Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C@@H:5]([CH3:7])[C@H:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[S:3]1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22]([N:1]=[C:2]2[N:6]([C:22](=[O:23])[NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C@@H:5]([CH3:7])[C@H:4]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[S:3]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc([C@@H]2SC(=N)N[C@H]2C)cc1
Reactant: O=C=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc([C@@H]2SC(=NC(=O)NC3CCCCC3)N(C(=O)NC3CCCCC3)[C@H]2C)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
1.0 g of trans-2-imino-4-methyl-5-(4-methylphenyl)thiazolidine was dissolved in 20 ml of benzene. To the solution were added 1.3 g of cyclohexylisocyanate and one drop of triethylamine, respectively. The mixture was stirred for an hour at room temperature and refluxed for further an hour. The reaction solution was condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 1.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(O)C>[Br: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[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CCO
Product: Brc1cn2ccnc2c(N2CCOCC2)n1
Yield: 27.8 %

Procedure:
A solution of 1 g (3,6 mol) of 6,8-dibromoimidazo[1,2-a]pyrazine and 1 g (11.2 mmol) of morpholine in 15 ml of anhydrous ethanol is brought to reflux for 12 hours. After evaporation of the solvant and chromatography on an alumina column (eluant=CH2Cl2), 0.88 g (Yld=85%) of 6-bromo 8-morpholinoimidazo[1,2-a]pyrazine (m.p. 191° C.) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])[CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][O:10][CH2:9][C:8]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:7]=[CH:6][CH:5]=1)([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: COCC(C)(C)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of 1-bromo-3-(2-methoxy-1,1-dimethyl-ethyl)-benzene (1.62 g, 6.69 mmol) and trimethylsilylacetylene (1.2 mL, 8.7 mmol, 1.3 eq.) in MeCN-Et3N (50 mL, 7:3) was added Pd(PPh3)2Cl2 (0.23 g, 0.33 mmol. 0.05 eq.), CuI (0.038 g, 0.2 mmol, 0.03 eq.) and the mixture refluxed for 16 h. After cooling to ambient temperature and concentration under reduced pressure the residue was chromatographed (EtOAc-hexane, 2:98) to obtain 1.54 g (89%) of the desired product. NMR (DMSO-d6): 7.28-7.00 (m, 4H), 3.16 (s, 2H), 2.98 (s, 3H), 1.00 (s, 6H), 0.1 (s, 9H). MS (DCI): 261 (M+1).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:34])[C@H:24]([CH:26](C(C)(C)C)[C:27]([OH:29])=[O:28])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]([O:29][C:27](=[O:28])[CH2:26][C@@H:24]([C:23]([OH:22])=[O:34])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:19])([CH3:7])[CH3:3]
Reactant: COC(=O)[C@@H](N)C(C(=O)O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
N-(Toluene4-sulfonyl)-L-proline hydrate was coupled to β-tert-butyl L-aspartic acid methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared, via hydrolysis of the methyl ester using LiOH in THF/water, as a solid, mp=153-155° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.60 g), methyl 3-(2-hydroxyphenyl)propionate (0.345 g), anhydrous potassium carbonate (0.529 g) and N,N-dimethylformamide (7 mL) was stirred at room temperature for 18 hrs., and further at 70° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (0.61 g, 70%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:19][CH2:18]1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CN1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Methyl diethylphosphonoacetate (88.69 g, 0.422 mol) was added dropwise to a stirred suspension of sodium hydride (18.56 g, 60% dispersion in oil, 0.464 mol) in THF (300 ml) under nitrogen, at such a rate as to maintain the temperature below 30° C. The mixture was stirred for 1 h and a solution of N-methyl-4-piperidinone (47.71 g, 0.422 mol) in THF (150 ml) was added dropwise. The mixture was heated at 60° C. for 4.5 h before removing the solvent under vacuum and redissolving the residue in dichloromethane (300 ml) and water (200 ml). The dichloromethane phase was separated, washed successively with water (200 ml) and saturated sodium bisulphite solution (2×70 ml) and dried (MgSO4). The crude product was chromategraphed on silica gel, eluting with methanol/ether (5:95) to give the title-product (19.75 g, 28%). 1H NMR (250 MHz, CDCl3) δ (3H, s, N-CH3), 2.35 (2H, t, J=6 Hz, CH2), 2.40-2.50 (4H, m, 2 of CH2), 3.00 (2H, t, J=6 Hz, CH2), 3.70 (3H, s, CO2CH3), 5.65 (1H, s, vinyl CH).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14].[CH3:15][C:16]([CH3:18])=[O:17].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16](=[O:17])[CH3:18])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: CC(C)=O
Reactant: COCOc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
4-Methoxymethyloxy-3-methoxybenzaldehyde (1j, 2.30 g, 11.7 mmol) and acetone (19, 8.75 ml, 118.4 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.80 g, 20.0 mmol) and water (20 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from hexane to give 2.70 g (97%) of a white solid: mp 73-75° C.; 1H NMR: δ 2.34 (s, 3H), 3.48 (s, 3H), 3.89 (s, 3H), 5.24 (s, 2H), 6.58 (d, 1H, J=16.1 Hz), 7.07 (m, 2H), 7.13 (d, 1H, J=8.7 Hz), 7.43 (d, 1H, J=16.1 Hz); 13C NMR: δ 27.4, 55.9, 56.3, 95.2, 110.4, 115.9, 122.5, 125.7, 128.7, 143.1, 148.7, 149.8, 198.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([I:15])[C:5]2=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([I:15])=[C:5]2[O:16][CH2:23][CH3:24]
Reactant: COc1cc2[nH]c(C)c(I)c(=O)c2cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(I)c(C)nc2cc(OC)c(Cl)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 6-chloro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one (2.00 g, 5.72 mmol) in dimethylformamide (57 ml) was added potassium carbonate (1.58 g, 11.4 mmol) at room temperature. The resulting suspension was stirred 0.5 hours at 50° C. Ethyl iodide was added dropwise at room temperature, and the reaction mixture was stirred 8 hours at 50° C. The solvent was removed in vacuo and the resulting residue was resuspended in ethyl acetate and water. The organic layer was extracted with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.12 g (99% yield) of 6-chloro-4-ethoxy-3-iodo-7-methoxy-2-methylquinoline as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.40 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 4.02 (s, 3H), 2.92 (s, 3H), 1.61 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)C1C=CC=CC=1.CON(C)[C:14](=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C[Li]>>[CH2:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14](=[O:38])[CH3:3])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CON(C)C(=O)CCCCCCCCCCCCCCCOCc1ccccc1
Agent: [H-]
Agent: [Li]C
Agent: [Na+]
Product: CC(=O)CCCCCCCCCCCCCCCOCc1ccccc1

Procedure:
More specifically, compound (I) where R1, R3, R4, R5 are methyl groups, R2 is a hydroxyl group, m=1 and n=13 can be prepared in the following manner: Oxacycloheptadecan-2-one reacts with dimethylhydroxylamine in the presence of trimethylaluminium at 0° C. and at atmospheric pressure to yield N-methoxy-N-methyl-16-hydroxyhexadecanamide. The hydroxy function of this compound is then protected in the presence of sodium hydride and benzyl bromide at −78° C. and atmospheric pressure. The resulting N-methoxy-N-methyl-16-benzyloxyhexadecanamide is subsequently treated with methyllithium at −78° C. and at atmospheric pressure to yield 17-benzyloxyheptadecan-2-one. This reacts with the vinylmagnesium to afford 18-benzyloxy-3-methyloctadec-1-en-3-ol that in the presence of trimethylhydroquinone, zinc chloride and concentrated hydrochloric acid yields 2-(15-benzyloxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol. Catalytic hydrogenation of this compound in the presence of palladium on charcoal affords 2-(15-hydroxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol.
Reaction SMILES: [F:1][C:2]([CH:4](O)[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3].S(Cl)([Cl:14])=O>CCCCCC.CN(C)C=O>[F:1][C:2]([CH:4]([Cl:14])[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(F)C(O)C#CC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=C(F)C(Cl)C#CC(C)(C)C
Yield: 90.4 %

Procedure:
Ten grams (0.064 mole) of 2-fluoro-3-hydroxy-6,6-dimethylhept-1-ene-4-yne was dissolved in 100 ml of hexane, and to 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 11.42 g (0.095 mole) of thionyl chloride were added to the resulting solution. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 10.1 g of 2-fluoro-3-chloro-6,6-dimethylhept-1-ene-4-yne.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]1=2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]3=4)[CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1CNCCC1(O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methyl-piperidin-4-ol (1.0 g, 4.6 mmol) in DMF (10 mL) with triethylamine (1.75 mL, 12.54 mmol), was added 5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (1.38 g, 4.18 mmol) dropwise for over a period of about 1.5 hours at about 50° C. The reaction was stirred overnight at about 50° C. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel:chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield a brown solid of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H][H]>[Pd].CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Yield: 99.7 %

Procedure:
A mixture of 5.0 g (20.6 mmol) of tert-butyl 3-(3-methyl-4-cyanophenyl)acrylate (from Step A) and 500 mg of 10% palladium on carbon in 200 mL of EtOAc was stirred under 1 atm of hydrogen at rt for 16 h. The catalyst was removed by filtration. The filtrate was concentrated to afford 5.04 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.53 (s, 3H), 2.55 (t, J=7.6, 2H), 2.93 (t, J=7.6, 2H), 7.12 (d, J=7.8, 1H), 7.17 (s, 1H), 7.51 (d, J=7.8, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:25]>C(O)C.Cl>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:21][C:4]=2[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (9.995 g, 30.73 mmol) in ethanol (170 ml) to 60° C. Add to this a solution of tin (II) chloride (29.1 g, 153.67 mmol) in 5.0 N hydrochloric acid (170 ml). Heat the resulting mixture to reflux for 18 hours. Cool the reaction to room temperature and place in a freezer for 24 hours. Precipitate the product from the solution and collect by filtration to btain 2.253 g of the title compound (6.79 mmol, 22% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 296(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C[O-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22]Cl>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10]
Reactant: O=CNc1ccccc1O
Reactant: ClCOc1ccccc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=CNc1ccccc1OCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
N-(2-hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9% ethanol (65 ml). Sodium methoxide 7.0 g, 130 mmol) was suspended in 99.9% ethanol (70 ml) and added dropwise over 30 minutes. The resulting mixture was stirred for 30 minutes. 1-Bromo-2-chloromethoxybenzene (26.1 g, 119 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at reflux temperature for 2 h, and stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in toluene (500 ml) and washed with a saturated sodium carbonate solution (2×200 ml). The organic phase was dried (MgSO4) and evaporated. The residue was suspended in ethanol (40 ml), filtered and washed with ethanol (3×10 ml). After drying, this afforded the product, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g, 37%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H][H]>C(O)C.[Pt](=O)=O>[C:1]([N:11]1[CH2:18][C@@H:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CC(=Cc2ccc(Cl)cc2)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H](Cc2ccc(Cl)cc2)CN1C(=O)OCc1ccccc1
Reaction time: 0.13 h
Yield: 87.9 %

Procedure:
A solution of 5.3 g (0.014 mole) of N-carbobenzyloxy-4-[(4-chlorophenyl)methylene]-L-proline in 150 ml of ethanol is treated with 0.45 g of platinum dioxide and shaken on a Parr hydrogenator at a starting pressure of 15 lbs. (bottle gauge). The uptake of hydrogen is carefully monitored and whenever the pressure falls to 5 lbs the bottle is replenished with hydrogen to 15 lbs. A noticeable slowing down of the rate of hydrogen uptake is observed after eight minutes and the hydrogenation is interrupted after a total of ten minutes (21.5 lbs of hydrogen). The catalyst is filtered off (celite bed under nitrogen atmosphere), washed well with ethanol, and the combined filtrates are evaporated, finally at 0.2 mm, to yield 4.6 g of N-carbobenzyloxy-cis-4-[(4-chlorophenyl)methyl]-L-proline as a colorless brittle foam.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[C:6]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:1]2=[O:3])=[CH:12][CH:13]=1
Reactant: O=CO
Reactant: Fc1ccc(C2=CCCC2)cc1
Agent: OO
Product: O=C1CCCC1c1ccc(F)cc1
Temperature: 40 °C
Yield: 69.8 %

Procedure:
A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% hydrogen peroxide (23 mL, 149 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol) while stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the contents of the separatory funnel were vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol, 69.9% yield) as a colorless oil. LC-MS (M+H)+=177.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.12-7.18 (2H, m), 6.98-7.04 (2H, m), 3.29 (1H, dd, J=11.6, 8.5 Hz), 2.42-2.54 (2H, m), 2.27 (1H, ddd, J=19.1, 10.5, 8.9 Hz), 2.12-2.20 (1H, m), 2.01-2.12 (1H, m), 1.87-1.99 (1H, m).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[CH3:41])=[O:29].O>CN(C=O)C>[F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=2[CH3:41])=[O:29])=[N:6][N:7]=1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(CF)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (87 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered. Purified by reverse phase HPLC resulted product as a solid in (53.3 mg, 50% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71-7.53 (m, 7H), 7.26 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 5.34 (dd, J=12.0, 27.3 Hz, 1H), 5.18 (dd, J=12.3, 26.4 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:38][CH2:37][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH3:46].[ClH:48]>CN(C=O)C.C(OCC)C>[ClH:48].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:12]2[C:11]3([CH2:37][CH2:38][N:8]([CH2:45][CH3:46])[CH2:9][CH2:10]3)[O:15][C:14](=[O:16])[N:13]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:35][CH:34]=1
Reactant: CCBr
Reactant: CC(C)COc1ccc(CN2C(=O)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2Cc2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN1CCC2(CC1)OC(=O)N(Cc1ccc(OCC(C)C)cc1)C2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
69NLS77 (190 mg, 0.45 mmol) was N-BOC deprotected as described in the preparation of 69NLS79-II and dissolved in DMF (3 mL). Potassium carbonate (250 mg, 1.80 mmol) was added, followed by ethylbromide (50 μL, 0.45 mmol)) and the mixture stirred overnight at rt. Workup was carried out as for 69NLS79-II. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-6% methanol in dichloromethane, followed by repurification of the compound by acidic ion-exchange SPE cartridge, to give 38-PH20 (77 mg, 38%) as a colourless oil. The compound was converted to its hydrochloride form by treatment with 2M HCl in diethylether as described above, giving the salt as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[CH3:12][CH2:13][C:14](=O)[C:15](=[O:18])[CH2:16][CH3:17].C(O)C>S(=O)(=O)(O)O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:14]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH3:12])([O-:3])=[O:2]
Reactant: CCC(=O)C(=O)CC
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCC(=O)C(CC)=NNc1ccccc1[N+](=O)[O-]
Yield: 96.1 %

Procedure:
A mixture of 2-nitrophenylhydrazine (2.00 g), hexane-3,4-dione (1.80 g), sulfuric acid (2 drops) and ethanol (20 mL) was heated under reflux for 1 hr. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and dried to give the title compound (3.13 g, 96%) as brown crystals. melting point 96-97° C.