Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH:37](O)[CH2:38][CH2:39][CH3:40])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1.[ClH:42].[O:43]1CCOCC1>CCOCC>[ClH:42].[OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:43])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[CH2:6][CH2:7]1
Reactant: C1COCCO1
Reactant: CCCC(O)CCOc1ccccc1C1(O)CCN(CCC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCCCCO)CC1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
In 50 mL of anhydrous ether was dissolved 500 mg (0.9 mmol) of 4-(4-hydroxy-4-(2-(3-hydroxyhexyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 35). To the resulting solution was added 0.4 mL of a 4N solution of hydrochloric acid and dioxane under ice cooling and stirring. The white precipitate thus formed was collected by filtration, washed with ether and dried, whereby 460 mg (yield: 86.3%) of 4-(4-hydroxy-4-(2-(6-hydroxyhexyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide hydrochloride (Compound No. 37) was obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1>CC(O)C.CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]5[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=5)[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: OCc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)cc1
Yield: 29 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 12 h), using 150 μmol (4-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 29% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:2]=12.O>COCCO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:2]12
Reactant: CC(C)(C)OC(=O)N1Cc2cccnc2C1
Agent: [Pd]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCCNC2C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
To a solution of tert-butyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (1.50 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2. The resulted mixture was cooled to rt, poured into 100 mL of water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as pale yellow oil (0.95 g, 65.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:24]
Reactant: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20-25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20-25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:32]Br>C(Cl)Cl>[Br:32][C:6]1[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[N:8][C:9]([NH:11][CH3:12])=[N:10][C:5]=1[NH:4][CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1]
Reactant: BrBr
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)nc(NC)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2nc(NC)nc(NCC(C)(C)C)c2Br)c1

Procedure:
3-[6-(2,2-Dimethyl-propylamino)-2-methylamino-pyrimidin-4-ylamino]-4,N-dimethyl-benzamide (35 mg), aq. sat. sodium bicarbonate (0.05 mL) and bromine (21 mg) were stirred in methylene chloride (1 mL) at room temperature for overnight. The product (4 mg) was purified with preparative thin layer chromatography. MS (m/z): 435 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]3[CH2:14][CH2:15][CH2:16][C:17](=O)[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N:25]=[C:26]=[N:27][Si](C)(C)C)(C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]3[CH2:14][CH2:15][CH2:16]/[C:17](=[N:27]\[C:26]#[N:25])/[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CCCc2sc(-c3cccc(C(F)(F)F)c3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CCCc2sc(-c3cccc(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-(3-(Trifluoromethyl)phenyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-one (0.252 g, 0.85 mmol) was dissolved in dichloromethane (2 mL). Titanium tetrachloride (1.7 mL, 1.0 M solution in dichloromethane, 1.7 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. Bis-trimethylsilylcarbodiimide (0.42 mL, 1.87 mmol) was then added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured onto ice/water and the product was extracted with dichloromethane. This was back extracted with water and saturated sodium carbonate (aq.) solution. The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give the title compound as a cream solid (0.27 g, 99%).
Reaction SMILES: [NH2:1][C:2](=[N:22][OH:23])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33](O)=O)[CH:30]=[CH:29][C:28]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]>>[CH3:18][O:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:19]=[CH:20][CH:21]=[C:3]([C:2]2[N:1]=[C:33]([C:31]3[CH:30]=[CH:29][C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[C:27]([CH2:26][O:25][CH3:24])[CH:32]=3)[O:23][N:22]=2)[CH:4]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COCCN(Cc1cccc(C(N)=NO)c1)C(=O)OC(C)(C)C
Product: COCCN(Cc1cccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 70 (194.03 mg; 0.60 mmol) and Intermediate 28 (161.47 mg; 0.63 mmol), the crude mixture was purified by flash chromatography (C-hex/(DCM/EtOAc 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.45 (d, J=1.4 Hz, 1H), 8.17 (dd, J=7.8, 1.7 Hz, 1H), 8.11-8.08 (m, 2H), 7.48 (t, J=7.7 Hz, 1H), 7.41-7.23 (m, 5H), 7.13 (d, J=7.3 Hz, 1H), 4.63-4.60 (m, 2H), 4.23 (s, 2H), 3.54-3.33 (m, 10H), 2.08 (s, 3H), 1.49 (br s, 9H).). LC/MS (Method B): 544.5 (M+H)+. HPLC (Method A) Rt 6.61 min (Purity: 99.5%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11]Cl)[N:8]=[C:5]2[S:6][CH:7]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O-:19])=[CH:15][CH:14]=1.[Na+]>C1COCC1>[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11][O:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)[N:8]=[C:5]2[S:6][CH:7]=1
Reactant: Cc1csc2nc(CCl)cn12
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc2nc(COc3ccccc3)cn12
Yield: 107.4 %

Procedure:
3.4 g of 3-methyl-6-chloromethyl-imidazo-(2,1-b)thiazole hydrochloride, prepared as described in Example 27, is introduced with stirring into a cooled solution of 3.5 g of sodium phenate in 100 ml of THF. After about 1 hour the sodium chloride which precipitates is filtered off, the solvent is evaporated and acidic water is added to the residue. The aqueous solution is extracted, at pH 3-6, with chloroform. The pH is then raised to 7-7.5 and the aqueous solution is again extracted with chloroform. This extract is dried and the solvent is then evaporated to yield 4 g of 3-methyl-6-phenoxymethyl-imidazo-(2,1-b)thiazole; m.p. 190°-192° (methyl-ethyl-ketone).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:27])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.9 %

Procedure:
An 8 mL vial is charged with N-[5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.044 g, 0.11 mol), (2-fluorophenyl)boronic acid (Combi-Blocks, 28 mg, 0.2 mmol), Na2CO3 (0.032 g, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) and isopropanol-water (1 mL, 3:1). The reaction mixture is stirred at 80° C. for 16 hr, then cooled, concentrated, taken into EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (25.4 mg, 55% yield). LCMS m/z=456.5 [M+H]+, tR=2.69 min. (compound same as Example 83)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=2)[CH:7]=1.[CH3:33][NH2:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:34][CH3:33])[CH2:13][C:12]=3[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=2)[CH:7]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3cc(Cl)ccc3OC)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.067 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.148 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 169-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C1(C)C(C)=CC=CC=1>[C:2]1([NH:1][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: O=C(O)c1cccnc1Nc1ccccc1

Procedure:
50 ml of distilled aniline and 43.2 g of 2-chloronicotinic acid are mixed in 126 ml of xylene. The mixture is brought to reflux for 4 hours. It is allowed to cool and the precipitate is filtered off and washed several times with water.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH2:11][CH2:12][CH2:13]Cl)=[CH:6][CH:5]=1.C(O)(=O)C>O>[CH:11]1([C:10]([C:7]2[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=2)=[O:15])[CH2:13][CH2:12]1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Yield: 119.9 %

Procedure:
Sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over a period of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w), 177 mL). Additional para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol) was added portionwise to the reaction mixture, followed by solid sodium hydroxide (40.4 g) resulting in the formation of a yellow precipitate. After refluxing for 60 minutes, water (50 mL) was added and the resulting mixture was refluxed for another 60 minutes, allowed to cool to ambient temperature, diluted with water (100 mL) and neutralized with acetic acid. The precipitate was collected by filtration, washed with water, air-dried, and triturated at 40° C. with chloroform (1.5 L). The chloroform solution was dried (MgSO4), filtered, and concentrated. The residue was crystallized from chloroform/hexanes to provide 26.65 g (95%) of the title compound.
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[N:12]([CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:13](=[O:32])[CH2:14][C:15]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=2[S:17](=[O:31])(=[O:30])[N:16]=1)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH3:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][N:12]1[C:13](=[O:32])[C:14]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)=[C:4]([OH:5])[CH:6]2[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCC21
Temperature: 60 °C
Reaction time: 13 h
Yield: 34.6 %

Procedure:
To a solution of cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclohexanecarboxylic acid ethyl ester (138.7 mg, 0.243 mmol) in absolute ethanol (10 mL) was added a 21% w/w solution of sodium ethoxide in ethanol (0.91 mL, 2.44 mmol). After stirring at 60° C. for 13 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-100% ethyl acetate in hexanes) to afford the desired product, N-{3-[2-(3,3-dimethylbutyl)-5-hydroxy-3-oxo-2-aza-bicyclo[4.4.0]dec-4-en-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (44.3 mg, 0.084 mmol, 35%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (9H, s), 1.10-1.87 (9H, m), 2.32 (1H, bs), 3.04 (3H, s), 2.92-3.82 (4H, m), 7.47-7.58 (3H, m), 10.13 (1H, bs). LC-MS (ESI) calcd for C23H32N4O6S2 524.18, found 525.3 [M+H+]. Anal. calcd for C23H32N4O6S2: C, 52.65; H, 6.15; N, 10.68; S, 12.22, found C, 52.56; H, 6.10; N, 10.71; S, 12.16.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH:23][C:35](=[O:36])[C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:38]([CH3:40])[CH3:39])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:30]([NH2:32])[CH3:31]>O1CCOCC1>[CH2:30]([NH:32][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[CH:27][CH:28]=1)[CH3:31]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(NC(=O)C3CCOCC3)cc2)cc1
Solvent: C1COCCO1
Product: CCNCCOc1ccc(NC(=O)C2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
4′-[2-(p-Toluenesulfonyloxy)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (1.7 g) solution in dioxane (20 ml) was added with 70% ethylamine aqueous solution (1.63 ml) and stirred for 6 hours at 90° C. The reaction mixture was concentrated under vacuum and dissolved into 2N HCl (20 ml). This solution was washed with ethyl acetate (20 ml) two times. Aqueous layer was neutralized with 2N sodium hydroxide (20 ml). Solid formed was extracted with ethyl acetate (50 ml), washed with water and then dehydrated with anhydrous magnesium sulfate. After filtration, filtrate was concentrated under vacuum and purified with silica-gel column chromatography to obtain 4′-[2-(ethylamino)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (0.77 g) as white solid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]2[O:17][C@@H:11]2[C@@H:10]1[C:18]1[C:19](C(OC)=O)=[C:20]([O:27]CC2C=CC=CC=2)[C:21]2[O:25][CH2:24][O:23][C:22]=2[CH:26]=1)=[O:7])(C)(C)C.C([O-])(=[O:46])C1C=CC=CC=1.[Na+]>O>[CH:26]1[C:18]2[C@H:10]3[C@@H:11]([OH:46])[C@H:12]([OH:17])[C@@H:13]([OH:16])[C@@H:14]([OH:15])[C@@H:9]3[NH:8][C:6](=[O:7])[C:19]=2[C:20]([OH:27])=[C:21]2[O:25][CH2:24][O:23][C:22]=12
Reactant: O=C([O-])c1ccccc1
Reactant: COC(=O)c1c([C@@H]2[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](O)[C@@H]3O[C@@H]32)cc2c(c1OCc1ccccc1)OCO2
Agent: [Na+]
Solvent: O
Product: O=C1N[C@H]2[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3
Temperature: 100 °C
Reaction time: 144 h
Yield: 1550.6 %

Procedure:
A suspension of epoxide 16 (109 mg, 0.21 mmol) and sodium benzoate (1 mg) in water (8 ml) was stirred at 100° C. for 6 days. The mixture was then concentrated and subjected to chromatography (CHCl3 /CH3OH, 4:1) to afford 35 mg (51%) of pancratistatin. 1H NMR (400 MHz, DMSO-d6) ε 13.06 (s, 1H), 7.51 (s, 1H), 6.48 (s, 1H), 6.05 (d, J=1.0 Hz, 1H), 6.02 (d, J=1.0 Hz, 1H), 5.35 (bs, 1H), 5.04 (bs, 2H), 4.84 (bs, 1H), 4.27 (bs, 1H), 3.95 (bs, 1H), 3.84 (bs, 1H), 3.74 (m, 2H), 2.96 (d, J=11.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[OH:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of silyl alcohol (Step V) (1.2 g) in THF (10 mL) and acetic acid (0.3 mL) was added tetrabutylammonium fluoride (3 mL of 1M solution). The reaction mixture was stirred 2 hrs, quenched with pH 7 buffer, extracted with ethyl acetate and the organic extract dried and evaporated. Flash chromatography using 25% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[C:21]([CH3:26])=[CH:22][N:23](C)C)=[CH:16][CH:15]=3.O.[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:34][N:23]=[CH:22][C:21]=1[CH3:26])=[CH:16][CH:15]=3
Reactant: NN
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 40 above, using 3-(2,4-dichlorophenyl)-6-(3-dimethylamino-2-methylacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from preparation 1.13 above and hydrazine hydrate.