Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]3[CH2:20][CH2:19][N:18](CC=O)[CH2:17][CH2:16]3)=[N:12][C:11]=2[CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:6][CH:5]=1.CO>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:12][C:11]=2[CH2:24][O:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:6][CH:5]=1
Reactant: O=CCN1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc(-c2oc(C3CCNCC3)nc2COCC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 170 g (4.25 mol) sodium hydroxide in 250 mL of water is added to a stirred solution of 84 g (210 mmol) 1-(4-[5-(4-fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidin-1-ethanone, prepared as in Part D, in 1L of methanol. The mixture is stirred at 50° C. for 8 hours, cooled to 20° C., and stirred for an additional 12 hrs. The methanol is removed from the reaction mixture under reduced pressure, and the residue is diluted with 1 L water. The mixture is extracted with methylene chloride (3×300 mL). The layers are separated and 50 g of sodium chloride is added to the aqueous phase. The aqueous phase is extracted with methylene chloride (3×300 mL). The organic phases are combined, dried with anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure. The residue is dissolved in 200 mL of ethyl acetate and 600 mL of saturated sodium bicarbonate solution is added and the mixture is stirred at room temperature for 12 hours. The solid is filtered and washed three times with 200 mL of water, and with ether (3×50 mL). The product is dried under reduced pressure at 40° C. to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C@H:15]1[O:17][CH2:16]1>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C@@H:15]([OH:17])[CH2:16][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: NCCc1ccc(O)cc1
Solvent: CS(C)=O
Product: Oc1ccc(CCNC[C@H](O)c2cccc(Cl)c2)cc1

Procedure:
Thus, for the preparation of the amine starting material in Example 11 hereinafter, tyramine was reacted with (R)-m-chloro-styrene oxide in DMSO while heating to give (R)-m-chloro-[[(p-hydroxyphenethyl)amino]methyl]benzyl alcohol and the latter was etherified by reaction with 2-ethoxyethylmethanesulphonate to give (R)-m-chloro-α-[[[(p-(2 -ethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol, [α]20/D=-20° (c=0.5 in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].C[N+]1C=CN([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32])[CH:15]=2
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)c1
Yield: 56.4 %

Procedure:
The title compound (120 mg, 56% yield) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[C:21]=2[F:29])[N:17]=[C:16]([C:30]([OH:32])=O)[C:15]=1[Cl:33].[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41]>C1COCC1>[NH2:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[C:21]=2[F:29])[N:17]=[C:16]([C:30]([NH:41][O:40][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:34]2)=[O:32])[C:15]=1[Cl:33]
Reactant: NOC1CCCCO1
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NOC3CCCCO3)n2)c1F
Temperature: 23 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
1,1′-Carbonyl diimidazole (110 mg, 0.66 mmol, 1.1 equiv) was added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (200 mg, 0.60 mmol, 1.0 equiv) in THF (3.0 mL) at 23° C. The resulting off-white suspension was stirred at 23° C. for 30 min O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (85 mg, 0.72 mmol, 1.2 equiv) was added and the off-white suspension was stirred at 23° C. for 18 h. The reaction mixture was concentrated by a nitrogen stream, and the residue was directly subjected to silica gel column chromatography (5% methanol in chloroform) to afford a white powder (180 mg, 69%): mp 176-179° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.66 (t, J=8 Hz, 1H), 7.42 (dd, J=2, 8 Hz, 1H), 7.20 (d, J=2 Hz, 1H), 6.75 (br s, 2H), 5.01 (m, 1H), 4.05-3.90 (m, 4H), 3.50 (m, 1H), 1.77-1.66 (m, 3H), 1.60-1.47 (m, 3H); IR (neat film) 3325 (w), 3198 (w), 2946 (m), 2873 (w), 1682 (s), 1634 (s) cm−1; ESIMS m/z 430.3 ([M+H]+).
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](/[CH:17]=[CH:16]/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:3]([CH2:1][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:4][CH:5]=2)=[N:19]1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
(E)-4-Formyl-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}benzamide (60 mg, 0.16 mmol) was dissolved in dichloroethane (1.5 mL) and acetic acid (10 μL) and morpholine (22 μL) and sodium triacetoxyborohydride (104 mg, 0.49 mmol) were added thereto. The mixture was stirred at room temperature for 20 hours, added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain Compound 80 (21 mg, 30%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-])=O)=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.N1C=CC=CC=1C(O)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:19]1[CH:24]=[CH:23][C:22]2[C:25]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:31][C:21]=2[CH:20]=1
Reactant: Oc1cccc(-c2ccc3ccccc3n2)c1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Product: c1cc(Oc2ccc3c(c2)[nH]c2ccccc23)cc(-c2ccc3ccccc3n2)c1
Temperature: 85 °C
Yield: 101.1 %

Procedure:
3-(quinolin-2-yl)phenol (3.68 g, 15.30 mmol, 1.0 eq), 4′-iodo-2-nitrobiphenyl (5.97 g, 18.36 mmol, 1.2 eq), CuI (0.15 g, 0.77 mmol, 0.05 eq), picolinic acid (0.19 g, 1.53 mmol, 0.1 eq) and K3PO4 (6.50 g, 30.60 mmol, 2.0 eq) were added to a dry pressure vessel equipped with a magnetic stir bar. The vessel was evacuated and back-filled with nitrogen. The evacuation and back-fill procedure was repeated twice. Then solvent DMSO (32 mL) was added under nitrogen. After bubbling with nitrogen for 20 minutes, the mixture was heated to 80-90° C. in an oil bath. The reaction was monitored by TLC and about 22 hours later the starting material 3-(quinolin-2-yl)phenol was consumed completely. Then the mixture was cooled to ambient temperature and diluted with water, extracted with ethyl acetate three times. The combined organic layer was washed with water three times and dried over sodium sulfate, and filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product as a sticky brown liquid (5.98 g), which was used directly for the next step. A solution of PPh3 (11.19 g, 42.6 mmol) and the sticky brown liquid (5.95 g) obtained in the last step in 1,2-dichlorobenzene (28.4 mL) was stirred at a temperature of 175-185° C. in oil bath and for 21 hours under nitrogen, cooled and the solvent was removed by distillation under high vacuum. The residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product 2-(3-(quinolin-2-yl)phenoxy)-9H-carbazole, which was further purified through recrystallization in ethyl acetate and hexane to get pure product as a white solid (4.45 g) in 75% total yield for the four steps. 1H NMR (DMSO-d6, 400 MHz): δ 6.96 (dd, J=8.4, 2.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.21 (dd, J=8.4, 2.4 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.57-7.61 (m, 2H), 7.74-7.77 (m, 1H), 7.99-8.03 (m, 3H), 8.05-8.09 (m, 2H), 8.14 (d, J=5.6 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.46 (d, J=9.2 Hz, 1H), 11.23 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](O)[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:64]([OH:67])(=[S:66])[CH3:65]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:66][C:64](=[O:67])[CH3:65])[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)=S
Reactant: COc1ccc(COC(=O)C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-p-methoxybenzyloxycarbonylmethyl-4-hydroxypyrrolidine (1.40 g) and triphenylphosphine (1.18 g) were dissolved in 7 ml of dry tetrahydrofuran under nitrogen stream. To the resulting solution was added 783 mg of diethyl azodicarboxylate at 0° C., followed by stirring at the same temperature for 30 minutes. Thereafter, 342 mg of thioacetic acid was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give (2R,4S)-1-(p-nitrobenzyl-oxycarbonyl)-2-p-methoxybenzyloxycarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:32]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 2-chlorobenzoyl chloride (1.3 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at room temperature for 4 hours.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1/[C:21](/[Br:25])=[C:22](\[Br:24])/[CH3:23].N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3](/[C:21](/[Br:25])=[C:22](\[Br:24])/[CH3:23])=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: C/C(Br)=C(\Br)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: C/C(Br)=C(\Br)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 60 °C

Procedure:
To a stirred solution of 5-amino4-(E-1,2-dibromopropenyl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.06 g) in tetrahydrofuran (1.5 ml) was added t-butyl nitrite (0.05 ml). The reaction mixture was heated at 60° C. for two hours. The reaction mixture was then evaporated and the residue was purified by column chromatography on silica gel (5 g) eluted with hexane: dichloromethane (100:0 to 20:70). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 134-135° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Cn1nccc1CCO
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (3.70 mL, 18.77 mmol) was added to 4-(1-(3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol (6.2 g, 17.06 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (2.368 g, 18.77 mmol) and triphenylphosphine (4.92 g, 18.77 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 1 day. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford crude product. Product was dissolved in DCM (100 mL) and washed with 2M NaOH (100 mL) twice. Organic layer was evaporated to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (4.95 g, 61.5%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([CH3:32])[C:7](=[O:31])[C@@H:8]([N:20]([CH2:28][CH:29]=C)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.C[N+]1([O-])CC[O:41]CC1.S(=O)(O)[O-].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.[Os](=O)(=O)(=O)=O.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([CH3:32])[C:7](=[O:31])[C@@H:8]([N:20]([CH2:28][CH:29]=[O:41])[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc2ccccc2c1)C(=O)N(C)Cc1ccccc1OC
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccc2ccccc2c1)N(CC=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Combine (S)-N-(2-methoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-allylamino]-3-(naphth-2-yl)-propionamide (0.46 g, 0.96 mmol), N-methylmorpholine-N-oxide (0.12 g, 1.06 mmol), acetone (20 mL), and water (10 mL). Add osmium tetraoxide (0.50 mL, 0.04M in THF, 0.02 mmol) and stir under an inert atmosphere for 18 hours. Pour the reaction mixture into a saturated solution of sodium bisulfite and extract the intermediate diol into ethyl acetate. Dry the separated organic layer over MgSO4, filter, and evaporate in vacuo to give the crude diol which is taken on to the next step without further purification. Dissolve the crude diol in chloroform (10 mL). Add a solution of lead tetraacetate (0.46 g, 1.06 mmol) in chloroform (10 mL). Stir for 30 minutes and then pour the reaction mixture into a saturated solution of sodium bicarbonate. Extract with dichloromethane and separate the organic layer. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo to give the title compound which may be used without further purification.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.CO>CO>[CH3:3][CH:2]([CH3:4])[C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.9 %

Procedure:
To a stirred mixture of tert-butyl 4-isobutyrylpiperazine-1-carboxylate (6.8 g, 26.5 mmol) in methanol (15 mL) was added hydrochloride/methanol (30 mL, 3M)) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give 2-methyl-1-(piperazin-1-yl)propan-1-one (5.5 g, yield 100%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.99-1.00 (d, J=6.4 Hz, 6H), 2.84-2.89 (m, 1H), 3.03-3.07 (d, 4H), 3.68-3.74 (d, 4H), 9.58 (s, 2H); LC-MS (ESI) m/z: 157(M+1)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]>CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reaction time: 8 h

Procedure:
1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc'd. for C12H16N2O—204.27.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:25]=1)=[C:8]([CH2:22][CH2:23][CH3:24])[CH:9]=[C:10]1[C:15]=2[O:14][CH2:13][C:12]2[CH:16]=[C:17]([O:20]C)[CH:18]=[CH:19][C:11]1=2.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:22]([C:8]1[CH:9]=[C:10]2[C:15](=[C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:25][C:7]=13)[O:14][CH2:13][C:12]1[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:11]2=1)[CH2:23][CH3:24]
Reactant: CCCc1cc2c(c3ccc(OC)cc13)OCc1cc(OC)ccc1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1cc2c(c3ccc(O)cc13)OCc1cc(O)ccc1-2
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a mixture of 2,8-dimethoxy-12-propyl-6H-dibenzo[c,h]chromene (220 mg, 0.658 mmoles) in CH2Cl2 (33 ml) at 0° C. was slowly added boron tribromide (3.95 ml of 1 N solution in CH2Cl2, 3.95 mmols). The reaction mixture was stirred at 0° C. for 3 h. 4 ml water was injected into the mixture with stirring in an ice-water bath. CH2Cl2 in the mixture was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and stripped of solvent to give 120 mg (60%) of the title compound as white solid. The analytical sample was obtained by purification with silica column chromatography (20%-30% ethyl acetate—hexane) and then recrystalliazation with ethyl acetate—hexane: mp 86-95° C.; 1H NMR (DMSO-d6): δ 1.00 (3H, t, J=7.24 Hz), 1.63-1.76 (2H, m), 2.87 (2H, t, J=7.22 Hz), 5.16 (2H, s), 6.69 (1H, d, J=2.28 Hz), 6.79 (1H, dd, J=8.39 Hz, J=2.28 Hz), 7.03 (1H, dd, J=9.02 Hz, J=2.18 Hz), 7.20 (1H, d, J=2.10 Hz), 7.60 (1H, s), 7.62 (1H, d, J=7.85 Hz), 7.99 (1H, d, J=9.01 Hz), 9.61 (1H, s), 7.76 (1H, s); MS (ESI) m/z 305 (M−H)−, 307 (M+H)+; HRMS: calcd for C20H18O3, 306.1256; found (ESI),305.11827.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:17])(=O)=O.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:17][N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: O=C1CC(c2ccccc2)CN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CC(c2ccccc2)CC1=O
Temperature: 36 °C
Reaction time: 5 h

Procedure:
A mixture of 4-phenyl-pyrrolidin-2-one (32.2 g; 0.2 mole), dimethyl sulfate (37.8 g; 0.3 mole), tetrabutyl ammonium hydrogensulfate (3.4 g; 0.01 mole), 50% aqueous sodium hydroxide solution (100 ml) and toluene (200 ml) is stirred at 36° C. for 5 hrs. After cooling, the aqueous phase is decanted, extracted with methylene chloride, and combined with the toluene phase. The organic phase is washed with water, dried and evaporated. The residue is distilled: b.p.0.2 mm Hg =120° C. Yield: 79%.
Reaction SMILES: C([N:4]([CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH:10]1[CH2:24][F:25])[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)CC=C)C=C.N12CCN(CC1)CC2.O>C(O)C.C(Cl)(Cl)Cl.CO>[NH2:4][CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH:10]1[CH2:24][F:25])[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3
Reactant: C=CCN(CC=C)CC1Oc2c(cc(C)c3[nH]c(=O)ccc23)C1CF
Agent: C1CN2CCN1CC2
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2CF
Yield: 56.8 %

Procedure:
2-Diallylaminomethyl-3-fluoromethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (609.8 mg, 1.78 mmol) was dissolved in ethanol (50 ml). To the solution, Wilkinson catalyst (100.0 mg, 0.108 mmol), 1,4diazabicyclo[2,2,2]octane (100.0 mg, 0.891 mmol) and water (10 ml) were added, and the mixture was refluxed with heat for 90 minutes. The reaction mixture was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: saturated ammonia--methanol=50:1). Pale yellow crude crystals were obtained. The crude crystals were dissolved in a solvent mixture of chloroform and methanol (4:1), to which 1.37N-HCl--methanol solution (1.0 ml, 1.37 mmol) was added. The resultant mixture was condensed under reduced pressure, then subjected to azeotropic distillation along with methanol (twice). The residue was recrystallized from methanol--ethanol--ether. 265.0 mg of the title compound was obtained as pale yellow powdery crystals (49.8%).