@H:28]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35]C)=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Li+]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([C@H:28]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H]1CC[C@H](N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3S)-methyl 3-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)cyclopentanecarboxylate 42 (303 mg, 589 μmol) in 8:1 MeOH/H2O (18 ml) was added lithium hydroxide hydrate (49.5 mg, 1180 μmol). The reaction mixture was stirred for overnight at 55° C. Volatiles were removed by concentration under reduced pressure. The leftover residue was treated with 10 mL water and 10 mL of aqueous 10% HCl. A precipitate formed upon addition of the acid. After standing for 10 min the precipitate was filtered and washed with copious of amounts of water. After drying under vacuum, the precipitate was purified by injection as a solution in DMF on a reverse phase HPLC column using 5->95% CH3CN/0.1% aqueous TFA as eluant. Product 43 was isolated as white solid (250 mg). LCMS (ES) calcd for C29H29N3O3S 499.2 found 500.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[H-].[Na+].FC(F)(F)S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:6]([C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCOCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Br)ccc2n1CC(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a mixture of (5-bromo-1H-indol-2-yl)-morpholin-4-yl-methanone (6.64 g, 20 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (60% dispersion in oil, 979 mg, 24 mmol) in several portions. The mixture was stirred 15 min at room temperature then 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.16 g, 27 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was washed with hydrochloric acid (1N) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel with dichloromethane:ethyl acetate (98:2 to 94:6 v/v) as eluant, to give 4.65 g (58%) of the desired compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([C:15]1[C:16]([CH3:35])([CH3:34])[S:17](=[O:33])(=[O:32])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2F)([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].CN(C=[O:41])C.C(=O)([O-])[O-].[Cs+].[Cs+].CS(CCO)(=O)=O>CCOC(C)=O.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:36])[N:7]([C:15]1[C:16]([CH3:35])([CH3:34])[S:17](=[O:33])(=[O:32])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[OH:41])([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: CN(C)C=O
Agent: CS(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2O)CS(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of (R)-tert-butyl-N-(5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (1.00 g, 1.888 mmol) (prepared according to the procedure detailed in Intermediate 32, Step 1) in DMF (8 ml) 2-(methylsulphonyl)ethanol (0.49 g, 3.95 mmol) and cesium carbonate (1.28 g, 3.93 mmol) were added and the mixture was stirred overnight at rt. Additional Cs2CO3 (610 mg, 1 eq) and 2-(methylsulphonyl)ethanol (250 mg, 1 eq) were added and stirring continued for additional 2 hrs. The mixture was diluted with EtOAc and saturated ammonium chloride. Organic layer was separated and washed twice with water, then with brine and concentrated. The residue was purified by FC on 40 g RediSep Gold column using 5-100% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-hydroxy-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxylcarbonyl-carbamate (940 mg, 1.782 mmol, 94% yield). LC/MS (ESI+) m/z=550 (M+Na)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH2:4][CH2:3]1.[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24](Cl)=[O:25]>C(Cl)Cl>[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([NH:19][C:11]1[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=[C:9]([CH2:8][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH:10]=1)=[O:25]
Reactant: CN1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1I
Reaction time: 20 h

Procedure:
To a solution of 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)-benzenamine (0.274 g, 1 mmol) in CH2Cl2 (3 mL) at room temperature was added 3-iodo-4-methylbenzoyl chloride (0.267 g, 0.95 mmol). The mixture was allowed to stir for 20 h. The reaction was concentrated under reduced pressure, and purified via column chromatography (0 to 20% methanol in dichloromethane) to afford 3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide. MS m/z=518. Calc'd for C24H18ClF3N4O: 517.33.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([OH:11])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19][CH2:20]CCCCC>C(O)C.O>[C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: CCCCCCC
Reactant: O=C(O)C=C1C[C@H]2CCC[C@@H]12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=C1C[C@H]2CCC[C@@H]12
Temperature: 75 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
The compound of Example 5 (10.5 Kg; 69.0 mol) was dissolved in absolute ethanol (52.5 L) and 98 wt % sulfuric acid (0.525 Kg; 5.36 mol) was added at 20–25° C. The reaction mixture was then heated to 75° C. over 0.5 hours and stirred for 24 hours. The reaction mixture was cooled to 10° C. and a 40 wt % solution of sodium hydroxide (3.17 L) diluted with demineralised water (28.6 L) was added slowly to maintain the reaction temperature below 20° C. n-Heptane (31.5 L) was added and the phases were separated. The aqueous phase was then extracted again with n-heptane (31.5 L). The combined organic phases were washed twice with demineralised water (63.0 L, then 31.5 L). The organic phase was separated to give the title compound (11.1 Kg) in 89% yield as an organic solution which is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CCOCC.C([Mg]Br)C(C)C>[CH3:2][CH:3]([CH3:8])[CH2:4][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)[N:14]=1)[OH:16]
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)C[Mg]Br
Solvent: CCOCC
Product: CC(C)CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Prepared from 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (500 mg, 1.99 mmol) in Et2O (20 mL) and isobutylmagnesium bromide (1.1 mL of a 2M solution in Et2O, 2.2 mmol) according to the procedure used for the preparation of Intermediate 47 to give, after purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) the title compound as a white crystalline solid (215 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([Cl:28])=[C:26]([Cl:29])[N:25]=[C:24]([NH:30][CH3:31])[N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:33]>C(OC(=O)C)C>[ClH:28].[ClH:33].[ClH:28].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[C:27]([Cl:28])=[C:26]([Cl:29])[N:25]=[C:24]([NH:30][CH3:31])[N:23]=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9]1
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Yield: 99 %

Procedure:
4.88 g (10 mmol) trans-(4-{2-[4-(5,6-dichloro-2-methylamino-pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester was deprotected at 10° C. using 100 ml ethylacetate saturated with gaseous hydrochloric acid. After 4 hours the precipitate was filtered giving the title compound (4.9 g, 99%), melting at 325-326° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)[CH2:15][CH2:14]1>>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:23]=1
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCN3CCOCC3)c2)c(=O)[nH]1
Yield: 10.8 %

Procedure:
According to the same manner as that of Example 16 except that 1.09 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 1.68 g of 3-(2-morpholinoethoxy)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.27 g of 4-hydroxy-3-[3-[3-(2-morpholinoethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-39)] was obtained as a yellow crystal.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1O)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([CH:2]([NH2:1])[CH3:3])[CH2:13]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(N)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 43 (400 mg, 1.19 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred for 2 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethanamine (0.31 g, 77.5%) as a mixture of two diastereomers (45 and 46).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>ClCCl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:12](=[O:13])[CH2:11][Cl:10]
Reactant: O=C(Cl)CCl
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(CNC(=O)CCl)OC
Yield: 62.7 %

Procedure:
A mixture of 105.1 grams (g) (1.0 moles) of aminoacetaldehyde dimethyl acetal, 80 g (1.0 moles) of a 50% aqueous solution of sodium hydroxide, and 200 ml dichloromethane are placed in a 1 liter flask fitted with a stirrer and thermometer. To this is added 113.0 g (1.0 moles) of chloroacetyl chloride dropwise with rapid stirring at 0°-10° C. After the addition is complete, the reaction is allowed to rise to room temperature and is stirred for 1 hour. Next the mixture is washed with 100 ml water, 100 ml sodium carbonate solution and 100 ml water, followed by drying and evaporation to give 113.8 g (63% yield) of the title compound, m.p. 33°-36° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3].C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36]>ClCCl>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH:12][S:37]([C:32]2[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=2)(=[O:39])=[O:38])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)ccc1-c1cc(F)ccc1OC
Reaction time: 8 h

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])(=[O:12])=[O:11])=[CH:7][CH:8]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([NH:27][S:29]([CH3:28])(=[O:31])=[O:30])=[N:5][C:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])(=[O:11])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)n2)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NS(C)(=O)=O)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 5 %

Procedure:
To a mixture of (E)-3-methoxy-6-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-2-amine (333 mg, 0.84 mmol) in dry pyridine (20 mL) cooling on an ice bath methanesulfonyl chloride (0.3 mL, 2 mmol) was added dropwise. The mixture was stirred at room temperature for 20 hours. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:1 v/v) to afford 20 mg of the title compound as white powder. 1H-NMR (DMSO-d6): δ 3.26 (s, 3H, OCH3), 3.82 (s, 3H, CH3), 3.85 (s, 9H, 3×OCH3), 4.45 (s, 2H, CH2), 6.30 (s, 2H, Ph-H), 7.14 (d, 1H, J=15.6 Hz, CH), 7.15 (d, 1H, J=8.8 Hz, Py-H), 7.41 (d, 1H, J=8.4 Hz, Py-H), 7.56 (d, 1H, J=15.6 Hz, CH), 9.73 (s, 1H, NH).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:4]1([C@@H:7]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:8][OH:9])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC/C=C\CCl
Reactant: N[C@@H](CO)c1ccccc1
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.N1CCCCC1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:16]/[C:17]([OH:19])=[O:18])[S:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)cs1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C
Yield: 100 %

Procedure:
4-Bromothiophenecarboxaldehyde (2.5 g, 13.1 mmol) was placed in a 25 ml round bottomed flask and charged with piperidine (0.14 ml, 0.11 mmol) and pyridine (7.1 ml). Malonic acid was then added (2.21 mg, 21.2 mmol) and the reaction heated to 100° C. and maintained for 24 h. The reaction was then allowed to cool to room temperature and the solvent removed in vacuo. The remaining residue was acidified with concentrated HCl to pH 3 and the solid collected, filtered and washed with distilled water (20 ml). It was then air and oven dried to yield a yellow solid (3.04 g, 100%).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.OS(C(F)(F)F)(=O)=O>C1C=CC=CC=1>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([C:5]4=[O:12])[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccccc1
Product: O=C1C2CC3CC1CC(c1ccccc1)(C3)C2

Procedure:
Friedel Crafts reaction of benzene with 5-hydroxy adamantanone in presence of triflic acid over a period of about 1-4 h at reflux temperature to obtain 5-phenyl adamantan one.