Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[C:22]([O:34][CH3:35])[CH:21]=4)C=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1>CS(C)=O>[NH2:13][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[S:18][C:17]=1[C:16]([NH:15][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:22]([O:34][CH3:35])[CH:21]=1)=[O:19]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2N)ccc1OCCN1CCCC1

Procedure:
Aqueous NaOH (4 mL, 1N) was added to a DMSO solution of 6-(4-chlorophenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl] thieno[3,2-d]pyrimidin-4(3H)-one (0.50 g, 0.001 mol) at 170° C. After 5 minutes a gummy precipitate was triturated with water and solidified to a tan solid (0.30 g, 60%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25]>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C@@H:23]([CH3:22])[C:24]([F:27])([F:26])[F:25])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: CC(N)C(F)(F)F
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)cn1
Yield: 61 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR AB146651) instead of L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR F07820EFA), to the title compound (81 mg, 61%) which was obtained as a light yellow oil after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=384.3 [M−H]−.
Reaction SMILES: [H-].[Na+].[Na].[C:4](#[N:10])[CH:5]([CH2:7][C:8]#[N:9])[OH:6].Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1>[Cu]Br.CN(C=O)C.C(O)(C)C>[S:14]1[CH:15]=[CH:16][C:12]([C:5]([CH2:7][C:8]#[N:9])([OH:6])[C:4]#[N:10])=[CH:13]1
Reactant: N#CCC(O)C#N
Reactant: Brc1ccsc1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: N#CCC(O)(C#N)c1ccsc1
Reaction time: 0.08 h

Procedure:
To 157.5 ml anhydrous i-propanol and 17.5 ml DMF, kept under N2 atmosphere, were added while stirring at 20°-35° C. 0.2 mole NaH and then, after the sodium isopropylate had been precipitated, 0.2 mole malonitrile. Within 5 minutes thereafter 0.1 mole copper (I) bromide and 0.1 mole 3-bromothiophene were added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester as a light yellow oil, MS: 405 (M, 1Cl).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([CH3:20])([S:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:5]>CC(O)=O.[Fe]>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[S:6][C:4]([CH3:20])([CH2:3][CH2:2][Cl:1])[CH3:5])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(SC(C)(C)CCCl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(SC(C)(C)CCCl)c(N)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-(4-chloro-2-methylbutan-2-ylthio)-3-nitrobenzoate (3.43 g, 10.8 mmol) in AcOH (100 mL) was added iron (2.413 g, 43.2 mmol). The reaction was heated to 70° C. and stirred at that temperature for 2 hours. The solvent was removed under reduced pressure and the resulting paste was diluted with H2O (250 mL). The solution was treated with K3PO4 until pH=6. The aqueous layer was extracted with EtOAc (3×150 mL). The combined organics were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL) then dried over Na2SO4 and concentrated in vacuo. The product was isolated as a brown solid and used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:18]([O-])=[O:19].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>Cl.O>[N:1]1([CH2:7][CH:8]2[N:13]([N:18]=[O:19])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NC(CN1CCOCC1)CO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=NN1c2ccccc2OCC1CN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (-)-3-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in 250 ml of 2N aqueous hydrochloric acid was cooled to 0° C. and treated with a solution of 4.8 g (0.070 mole) of sodium nitrite in 50 ml of water. The solution was stirred for one hour at 0° C., poured into a mixture of 1500 ml of water and 1 liter of ethyl acetate and neutralized carefully by the addition of solid sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with an additional 400 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and taken to dryness to give (-)-3-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:26])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Yield: 45.8 %

Procedure:
To a dichloromethane solution (92 mL) of tert-butyl 4-[5-(4-chlorobenzyl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl]piperazine-1-carboxylate (9.20 g, 22.7 mmol) synthesized in Reference Synthesis Example 8, trifluoroacetic acid (40 mL) was added and the resultant solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and pH was adjusted to 7 by adding water and saturated sodium bicarbonate aqueous solution. Extraction with ethyl acetate from the resultant liquid was performed three times, and the organic layer was washed with brine. A deposited solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to obtain the title compound (3.18 g, yield 46%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][CH:32]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:13]=2[C:26]([O:28]CC)=[O:27])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:35][CH:36]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:13]=2[C:26]([OH:28])=[O:27])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(C(c2ccc(OCOC)cc2)c2ccc(OCOC)cc2)c2ccccc2n1CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Yield: 63.6 %

Procedure:
The crude ethyl 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylate (16.4 g, approximately 27.0 mmol) obtained in Example 47 was dissolved in 100 ml of ethanol, and a 2N aqueous sodium hydroxide solution (40 ml) was added thereto, followed by heating under reflux for 3 hours. The solvent was distilled off under reduced pressure, water was added to dissolve the residue, and the pH of the solution was adjusted to 5 by adding 2N hydrochloric acid, followed by extraction with chloroform. The resulting organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 14.4 g of a crude product. The obtained crude product was crystallized from ethyl acetate to give 8.9 g (yield: 64%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:10][CH2:9][S:8][C:7]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCN1CCCC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.54 g, 1.980 mmol) in dry acetonitrile (20 mL) was treated with pyrrolidine (1.637 mL, 19.80 mmol), potassium carbonate (2.74 g, 19.80 mmol), and potassium iodide (0.657 g, 3.96 mmol) at room temperature. The resulting mixture was stirred at 60° C. overnight (18 hours). The reaction was brought to room temperature and diluted with water (50 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by flash column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2) to obtain the title product (0.57 g, 94%) as a syrup. 1H NMR (DMSO-d6) δ 7.84-7.80 (m, 2H), 6.87 (d, 1H, J=9.6 Hz), 3.79-3.75 (m, 2H), 3.49 (t, 2H, J=6.9 Hz), 3.08-3.05 (m, 2H), 2.44-2.40 (m, 6H), 1.76-1.69 (m, 6H); ESI-MS (m/z, %): 308 (MH+, 100).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[Cl-].[Na+]>O.OC1CC(C)(C)[NH+]([O-])C(C)(C)C1>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: COC(CN)OC
Reactant: C=CC(=O)Cl
Agent: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CC(=O)NCC(OC)OC
Temperature: 0 °C
Yield: 81.7 %

Procedure:
40 g (1.0 mol) of sodium hydroxide are dissolved in 100 g of water and 200 g of ice in a 1-litre reactor having a stirrer and a cooling system. The sodium hydroxide solution is cooled to 10° C., and 105.1 g (1.0 mol) of aminoacetaldehyde dimethylacetal and 10 mg of the inhibitor 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxide are added. 99.5 g (1.1 mol) of acrylic acid chloride are slowly added to that solution at 10° C. over a period of 2 hours. The pH value drops slowly and ultimately is adjusted to 7. According to GC, amine is no longer present. The reaction mixture is saturated with sodium chloride and extracted three times with 200 ml of tert-butyl methyl ether. The organic phase is dried, filtered and concentrated using a rotary evaporator. The resulting oil is extracted three times with petroleum ether and then dried again using a rotary evaporator. 130 g of acrylamidoacetaldehyde dimethylacetal (81% of theory) are obtained in the form of an oil; the product is 99% according to GC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 33.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.2 g), 1-(4-chlorophenyl)-N-[3-cyano-4-(4-morpholinopiperidin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide (1.3 g) was obtained, melting point: 249–250° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[BrH:10]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:10])=[N:4][CH:5]=1
Reactant: OCc1ccc(Br)cn1
Reactant: Br
Product: BrCc1ccc(Br)cn1
Temperature: 150 °C
Yield: 87 %

Procedure:
Dissolve 2-hydroxymethyl-5-bromopyridine (5.21 g, 27.7 mmol) in 48% aqueous hydrobromic acid (20 mL). Heat the mixture at 150° C. for 2 h. Cool to ambient temperature and remove excess hydrobromic acid under vacuum. Dilute with water, add cautiously saturated aqueous NaHCO3 and extract three times with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound as pink oil (6.0 g, 87%) that crystallizes in the freezer.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.CN(C)[CH:28]=[O:29].[Cl-].[NH4+].C(OCC)(=O)C>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:28]=[O:29])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: Fc1ccccc1CCN1CCC(N2CCc3ccc(Br)cc32)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccccc3F)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
A 1.6 M solution (24 ml) of n-(butyllithium) in hexane was added dropwise at −78° C. over 10 min into a solution of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (12 g) obtained in Example 348-2) in tetrahydrofuran (200 ml). After 10 min, dimethylformamide (3.5 ml) was added thereto and the resultant mixture was allowed to warm to room temperature. Then a saturated aqueous solution (100 ml) of ammonium chloride and ethyl acetate (200 ml) were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting obtained was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (9.6 g) as a yellow powder (yield: 91.5%).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:47])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(S(Cl)(=O)=O)CC>>[CH3:34][C@:31]12[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:36])([CH3:37])[C:25]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19][C@@H:18]1[C@H:17]1[C@H:48]([C:51]([CH3:53])=[CH2:52])[CH2:49][CH2:50][C@:16]1([NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:8][CH2:9]1)[CH2:33][CH2:32]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCS(=O)(=O)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)CCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using propane-1-sulfonyl chloride as the reagent in Step 1. The product was isolated as a white solid (8 mg, 48%). LCMS: m/e 748.6 (M+H)+, 2.30 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 5.34 (d, J=4.5 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.59-3.26 (m, 7H), 3.23-3.11 (m, 1H), 3.09-2.95 (m, 6H), 2.93-2.80 (m, 1H), 2.27-1.02 (m, 24H), 1.73 (s, 3H), 1.24 (s, 3H), 1.10 (s, 3H), 1.07 (s, 3H), 1.05 (t, J=8.3 Hz, 3H), 0.98 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CO.C(Cl)(Cl)Cl>[CH3:3][O:2][N:4]=[C:14]([CH:13]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:5])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: O=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CON=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Reaction time: 24 h
Yield: 86 %

Procedure:
Methoxyl-amine hydrochloride (30-35 wt % in H2O, 0.30 mL, 1.12 mmol) was added in one portion to a solution of 1,5-bis(2-hydroxyphenyl)penta-1,4-dien-3-one (EF1) in methanol/CHCl3 (2/3) (5 mL). The reaction proceeded at room temperature for 24 hrs, then additional methoxylamine hydrochloride (0.15 mL, 0.56 mmol) was added and the reaction stirred for an additional 24 hrs. After completion (TLC) the solvent was evaporated, the residue dissolved in methanol, stirred with silica gel and purified after concentration by chromatography on silica gel using 30% EtOAc/hexanes. The product was obtained as a pale yellow foam (86%). 1H NMR (400 MHz, CDCl3) δ 7.56 (1H, dd, J=8.0 Hz, J=1.6 Hz), 7.48 (1H, dd, J=8.0 Hz, J=1.6 Hz), 7.41 (1H, d, J=16.0 Hz), 7.39 (1H, d, J=16.8 Hz), 7.28 (1H, d, J=16.8 Hz), 7.20-7.13 (2H, m), 6.97-6.90 (2H, m), 6.94 (1H, d, J=16.0 Hz), 6.80 (1H, dd, J=8.0 Hz, J=1.6 Hz), 5.53 (1H, s-br), 5.36 (1H, s-br), 4.02 (3H, s). 13C NMR (100 MHz, CDCl3) δ 155.43, 153.86, 153.70, 132.28, 130.25, 130.10, 129.71, 128.00, 127.91, 124.16, 123.88, 123.57, 121.40, 121.30, 118.45, 116.37, 116.33, 62.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Mg]Br>CCOCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[CH3:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
At 0° C. to a solution of 3-(3,4-dichlorophenyl)-N-methoxy-N-methylpropanamide (569 mg, 2.17 mmol) in ether (10 mL) was added drop wise methyl magnesium bromide (2.17 mL, 6.51 mmol) and the solution was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm up to rt and stirred for 18 h. The reaction mixture was cooled to 0° C. and brine was added to quench the reaction. The aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50% over 20 min, column 40 g, flow rate 40 mL/min) to give Intermediate 15B (292 mg, 1.34 mmol, 62.0% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (3H, s), 2.75 (2H, t, J=6.9 Hz), 2.80-2.90 (2H, m), 7.02 (1H, dd, J=8.2, 2.2 Hz), 7.28 (1H, d, J=2.2 Hz), 7.33 (1H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>COCCOC>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:10]2=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[C:11]2=[CH:12]1
Reactant: CN(C)CCCCl
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)CCCn1cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c2ccccc21
Temperature: 25 °C

Procedure:
The mixture of 10.0 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 1.8 g of 50% sodium hydride in mineral oil and 250 ml of 1,2-dimethoxyethane is stirred at 100° until dissolution. It is cooled to room temperature and 15.0 g of 3-dimethylaminopropyl chloride in 10 ml of 1,2-dimethoxyethane are added. The mixture is stirred at 150° overnight, cooled, the supernatant solution decanted off and the residue treated with said solvent, to yield the 5-(3-dimethylaminopropyl)-2-(p-chlorophenyl)-pyrazolo-[4-3-c]quinolin-3-one melting at 189°-191°. Similarly the 5-(2-dimethylaminoethyl)-analog is obtained, m.p. 184°-186°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH2:31][CH3:32])=[CH:20]\[CH:21]=[CH:22]\[C:23](\[CH3:30])=[CH:24]\[C:25]([O:27]CC)=[O:26])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH:16]([CH3:18])[CH3:17])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:19](/[CH2:31][CH3:32])=[CH:20]\[CH:21]=[CH:22]\[C:23](\[CH3:30])=[CH:24]\[C:25]([OH:27])=[O:26])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(=C\C=C\C(C)=C\C(=O)O)CC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl 7-(7-ethoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-nona-2E,4E,6Z-trienoate (Compound 38,30 mg, 0.70 mmol) was hydrolyzed with 1M NaOH. Purification by column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile gave rise to the title compound as a light yellow solid.