Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C:20]4=[CH:19][CH:18]=[C:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].Cl>CC(=O)CC>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:28])[C@H:12]([C:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:27])[C:20]([CH2:25][C:24](=[O:26])[CH2:23][CH2:22]2)=[CH:19][CH:18]=3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CCC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 103.1 %

Procedure:
1.15 g of dehydrocholesterol was dissolved in 15 ml of 2-butanone, 0.34 g of aluminum isopropoxide was added, and the mixture was heated at reflux temperature for 75 mutes. After cooling on an ice bath, 15 ml of 2N hydrochloric acid was added, the phases were separated, and the organic phase was washed twice with 7.5 ml of 2N hydrochloric acid. The aqueous phase was extracted with toluene, and the combined organic phases were washed with water and brine, dried, and evaporated to yield 1.18 g of crude cholesta-5,7-diene-3-one as a viscous oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[C:21]([CH3:23])[N:20]=[C:19](Cl)[C:18]=4[CH3:25])[CH2:13][CH2:12]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:26][CH2:27][C@@H:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].[F-].[Cs+]>COCCOC>[CH3:46][C:43]([O:42][C:40](=[O:41])[C@H:28]([CH2:27][NH:26][C:19]1[C:18]([CH3:25])=[C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[N:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][NH:1]4)=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)[N:22]=[C:21]([CH3:23])[N:20]=1)[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: Cc1nc(Cl)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1nc(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Yield: 14.5 %

Procedure:
A mixture of 2.2 g (6.15 mmoles) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-2,5-dimethyl-4-chloro-pyrimidine and 2.17 g (7.38 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), is heated under reflux for 24 hours in the presence of 1.31 g (8.61 mmoles) of caesium fluoride, 383 mg (0.615 mmoles) of (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(0), in 55 ml of 1,2-dimethoxyethane. The reaction mixture is then returned to ambient temperature, 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(0) is added, then the reaction mixture is taken to reflux for another 24 hours. After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50). The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10. 550 mg (Yield=15%) of expected product is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[CH2:14]([O:21][C:22]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24](O)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:14]([O:21][C:22]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:12][CH3:13])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OC
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Anhydrous potassium carbonate (450 mg, 3.26 mmol) and dimethyl sulphate (0.25 ml, 2.64 mmol) were added to a suspension of methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (650 mg, 2.17 mmol) in acetonitrile (20 ml) and the mixture was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (20 ml). The organic material was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were evaporated in vacuo to afford methyl 4-benzyloxy-5-isopropyl-2-methoxybenzoate (644 mg, 95%) as a pale yellow solid. 1H NMR (DMSO-d6) 7.56 (1H, s), 7.50 (2H, d), 7.43 (2H, t), 7.37 (1H, t), 6.80 (1H, s), 5.26 (2H, s), 3.83 (3H, s), 3.75 (3H, s), 3.19 (1H, m), 1.17 (6H, d). MS: [M+H]+ 315.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:23]#[N:24])=[CH:13]2)[CH:6]=1)C.O1CCCC1.C(O)C.[OH-].[Li+]>O>[C:23]([C:14]1[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][N:12]([C:7]2[CH:6]=[C:5]([C:10]([OH:11])=[CH:9][N:8]=2)[C:4]([OH:25])=[O:3])[CH:13]=1)#[N:24]
Reactant: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1cn(-c2cc(C(=O)O)c(O)cn2)cc1-c1ccccc1
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a solution of 2-(3-cyano-4-phenylpyrrole-1-yl)-5-hydroxyisonicotinic acid ethyl ester (0.050 g) in a mixed solvent of tetrahydrofuran (3.6 mL) and ethanol (1.2 mL) was added 1 mol/L aqueous lithium hydroxide solution (1.2 mL) at room temperature, and this mixture was stirred at same temperature for 5 hours. This mixture was poured into water, this mixture was washed with diethyl ether. To this aqueous layer was added 1 mol/L hydrochloric acid (1.2 mL), and the precipitated solid was collected by filtration, and washed with water and n-hexane. This solid was dried under reduced pressure at 50° C. to give the title compound (0.030 g).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].CN(C1C=CC=CN=1)C.[CH:17]1([CH2:23][CH2:24][C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC.[K+].[Br-]>CN(C)C=O.C(N(CC)CC)C>[CH:17]1([CH2:23][CH2:24][C:25]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCC1CCCCC1)C1=C(O)COC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 2.0 g of tetronic acid in 40 ml of dry N,N-dimethylformamide was added (at 0° C.) 3.1 ml of triethylamine and 0.81 g of dimethylaminopyridine. After stirring for 5 minutes, 3.4 ml of 3-cyclohexylpropanoic acid was added, followed by 4.6 g of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. After 10 minutes the ice bath is removed and the mixture is allowed to stir overnight. The reaction mixture is quenched with 1N hydrochloric acid and the solution is washed 3 times with hexanes. The combined organic layers are combined, washed with brine, dried over magnesium sulfate and evaporated to give a yellow solid, which is recrystallized from hexanes to give light yellow crystals: m.p. 75°-78° C.; IR (KBr) 2910, 2820, 1750, 1640, 1600 cm-1 ; NMR (CDCl3) δ0.9-1.8 (11H, m), 2.9 (t, 2H, J=6 Hz), 4.7 and 4.5 (s, 2H (tautomers)); MS EI+ 238 Anal. Calc'd. for C13H18O4 : C, 65.53; H, 7.61 Found: C, 65.23; H, 7.74
Reaction SMILES: [OH-].[Na+].CS([C:6]1[N:11]=[CH:10][C:9]2=[CH:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:8]2[N:7]=1)=O.C(O)(=[O:25])C>O>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[N:8]2[C:9]([CH:10]=[N:11][C:6]([OH:25])=[N:7]2)=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1-c1ccc2cnc(O)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Into a 8-dram vial, 19.10 M of Sodium hydroxide in Water (10.0 mL, 191 mmol) and Water (10.0 mL) water were added. The mixture was heated at 100° C. 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (2.00 g, 6.96 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested no SM. The reaction was cooled to room temperature. Glacial acetic acid was added to adjust pH to 4. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and subsequently with Et2O. The resulting solid was dried under vacuum overnight to give 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a yellow solid (1.50 g, 85%). LCMS 242.15 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23]C(O)=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.O=C1N(C2[CH:48]=[CH:47][C:46]([CH2:49][C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:45][CH:44]=2)C(=O)C2C(=CC=CC=2)N1CC(O)=O.C1(N)CCCC1.ClC1C(OC)=CC(OC)=C(N)C=1>>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([C:23]3[CH:48]=[CH:47][C:46]([CH2:49][C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:45][CH:44]=3)[C:13]2=[O:27])[CH:7]=1
Reactant: O=C(O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: COc1cc(OC)c(Cl)cc1N
Agent: NC1CCCC1
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(-c3ccc(CC(=O)NCCc4ccccc4)cc3)c(=O)c3ccccc32)cc1Cl

Procedure:
This compound is made analogously to Example 1-2 by replacing {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (Intermediate A) with ({2,4-dioxo-3-[4-(phenethylcarbamoyl-methyl)-phenyl]-3,4-dihydro-2H-quinazolin-1-yl}-acetic acid) (Intermediate D) and by replacing cyclopentylamine with 5-chloro-2,4-dimethoxy-phenylamine to afford the title compound. The reaction is carried out using DMF as the solvent.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[N:11]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc(C)cc23)cc1
Yield: 35 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (50.3 mg, 0.16 mmol) in ethanolamine (1.5 mL) was heated to 140° C. in the microwave for 20 min. The reaction was then concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0-100%, EtOAc/hexanes, 20 min). 19.1 mg (35%) of the title compound was isolated: 1H NMR (DMSO-d6) δ 7.33 (d, 1 H), 7.21 (dd, 1 H), 7.04-7.10 (m, 2H), 6.86-6.92 (m, 2H), 6.57-6.62 (m, 1H), 5.44 (br s, 1H), 3.82-3.94 (m, 2H), 3.83 (s, 3H), 3.62-3.67 (m, 2H), 3.48 (s, 3H), 2.01 (s, 3H). HRMS (ES) calcd for C19H23N4O2 [(M+H)] 339.1816, found 339.1854.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[NH:13][CH:12]=1)=O.O.NN.[OH-].[K+].O>C(O)COCCO>[F:1][C:2]1[C:3]([CH2:9][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3cccs3)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1cccc(Cc2c[nH]c3ncc(-c4cccs4)cc23)c1F

Procedure:
To (2-fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0521, 50.0 mg, 0.15 mmol) in diethylene glycol (5.0 mL) were added hydrazine hydrate (1.0 mL, 0.020 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated in a CEM Discovery microwave instrument at 180° C. for 20 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0052, 10 mg, 20%). MS (ESI) [M+H+]+=325.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Yield: 93.7 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3-nitroaniline (0.070 g, 0.142 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.060 g, 0.133 mmol, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:21][C@@H:22]1[CH2:24][O:23]1>CN(C=O)C>[OH:23][C@H:22]([CH3:24])[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:13]#[N:14])=[N:8]1
Reactant: C[C@@H]1CO1
Reactant: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Yield: 96.8 %

Procedure:
5-nitro-1H-indazole-3-carbonitrile (600 mg, 3.19 mmol, Example 391E) was taken up in DMF (3 ml), and K2CO3 (580 mg, 4.20 mmol) and (R)-2-methyloxirane (1.85 ml, 26.4 mmol) were added. The reaction mixture was heated at 85° C. for 1 h. The reaction mixture was partitioned between half-saturated aq. NH4Cl solution and EtOAc. The organic layer was washed with half-saturated aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness. The crude material was purified by flash column chromatography eluting with 0-50% EtOAc/DCM. (R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (760 mg) was obtained as a colorless film.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1)[CH3:18]
Reactant: CCOC(=O)CCl
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (87 mg), ethyl chloroacetate (85 mg) and Cs2CO3 (375 mg) in acetone (4 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give (4-formyl-3,5-dimethyl-phenoxy)-acetic acid ethyl ester: MS (m/z) 237 (M+1); 1H NMR (CDCl3, 400 MHz) δ 10.48 (s, 1H), 6.59 (s, 2H), 4.66 (s, 2H), 4.29 (q, 2H), 2.60 (s, 6H), 3.29 (t, 3H).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C@@:4]12[C@H:13]3[CH2:14][CH:15]=[C:16]4[C@@H:21]5[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH2:25][C@:20]5([C:28]([OH:30])=[O:29])[CH2:19][CH2:18][C@@:17]4([CH3:31])[C@:12]3([CH3:32])[CH2:11][CH2:10][C@H:9]1[C:8]([CH3:34])([CH3:33])[C@@H:7]([OH:35])[CH2:6][CH2:5]2.O.ClCCl>C(OCC)C>[CH3:3][C@@:4]12[C@H:13]3[CH2:14][CH:15]=[C:16]4[C@@H:21]5[CH2:22][C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25][C@:20]5([C:28]([O-:30])=[O:29])[CH2:19][CH2:18][C@@:17]4([CH3:31])[C@:12]3([CH3:32])[CH2:11][CH2:10][C@H:9]1[C:8]([CH3:34])([CH3:33])[C@@H:7]([OH:35])[CH2:6][CH2:5]2.[Na+:2]
Reactant: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CC[C@]2(C(=O)[O-])CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1

Procedure:
A 10% aqueous solution of sodium hydroxide is added to an almost saturated solution of oleanolic acid in a water immiscible solvent, for example dichloromethane or diethyl ether. The volume of the sodium hydroxide solution is controlled by the amount of oleanolic acid taken; the final mixture should contain at least one, preferably 1,5 to 3, mole sodium hydroxide per mole oleanolic acid--a large excess of the sodium hydroxide solution may lower the yield. The mixture is mixed well (vigorous stirring or shaking) and the precipitated sodium oleanolate is separated. The sodium oleanolate can be recrystallised from aqueous organic solvents, preferably aqueous methanol or aqueous ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=3)[CH2:3][CH2:2]2)=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(NC2CCNCC2)nc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.2 %

Procedure:
A mixture of methyl 6-(4-piperidylamino)nicotinate (1.0 g), 4-chlorobenzoic acid (699 mg), HOBt (603 mg) and EDCI (693 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinate (1.21 g)
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([O:22][CH2:23][CH2:24][O:25][C:26]3[C:27]([N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:28][CH:29]=[CH:30][N:31]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[N:32]1([C:27]2[C:26]([O:25][CH2:24][CH2:23][O:22][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:21]=[CH:20]4)=[N:31][CH:30]=[CH:29][N:28]=2)[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Reaction time: 1 h

Procedure:
TFA (1.5 mL) was added to a solution of the product from Step 2 (112 mg, 0.22 mmol) in CH2Cl2(1.5 mL) at 0° C. and the mixture was stirred under inert atmosphere for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 2 M aqueous NaOH (×4) and brine. The organic layer was dried (MgSO4) and concentrated. The crude solid product (83 mg) was purified by column chromatography on silica using CHCl3/MeOH (9:1)+1% NH3 as eluent to give the title compound as an oil that solidified after repeated additions of pentane: yield 67 mg (75%); MS m/z 409 (M+H)+. Anal. (C21H24N6O3.0.6H2O.0.1C5H12) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)nc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C)cc(C)n2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4,6-dimethylpyridine*.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:45]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[CH3:55][NH:56][CH3:57]>C(N(CC)CC)C>[CH3:55][N:56]([CH3:57])[CH2:33][CH2:32][CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:29][CH:28]=1
Reactant: CNC
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCN(C)C)cc3)cc21

Procedure:
A solution of 0.21 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(toluene-4-sulphonyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.140 g of triethylamine and 1.892 g of dimethylamine (33% in ethanol) is stirred at room temperature for 3 days and then concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.49.
Reaction SMILES: [CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@H:18]4[O:23][P:21]([O-:24])(=[O:22])[O:20][C@H:19]4[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12.[Na+].[OH2:28]>>[CH:1]1[C:2]2[C@H:15]3[C@@H:16]([OH:26])[C@H:17]([OH:25])[C@@H:18]([OH:23])[C@@H:19]([O:20][P:21]([OH:24])([OH:22])=[O:28])[C@@H:14]3[NH:13][C:11](=[O:12])[C:3]=2[C:4]([OH:10])=[C:5]2[O:9][CH2:8][O:7][C:6]=12
Reactant: O=C1N[C@H]2[C@@H]3OP(=O)([O-])O[C@@H]3[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3
Reactant: O
Agent: [Na+]
Product: O=C1N[C@H]2[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3

Procedure:
Sodium pancratistatin 3,4-cyclic phosphate (5a, 0.0165 g, 0.04 mmol) was dissolved in water (1 ml) and eluted through a column containing Amberlite IR 120 (H+) resin. The uv active fractions were combined and freeze dried, 0.011 g, 69%, mp. 150° C. (dec). The material was found to be unstable and decomposed over several days. 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (s, 1H), 8.12 (s, 1H), 6.49 (s, 1H), 6.04-6.02 (m, 2H), 4.43 (m, 1H), 4.30 (m, 1H), 3.98-3.87 (m, 3H), 3.07-3.01 (m, 1H).