Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:28]([C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:30]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[O:24][C:25]1=[O:29])[CH3:3]
Reactant: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.08 h

Procedure:
1.60 ml of a solution of diethyl azodicarboxylate in toluene (40%) (3.52 mmol) was added to a solution of 1.05 g of N-{(S)-2-hydroxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (106f) (2.93 mmol) and 923 mg of triphenylphosphine (3.52 mmol) in tetrahydrofuran (30 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 916 mg of the title compound (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18]Br.CO>CN(C)C=O>[Br:18][CH2:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1.5 h

Procedure:
Methyl 3-methyl-2-quinoxalinecarboxylate-1,4-dioxide (1.2 moles) were suspended in 475 ml of dimethylformamide and 64 ml of bromine was added dropwise with stirring over 1.5 hours while the temperature rose to 42° C. After additional stirring for 48 hours 1.5 liters of methanol were added and stirred for about 1/2 hour. The precipitated product was removed by filtration, washed with water and dried. Yield, 251 grams (68%); m.p. 113°-16° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>>[CH3:19][O:15][C:14](=[O:16])[CH2:13][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:12]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2 Parts of N-p-chlorobenzenesulfonyl-sarcosine is added to a diazomethane-ethereal solution. After the generation of nitrogen has ceased, the precipitated reaction product is collected by filtration to obtain 1.2 parts of N-p-chlorobenzenesulfonyl-sarcosine methyl ester, m.p. 80°-80.5° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36](=[O:38])[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36]6([CH2:8][O:38]6)[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-n2ncc3cc4c(nc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Sodium hydride (60 wt % in oil, 0.454 g, 11.35 mmol) and DMSO (25 mL) were heated to about 65° C. for about 30 min then cooled to rt. THF (50 mL) was added then the mixture was cooled to about 0° C. Trimethylsulfoxonium iodide (2.56 g, 11.63 mmol) was added then after about 30 min rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (2.5 g, 5.68 mmol) was added. The mixture was allowed to warm to rt and stir for about 12 h. The mixture was concentrated under reduced pressure then the material was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL) then the organic solutions were combined and washed with water (75 mL) then brine (30 mL), dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (120 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-3,2′-oxirane] (119, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (1.865 g, 72.3%); LC/MS, method 3, Rt=2.65 min, MS m/z 455 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.42-8.34 (m, 2H), 8.32-8.28 (m, 1H), 8.20 (s, 1H), 7.75-7.72 (m, 1H), 7.49-7.37 (m, 3H), 7.06 (ddd, J=5.2, 4.5, 0.9 Hz, 1H), 6.72-6.67 (m, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.59-3.47 (m, 1H), 3.42-3.33 (m, 1H), 3.02 (d, J=12.9 Hz, 1H), 2.70-2.56 (m, 1H), 2.44-2.34 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.81 (m, 2H), 1.79-1.58 (m, 3H), 1.35-1.21 (m, 3H), 1.21-1.10 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[O:18].O>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH2:21][CH2:22][Cl:23])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCCCCl
Reactant: Nc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(CO)c1)OCCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.7 g (30 mmol) of 3-aminobenzyl alcohol are dissolved in 50 ml of acetone, and 3.2 g (30 mmol) of sodium carbonate are added. 5.7 g (36 mmol) of 3-chloropropyl chloroformate are metered into this suspension at 25° C. The reaction mixture is stirred at room temperature for a further 18 h. Water is added to the reaction mixture for hydrolysis, and the solid is subsequently filtered off. The solution is concentrated by distillation, during which the product deposits as an oil. The product phase is separated off. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The mixture is subsequently evaporated to dryness. The crude product is reacted further directly without further purification;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.C([BH3-])#N.[Na+].C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:23]=1
Reactant: Cc1cccc(C)c1-c1cccc(C=O)c1
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Temperature: 25 °C
Reaction time: 55 h
Yield: 61 %

Procedure:
To a solution of methyl 3-(4-aminophenyl)propanoate (3.33 g, 18.6 mmol) and 2′,6′-dimethylbiphenyl-3-carbaldehyde (3.91 g, 18.6 mmol) in toluene (40 mL) were added molecular sieves (0.4 nm, beads, 7.2 g), and the mixture was stirred at room temperature for 55 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (100 mL). Sodium cyanoborohydride (2.53 g, 40.3 mmol) and acetic acid (2.31 mL, 40.3 mmol) were successively added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-40% ethyl acetate/hexane) to give the title compound (4.24 g, yield 61%) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:4][CH2:3][C@H:2]([C:5]2[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH3:12])=[CH:7][CH:6]=2)[OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CO)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2ccc([C@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
4.32 g of the compound [5-2] was dissolved in 50 mL of pyridine, and 3.66 g of p-toluenesulfonyl chloride was added thereto under an ice-cold condition. The reaction mixture was stirred overnight at 0° C., water was added thereto, and then the mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=50/50-0/100), to obtain 6.52 g of (2S)-2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-hydroxyethyl 4-methylbenzenesulfonate [5-3] (hereinafter, referred to as the compound [5-3]) as a colorless amorphous.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (632 mg, 2.00 mmol) in DMSO (10 ml) was added DIEA (516 mg, 3.99 mmol) and piperazine (688 mg, 7.99 mmol). The resulting solution was stirred for 3 hours at 80° C. and then quenched by the addition of water (100 ml). The solids were collected by filtration to afford methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (540 mg, 74%).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:27](=[O:41])[N:28]([CH:38]3[CH2:40][CH2:39]3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25]O)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:51][C:52]1[C:53]([F:60])=[C:54]([OH:59])[C:55]([F:58])=[CH:56][CH:57]=1>>[C:45]([O:44][C:42]([N:12]1[CH2:13][CH:14]2[N:9]([C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])[CH:10]([CH2:17][C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:59][C:54]4[C:55]([F:58])=[CH:56][CH:57]=[C:52]([Cl:51])[C:53]=4[F:60])[CH:19]=3)=[C:15]2[C:27](=[O:41])[N:28]([CH:38]2[CH2:39][CH2:40]2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:11]1)=[O:43])([CH3:46])([CH3:47])[CH3:48]
Reactant: Oc1c(F)ccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCOc4c(F)ccc(Cl)c4F)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E6 and 3-chloro-2,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.30 min, ES+: 941.29.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=O)[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>>[Cl:26][C:13]1[N:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCn1c(Cl)nc2cccc(C(CC)CC)c21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
The mixture of ethyl 4-[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate (Reference Example 31; 1.94 g, 6.09 mmol) and phosphorus oxychloride (4.33 mL) was stirred at 100° C. for 2.5 hr. After cooling, the mixture was poured into ice water and neutralized with sodium hydrogen carbonate. The precipitate was removed by filtration and the filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (942.6 mg, 2.80 mmol, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[BrH:11]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:11])=[CH:5][CH:4]=1
Reactant: Br
Reactant: COc1ccc(CO)cc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzylalcohol (10 g) in ether (300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The organic phase was washed with saturated sodium bromide, dried (K2CO3) and the solvents removed in vacuo to give 4-methoxybenzylbromide (113.17 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:53])([CH3:52])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:51])([C@@:18]4([CH3:50])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:53])([CH3:52])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:51])([C@@:18]4([CH3:50])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:44][CH2:45]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 52.7 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-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)benzoate (0.056 g, 0.074 mmol) in 1,4-dioxane (2 mL) was added NaOH (1N) (0.372 mL, 0.372 mmol). The mixture was heated to 60° C. for 6.5 h then was cooled to rt. The mixture was diluted with methanol and 1,4-dioxane, was filtered through a plug of glass wool and was purified by prep HPLC. The fractions containing the expected product were combined and were concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-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 (30.1 mg, 0.039 mmol, 52.0% yield) as a white solid. LCMS: m/e 738.6 (M+H)+, 1.66 min (method 2). 1H NMR (400 MHz, Acetic acid d4) 67.92 (t, J=7.9 Hz, 1H), 7.04 (dd, J=8.0, 1.5 Hz, 1H), 7.01-6.96 (m, 1H), 5.38 (d, J=5.0 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.59-3.25 (m, 8H), 3.15 (br. s., 4H), 2.90 (s, 3H), 2.94-2.81 (m, 1H), 1.72 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 2.23-0.83 (m, 22H).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as described for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) in dimethylformamide (400 ml) was added benzyl bromide (9.20 g, 54.0 mmol). After stirring for 12 hours, the mixture was poured into cold water (680 ml). The precipitate was filtered, washed with water (3x 50 ml), ether (3x 50 ml) and dried under vacuum to provide 7-benzyl-8-bromo-3-methylxanthine (14.92 g, 89% yield) as a white powder.
Reaction SMILES: C(O[C:4]([S-])=[S:5])C.[K+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH2:18])[C:14]([CH3:20])([CH3:19])[C:13](=[O:21])[C:12]2([CH3:23])[CH3:22].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O>[SH:5][C:4]1[NH:18][C:17]2[CH:16]=[C:15]3[C:11](=[CH:10][C:9]=2[N:8]=1)[C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[C:14]3([CH3:19])[CH3:20]
Reactant: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: CCOC(=S)[S-]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
20 ml of water and 17.0 g of purified potassium ethylxanthate were added to 20.0 g of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone, dissolved in 200 ml of alcohol, in a 750 ml sulfonation flask equipped with stirrer, thermometer, reflux condenser. The mixture was left to boil at reflux overnight, then diluted with 200 ml of water, neutralized with 20 ml of glacial acetic and stirred at 60°-70° C. for an additional 1 hour. After cooling to 20° C., the crystals were removed by filtration under suction. There were obtained 18.8 g (78.9% of theory) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno(5,6-d)-imidazol-6(1H)-one with a melting point above 300° C.
Reaction SMILES: [C:1]1([C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:9][CH2:8][C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL) followed by addition of 1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to turn the slurry into a solution. To the stirred solution, sodium triacetoxyborohydride (60.3 g, 284 mmol) was slowly added. A slight exotherm resulted and a slurry was produced. The reaction mixture was stirred for an additional 3 hours at room temperature. The reaction was then quenched by addition of 2.0 N sodium hydroxide (1050 mL) producing a pH of about 10 for the quenched reaction mixture. The mixture was then extracted with methylene chloride (2 times, 1L and 300 mL). The organic extracts were combined, washed successively with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the final title compound as a thick oil;
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][N:36]([C:9]([C:8]1[CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:15][CH3:16])=[CH:6][C:7]=1[O:13][CH3:14])=[O:11])[CH2:35]2
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)O
Reactant: Brc1ccc2c(c1)CNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (×2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone as a beige solid (3 g). 1H NMR (Me-d3-OD) 7.60-7.13 (3H, m), 7.14 (1H, s), 6.71 (1H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.