Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][N+:21]([O-])=O)=[CH:17][C:16]=1[O:26][CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][NH2:21])=[CH:17][C:16]=1[O:26][CH3:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=CN)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirred suspension of LAH (8.0 g, 0.21 mol) in THF (300 mL) is cooled in an ice bath and a solution of 4-benzyloxy-3-methoxynitrostyrene (15.0 g, 52.6 mmol) in THF (300 mL) is added dropwise. The green reaction mixture is allowed to warm to room temperature over 0.5 h, and is then refluxed for 4 h. The grey reaction mixture is treated successively with water (8 mL), 15% aqueous NaOH (8 mL), and water (24 mL). The resulting gray suspension is stirred at 50° C. for 20 min. The resulting yellow suspension is filtered, and the residue is washed with EtOAc. The combined filtrates are evaporated to provide the title compound as yellow oil which is used without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17]O)[CH:14]=[N:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CS([Cl:32])(=O)=O.[Cl-].[Li+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[C:1]([N:5]1[C:9]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][Cl:32])[N:16]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nccc1Nc1cncc(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1nccc1Nc1cncc(CCl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 507.3 mg of (6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyrazin-2-yl)methanol in 6.8 ml of chloroform were successively added 1.08 ml of diisopropylethylamine and 0.24 ml of methylsulfonyl chloride under cooling with ice, followed by stirring the reaction mixture at room temperature for 1.5 hours. To the reaction mixture were successively added 442.9 mg of lithium chloride and 6.8 ml of N,N-dimethylformamide, followed by stirring the reaction mixture at room temperature for 2 hours. After diluting the reaction mixture with ethyl acetate, the ethyl acetate solution was successively washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1-1/4) to give the title compound as a yellow solid.
Reaction SMILES: CC([O:4]C(/N=N/C(OC(C)C)=O)=O)C.CC1N=CSC=1CCO.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:37]1([P:30](=[O:4])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncsc1CCO
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
DIAD (3.16 ml, 16.1 mM) was added to a stirred solution of methyl 3-nitro-5-hydroxy benzoate (2.11 g, 10.7 mM), 2-(4-methylthiazol-5-yl) ethanol (1.55 ml, 12.8 mM) and triphenylphosphine (4.21 g, 16.1 mM) in THF (50 ml) under an argon atmosphere at room temperature. After 1 hr reaction mixture concentrated in vacuo, and the residue triturated with diethyl ether to give a colourless solid (triphenylphosphine oxide). Diethyl ether conc. to give a dark brown gum, purification on silica gel (50% to 75% EtOAc/iso-hexane) gave the product contaminated with reduced DIAD and triphenylphosphine oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 ml), 2M NaOH (20 ml, 40 mM) added, heated at 65° C. for 4 hrs then cooled and concentrated. The residue was diluted with water (140 ml)/2M NaOH (40 ml), the precipitated triphenylphosphine oxide filtered, then acidified with c. HCl to pH=1–2. The precipitate was filtered, washed with water, dried under high-vacuum to give 3-nitro-5-(4-methyl-thiazol-5-yl) ethoxy] benzoic acid as a colourless solid (3.12 g, 79% over 2 steps); 1H NMR δ (d6-DMSO): 2.39 (s, 3H), 3.23 (t, 2H), 4.35 (t, 2H), 7.78 (s. 1H), 7.90 (m, 1H), 8.22 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:16]([CH:20]=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1)C1C=CC=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]2[N:11]([C:16]([CH:20]=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Cl)cn2c1C=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2c(O)cc(Cl)cn2c1C=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 0.5 g 8-benzyloxy-6-chloro-3-formyl-2-methyl-imidazo[1,2-a]pyridine, 2.5 ml acetic acid and 2.5 ml 48% aqueous hydrogen bromide solution is heated under reflux for 2 hours. The mixture is cooled to room temperature, poured over 50 ml icewater, neutralized with 1 N-sodium hydroxide solution and extracted 3×with 20 ml ethyl acetate each time. The combined extracts are dried over sodium sulfate, the solvent is stripped off and the solid residue is recrystallized from dioxane. 0.2 g of the title compound of m.p. 256° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[CH3:16][N:17](C)C=O.S(Cl)(Cl)=O.CN>ClCCCl.C(O)C>[CH3:16][NH:17][C:13]([C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1])=[O:15]
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CCO
Product: CNC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50.0 g (0.25 mol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid in 1.2 l of 1,2-dichloroethane (DCE) is added 1.9 ml dimethyl formamide (DMF) and 21.4 ml (0.3 mol, 1.2 eq.) of thionyl chloride. The mixture is stirred for 2 h at reflux until a clear, yellow solution is formed. The solution is cooled to room temperature and then slowly added to a 8M solution of methylamine in ethanol (146 ml) at 5° C. The suspension is poured onto methylene chloride, washed with sat. NaHCO3-solution, dried over Na2SO4 and concentrated. This yields 52.3 g (99%) of the title compound as light brown solid, which is used for further reaction without purification. Mass spectrum: m/z (M+H)+: 217.1
Reaction SMILES: [NH:1]([C:8]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH:1]([C:8]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]([C:10](=[O:11])[CH:9]=1)=[CH:17][C:16]([F:18])=[C:15]([Cl:19])[N:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (2.3 g, 5.7 mmol) and t-BuOK (1.28 g, 11.4 mmol) in dioxane (80 mL) was stirred at 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (1.0 g, 50%10) as a light yellow solid: LCMS RT: 2.60 min, MH+: 366.8. Tis transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:45]([OH:47])=O)=[N:37][C:38]=2[O:39][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:48][O:49][C:50](=[O:57])[C:51]([NH2:56])([CH2:54][CH3:55])[CH2:52][CH3:53]>>[CH3:48][O:49][C:50](=[O:57])[C:51]([NH:56][C:45]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:38]([O:39][CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[N:37]=1)=[O:47])([CH2:54][CH3:55])[CH2:52][CH3:53]
Reactant: CC(C)(C)COc1nc(C(=O)O)cnc1NC1CCCCC1
Reactant: CCC(N)(CC)C(=O)OC
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCC(C)(C)C)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2,2-dimethyl-propoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 435.4 (M+H).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:6]([N:8]1[C@H:12]([C:13]([O:15]CC2C(C)=CC(C)=CC=2C)=[O:14])[CH2:11][S:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].Br>C(O)(=O)C>[C:1]([S:4][CH:5]([CH2:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][S:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)OCc1c(C)cc(C)cc1C
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)O

Procedure:
A mixture of 1.0 g. of [4R]-3-(2-acetylthio-3-benzoylpropionyl)-4-thiazolidinecarboxylic acid, 2,4,6-trimethylbenzyl ester, 10 ml. of acetic acid and 10 ml. of acetic acid saturated with hydrogen bromide gas is stirred at room temperature for 10 hours. The solvent is removed and the residue is chromatographed on a column of silica gel to give the product of the Example as a glass.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[O:23])=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C(=O)([O-])O.[Na+]>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH2:35][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[O:23])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2ccnnc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccnnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.07 ml, 0.85 mmol) followed by acetic acid (0.03 ml, 0.57 mmol) were added to a suspension of 2-([(4-fluorophenyl)methyl]oxy)-5-formyl-N-4-pyridazinylbenzamide (may be prepared as described in Example 84; 200 mg, 0.57 mmol) in DCE (10 ml). The mixture was stirred at room temperature for 10 min and then sodium triacetoxyborohydride (133 mg, 0.63 mmol) was added. The mixture was warmed to 50° C. for 3 hrs. The reaction mixture was diluted with dichloromethane (25 ml) and saturated sodium hydrogen carbonate was added to this mixture until no effevervesence was observed. The mixture was separated and the organic layer was evaporated under reduced pressure. The residue was purified using MDAP to yield the title compound. 180 mg.
Reaction SMILES: [OH:1][CH:2]([C:4]1[S:8][C:7]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH:13]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:6][CH:5]=1)[CH3:3].C([O-])(=O)C.[NH4+:37].[OH-].[Na+]>C(O)(=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH:13]([C:12]2[NH:37][C:9]([C:7]3[S:8][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][N:6]=3)=[CH:10][CH:11]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A mixture of 1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.57 g), ammonium acetate (0.46 g) and acetic acid (5 mL) was stirred at 90° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1 mL), tetrahydrofuran (4 mL) and methanol (4 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.19 g, yield 34%) was obtained as a yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 461 (MH+).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)(=O)C>O>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N2C(=O)c3cccc4c(Br)ccc(c34)C2=O)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
A mixture of 4-Bromo 1,8 naphthalic anhydride (10 g), p-toluidine (4.08 g) and acetic acid (75 ml) was refluxed with stirring for 10 hours. Water (200 ml) was added at room temperature, the separated solid was filtered, washed with acetic acid followed by water and dried at 100° C. for 8 hours to yield 11.5 g of the product.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:15]4[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:21][O:20][C:16]1[C:15]2[CH:11]([NH:10][C:7]3[O:8][CH2:9][C:4]4[CH:3]=[C:2]([NH:24][C:25]5[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:12][O:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Reactant: Nc1nccc(C(F)(F)F)n1
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nccc(C(F)(F)F)n4)cc3CO1)CO2
Yield: 59 %

Procedure:
The title compound (135 mg, 59%), yellow foam, MS (ISP): m/e=458.2 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (example 54) (188 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[C:13]([O:15]CC)=[O:14].C(O)(=O)C>[OH-].[Na+].CO.O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)[C@H](CCCCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NCCCCCCCC[C@H](N[C@H]1COc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 3(S)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.2 g) in 1N sodium hydroxide solution (6 ml) is allowed to stand for 30 minutes at room temperature. Acetic acid (1.5 ml) is added and the resulting mixture is subjected to Amberlite XAD-2 column chromatography using methanol-water (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[9-amino-1(S)-carboxynonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.15 g) as colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:20]=3[CH2:21][CH2:22][C:13]=2[C:12]([C:23]([O:25]C)=[O:24])=[CH:11]1.C1COCC1.CO.O.O.[OH-].[Li+]>C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:20]=3[CH2:21][CH2:22][C:13]=2[C:12]([C:23]([OH:25])=[O:24])=[CH:11]1
Reactant: COC(=O)c1cn(CCOC2CCCCO2)c2c1CCc1cnccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cn(CCOC2CCCCO2)c2c1CCc1cnccc1-2
Yield: 63 %

Procedure:
To a solution of methyl 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylate E17 (1.4 mmol) in 30 mL of a mixture THF/MeOH/H2O 8:1:1, lithium hydroxide monohydrate (2.8 mmol) was added. The resulting solution was stirred at reflux for 6 h. The solvent was removed, the residue redissolved in water and neutralized with aq KH2PO4. The desired product was extracted with DCM/methanol 9:1 and the organic layer was dried (Na2SO4) and evaporated to give, after trituration with diethylether, the title compound (63% yield). ESI (+) MS: m/z 343 (MH+); MS (ES−) 341. 1H NMR: 1.30-1.55 (m, 6H), 2.79-2.86 (m, 2H), 2.87-2.97 (m, 2H), 3.31-3.51 (m, 2H), 3.68-3.75 (m, 1H), 3.86-3.94 (m, 1H), 4.49-4.57 (m, 3H), 7.63-7.67 (m, 1H), 7.68 (s, 1H), 8.44 (d, J=5.61, 1H), 8.47 (s, 1H), 12.06 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])CO)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:21]([CH2:19][CH3:20])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Reactant: CCCCC(CC)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCC(CC)COC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
5.0 Parts of methyl 5-(2',4'-dihydroxyphenyl)-5-methyl-hexanoate, 50 parts of 2-ethyl-hexanol and 0.5 parts of p-toluene sulphonic acid were heated on a steam-bath for 18 hours. The reaction mixture was then diluted with ether, washed with sodium bicarbonate solution, water, and evaporated. The residue, after stripping off excess 2-ethylhexanol on a rotary evaporator at 100° C. and 0.1 mm pressure, gave 2-ethylhexyl 5-(2',4'-dihydroxyphenyl)-5-methyl-hexanoate as a viscous amber liquid with the following percentage composition by weight.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(N[C@H](C(O)=O)CCC(=O)N)=O)CC(C)C.N[C@H](C(N[C@H](C(O)=O)CCC(=O)N)=O)CC1CCCCC1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: NC(=O)CC[C@H](NC(=O)[C@@H](N)CC1CCCCC1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
A10, Leu, Leu-Gln, or Cha-Gln;
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=1.[CH3:22][CH2:23][CH2:24][C:25]1[C:30]([OH:31])=[C:29]([C:32]([CH3:34])=[O:33])[CH:28]=[CH:27][C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:35][CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=2)=[C:25]([CH2:24][CH2:23][CH3:22])[C:30]=1[OH:31])(=[O:33])[CH3:34]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCC(=O)c1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O

Procedure:
The compound of Step A above, (2.0 g, 5.36 mmoles), 2,4-dihydroxy-3-propylacetophenone (2.08 g, 10.72 mmole) and potassium carbonate (3.0 g, 21.44 mmole) were stirred in methyl ethyl ketone (100 ml) and heated at reflux for three hours. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in ether-methanol and extracted with 1N NaOH (3×50 ml). The organics were dried and concentrated in vacuo. The residue was triturated with methanol, filtered and dried, to yield the title compound. NMR (CDCl3): 0.94 (3H, m), 1.73 (6H, m), 2.28 (6H, m), 2.95 (2H, m), 3.22 (2H, m), 3.66 (3H, s), 4.17 (2H, m), 6.42 (1H, d), 7.40 (2M, d), 7.61 (1H, d), 7.90 (2H, d), 12.73 (1H, s).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30])(C(C)(C)C)(C)C.Cl.O>O1CCCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (400 mg, 0.72 mmol) obtained in Example 29 was dissolved in tetrahydrofuran (40 ml), and 3N--HCl (2 ml) was added thereto. The reaction mixture was stirred for 3 hours at room temperature. When the reaction is completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=7:3) to obtain 235 mg (yield: 74%, 3RS,4RS/3RS,4SR=9:1) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2](=[O:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.CC(C[AlH]CC(C)C)C>ClCCl>[CH3:1][CH:2]([OH:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 5-α-pregn-2-en-20-one (11) (860 mg, 2.86 mmol) in anhydrous dichloromethane (120 mL) at −78° C. under an argon atmosphere was slowly added DIBAL-H (1.0 M in hexane) (5.72 mL, 5.72 mmol). The solution was stirred at −78° C. over a period of 3 h and successively washed with an aqueous HCl solution (5%) and a Rochelle salt solution. The organic phase was then filtered using a phase separator syringe (Biotage) and evaporated. Purification by FCC (EtOAc/hexanes, 5:95) yielded 672 mg (78%) of title compound 12 as a white solid. 1H NMR (CDCl3) δ: 0.76 (s, 18-CH3 and 19-CH3), 1.13 (d, J=6.1 Hz, 21-CH3), 0.70-2.10 (residual CH and CH2), 3.73 (m, 20-CH), 5.58 (m, 2-CH and 3-CH). 13C NMR (CDCl3) δ; 11.7, 12.5, 20.8, 23.6, 24.4, 25.6, 28.7, 30.3, 31.9, 34.6, 35.4, 39.8, 40.1, 41.4, 42.4, 54.0, 55.9, 58.6, 70.6, 125.8, 126.0. LRMS for C21H33 [MH—H2O]+: 285.2 m/z.