Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][CH:6]1[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33]S[S:35][C:31]=23)=[O:28])=[O:18])[O:8][CH2:7]1.O[O:45][S:46]([O-:48])=O.[K+].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:1][C@@H:2]([C@@H:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([C@H:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33][S:46]([S:35][C:31]=23)(=[O:48])=[O:45])=[O:28])=[O:18])[O:8][CH2:7]1
Reactant: O=S([O-])OO
Reactant: C/C(=C\C(=O)OCCCCCCCC(=O)Nc1c2sscc-2[nH]c1=O)C(O)C1OCC(C/C=C/C(C)C(C)O)C(O)C1O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCC(=O)NC1=C2SS(=O)(=O)C=C2NC1=O)[C@@H](O)[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Yield: 75 %

Procedure:
100.9 mg of thiomarinol (prepared as described in Example 6) were dissolved in a mixture of 5 ml of acetone and 5 ml of water, and then the resulting solution was ice-cooled. 112.2 mg of OXONE (a trade name for a product of Aldrich Chemical Co., Inc.) were added to the resulting solution, and then the mixture was stirred, whilst ice-cooling, for 40 minutes. At the end of this time, 1.2 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to this mixture, and the mixture was again stirred, whilst ice-cooling, for 30 minutes. 5 ml of water were then added to the reaction mixture, which was then extracted with a 10:1 by volume mixture of methylene chloride and tetrahydrofuran. The extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was then isolated and purified by reverse phase, high performance liquid chromatography (using a Senshu Pak ODS-5251-N column, and 40% v/v aqueous acetonitrile as the eluent), to obtain 79.5 mg (yield 75%) of thiomarinol B having a light yellow color and having the physico-chemical properties listed above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:25]2[CH2:27][CH2:26]2)=[CH:9][CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.C1C=CC=CC=1.[H][H]>[Pd].C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:25]2[CH2:26][CH2:27]2)[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Clc1ccc(C(=CC=Cc2cccc(Oc3ccccc3)c2)C2CC2)cc1
Agent: [Pd]
Agent: [Rh]
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccccc1
Product: Clc1ccc(C(CCCc2cccc(Oc3ccccc3)c2)C2CC2)cc1
Yield: 23 %

Procedure:
A mixture of 2.3 grams (0.006 mole) of 1-(4-chlorophenyl)-1-cyclopropyl-4-(3-phenoxyphenyl)-1,3-butadiene, 2.3 grams (0.002 mole) of 10% palladium on carbon, 0.25 gram (0.0002 mole) of tris(triphenylphosphine)rhodium (I) chloride, and 25 mL of benzene in 100 mL of ethanol was hydrogenated at 40° C. using a Parr hydrogenator. Upon completion of the uptake of the theoretical amount of hydrogen (two hours), the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was taken up in hexane and filtered. The filtrate was dried with sodium sulfate and filtered again. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to rotating disk thin layer chromatography. Elution was accomplished using 20% toluene in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.52 gram of 1-(4-chlorophenyl)-1-cyclopropyl4-(3-phenoxyphenyl)butane as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1ccc(-c2cnn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 34) (1 eq, 0.073 mmol, 30 mg) and ethanol amine (10 eq, 0.73 mmol, 0.04 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.11 mmol, 15.1 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is then removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-Hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-b]-pyridazin-7-yl]-benzamide as a yellow solid; [M+H]+=425
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>O>[N+:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:23])=[O:22]
Reactant: c1ccc(-c2cccn3ccnc23)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cccn3ccnc23)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Add 20 g (0.10 mole) of the product from Example 4 slowly to 150 ml of concentrated sulfuric acid at -15° C. Add 7 ml of concentrated nitric acid slowly, maintaining the temperature -10° C. Stir at -10° C. for 30 minutes. Pour onto 500 g of ice. Add 2 L of water and neutralize with potassium carbonate. Extract with three 500 ml portions of methylene chloride. Combine the extracts, dry over magnesium sulfate, treat with charcoal and remove the solvent in vacuo. The residue is crystallized from ether to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Yield: 147.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-(5-bromo-7-cyano-1H-indazol-3-yl)-1-piperidine-carboxylate (Intermediate 3) (0.200 g, 0.493 mmols) and trifluoroacetic acid (0.25 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 hrs. The solution was cooled and the solvent removed in vacuo to give the crude amine (222 mg) trifluoroacetate salt, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH:42]([N:45]=[C:46]=[O:47])([CH3:44])[CH3:43]>>[CH3:43][CH:42]([NH:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:47])[CH3:44]
Reactant: CC(C)N=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Product: CC(C)NC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]-methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and isopropyl isocyanate by the procedure described in Example 2, Step C. 1H NMR (400 MHz, CDCl3): δ 1.06 (d, 3H) 1.07 (d, 3H), 1.32 (s, 3H), 1.39 (s, 9H), 1.88 (m, 1H), 2.48 (dd, 1H), 2.50 (m, 1H), 2.62 (m, 2H), 3.80 (m, 1H), 4.52 (m, 1H), 4.98 (d, 1H), 5.10 (d, 1H), 5.28 (br s, 1H), 6.08 (br s, 1H), 6.68 (br s, 1H), 7.22 (m, 11H), 7.70 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:15][C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:23])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid methyl ester (414 mg) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (72 mg) in water (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After such time 1.72 mL of 1N aqueous hydrochloric acid solution was added. The reaction mixture was then concentrated in vacuo, and the resulting precipitate was then washed several times with water to yield the title compound as a white solid (367 mg). MS (m/e): 347.1 (M−H, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[N:9]([CH2:17][C:18](OCC)=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:18](=[O:19])[CH2:17][N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(C(=O)NCc1ccc(C)cc1)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN2C(=O)CN(c3ccc(C)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
Ethyl bromoacetate (4.0 g, 30.0 mmol) was added to a solution of p-toluidine (2.1 g, 20 mmol) and sodium acetate (2.1 g, 26 mmol) in ethanol (26 mL). The resulting solution was warmed to 80° C. and stirred for 1 h before being cooled to room temperature. The reaction was quenched with water (20 mL) and the aqueous fraction extracted with ethyl acetate (3×20 mL). The organic fractions were combined, dried (MgSO4) and filtered, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-(p-tolylamino)acetate as a pale oil (1.9 g, 50%). Ethyl 2-(p-tolylamino)acetate (260 mg, 1.4 mmol) was dissolved in toluene (5 mL). Methyl benzylisocyanate (200 mg, 1.4 mmol) was added to this solution. The mixture was heated to reflux and stirred for 5 h, until TLC analysis demonstrated that the reaction was complete. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate as a pale oil (455 mg, 98%). Ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate (455 mg, 1.3 mmol) was dissolved in THF (10 mL) and added dropwise to a solution of NaH (68 mg, 2.8 mmol) in THF (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred for 18 h before the reaction was quenched with water (5 mL). The aqueous fraction was then extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. Column chromatography (0-20% ethyl acetate/hexane) provided 14 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[OH:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:17][C:18]1[C:23]([CH2:24][OH:25])=[CH:22][N:21]=[C:20]([CH3:26])[C:19]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ncc(CO)c(CN(CCCCCC(=O)O)C(=O)OC(C)(C)C)c1O
Reactant: ClCc1ccccc1
Product: Cc1ncc(CO)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 72.9 %

Procedure:
The coupling of 6-[tert-butoxycarbonyl-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-hexanoic acid (41) (3.0 g, 7.8 mmol) and benzyl chloride (7.0 g, 55 mmol), as described in Example 3, gave 6-[(3-benzyloxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-tert-butoxycarbonyl-amino]-hexanoic acid benzyl ester (42) (3.2 g, 73% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9])([O-])=O.[H][H]>S(=O)(=O)(O)O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=S(=O)(O)O
Product: N#CCc1cccc(N)c1

Procedure:
A correspondingly substituted benzyl cyanide of the formula Ve is nitrated in concentrated sulfuric acid. The formed 3-nitrobenzyl cyanide of the formula Vf is subsequently hydrogenated in the presence of a catalyst with hydrogen to obtain 3-aminobenzyl cyanide of the formula Vg. By treatment with isopentyl nitrite in the presence of sodium and ethanol, there is formed the Na salt of 3-aminobenzoyl cyanide oxime of the formula Vh, which is reacted with an ester of the formula VIII to obtain 3-aminophenoxime ether of the formula Va. This can be subjected to a condensation reaction, as described above, with the 3,4,5,6-tetrahydrophthalic anhydride of the formula II.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:14]3[CH:13]=[CH:12][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Clc1ccc2ncc(I)n2n1
Product: Clc1ccc2ncc(-c3ccc4ccccc4c3)n2n1

Procedure:
1.03 g of 6-chloro-3-naphthalen-2-ylimidazo[1,2-b]pyridazine were prepared from 5 3.5 g (12.52 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (Example 1.2) and 2.37 g (13.78 mmol) of 2-naphthylboronic acid (CAS No. 32316-92-0) in analogy to Example 1.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]3[O:36][CH2:35]3)[C:29]([O:31]C)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]([OH:36])[CH2:35][S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:29]([OH:31])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(S)cc1
Product: COc1ccc(SCC(O)CC(NS(=O)(=O)c2ccc(-c3ccc(OC)cc3)cc2)C(=O)O)cc1

Procedure:
Example 44 is prepared from 4-methoxybenzenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:30][O:31][C:32]1[C:36](OC)=[N:35][S:34](=[O:39])[N:33]=1>CO>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]2[C:32]([O:31][CH3:30])=[N:33][S:34](=[O:39])[N:35]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: CCOC(=O)C1=C(COCCNC2=NS(=O)N=C2OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) and 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.2 g) were dissolved in methanol (15 ml) and heated at reflux for 14 hours. The solvent was evaporated and the residue chromatographed on silica "Kieselgel 60H" (Trade Mark), eluting with ethyl acetate. The product-containing fractions were combined and evaporated to give an oil which was triturated in ethyl acetate to give the title compound as a solid, yield 0.14 g, m.p. 183°-185°.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=N[C:46]([CH3:49])=[CH:47][CH:48]=1)[CH2:4][CH2:3]2.BrC1C=CC=[C:53]([S:57]C)N=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:49]([S:57][CH3:53])[N:44]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)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
Reactant: CSc1cccc(Br)n1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccc(SC)n3)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
Yield: 12 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-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, except 2-bromo-6-(methylthio)pyridine (0.020 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (10.3 mg, 12% yield) bis TFA salt. LCMS: m/e 696.5 (M+H)+, 2.34 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.95-7.85 (m, J=8.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.20-7.12 (m, J=8.2 Hz, 2H), 6.53 (d, J=7.6 Hz, 1H), 6.37 (d, J=7.9 Hz, 1H), 5.25 (d, J=4.6 Hz, 1H), 4.85 (s, 1H), 4.72 (br. s., 1H), 3.96 (s, 1H), 3.78-3.59 (m, 2H), 3.28-3.13 (m, 2H), 2.95-2.83 (m, 1H), 2.49 (s, 3H), 2.08-1.86 (m, 6H), 1.78-1.69 (m, 4H), 1.69-1.52 (m, 5H), 1.52-1.31 (m, 6H), 1.31-1.07 (m, 7H), 1.01 (s, 3H), 0.95-0.83 (m, 9H), 0.57 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:23]5[S:22][CH:26]=[CH:25][CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1cccs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cccs4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (100 μL) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (1.0 g, 3.81 mmol) in dichloromethane (10 mL) was added triethylamine (1.0 mL, 7.63 mmol) and methanesulfonyl chloride (0.60 mL, 7.63 mmol). The resulting mixture was stirred for 1.5 hours at room temperature. Product was collected by filtration, washed with dichloromethane (10 mL) and dried under reduced pressure to provide the product as a purple solid (1.1 g, 85%). M.p.=230-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=6.8 Hz, 1H), 7.75 (m, 2H), 7.56 (m, 1H), 4.81 (m, 1H), 4.65 (m, 1H), 4.54 (m, 1H), 3.05 (m, 2H), 1.16 (m, 3H); LCMS: 341 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([CH:14]=[CH2:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C[N+]1([O-])CCOCC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:36].C(O)(C)(C)C.[OH2:42]>C(O)(C)(C)C.O=[Os](=O)(=O)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([CH:14]([OH:42])[CH2:15][OH:36])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[C:4]([C:18]([F:19])([F:20])[F:21])[CH:3]=1
Reactant: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OC
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CO
Temperature: 25 °C
Reaction time: 60 h

Procedure:
460 mg (1.5 mmol) of methyl 2-(4-fluoro-2-trifluoromethylbenzoylamino)but-3-enoate were dissolved in tert-butanol/water, and 360 mg (3 mmol) of N-methylmorpholine N-oxide and 1.5 g (0.15 mmol) of a 2.5% strength solution of OsO4 in tert-butanol were added. The mixture was stirred at RT for 60 hours. 3.2 g of sodium sulfite, water and ethyl acetate were then added, and the phases were separated. The aqueous phase was reextracted with ethyl acetate. The combined organic phases were washed and dried, and the solvent was removed. This gave 440 mg (86% of theory) of crude product (diastereomer ratio about 2:1) which was used for the next step without further purification.