Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].N1C=CC=CC=1.C([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=O)C>CCOCC>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([OH:26])=[CH:28][CH:29]=1)#[N:12]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
In 60 ml of ether were dissolved 2.6 g of 2-(2-aminophenylthio)benzonitrile (prepared in accordance with Reference Example 5, Step 4) and 2.8 g of pyridine, followed by dropwise addition of a solution of 2.7 g of 4-acetoxybenzoyl chloride in ether with ice-cooling and stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 10 hours. The ether was then distilled off and ethanol was added to the residue. The resulting crystals were collected by filtration and washed with ethanol. The crystals were then suspended in 70 ml of ethanol, and after 7 ml of 10% aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The crystals separated out therefrom were collected by filtration and dried to give 3.3 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Li].[Na].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>O1CCCC1>[CH2:14]([O:13][C:7](=[O:12])[CH2:8][C:9](=[O:10])[CH2:11][CH:1]([OH:4])[CH:2]=[CH2:3])[CH3:15]
Reactant: C=CCO
Reactant: CCOC(=O)CC(C)=O
Agent: [Li]
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC(O)CC(=O)CC(=O)OCC

Procedure:
The allyl alcohol, 8, is reoxidized to the aldehyde, 9, by Swern oxidation, followed by an aldol condensation to the sodium lithium dianion of ethyl acetoacetate at -78° C. in tetrahydrofuran. (See Kraus, et al, J. Org. Chem., 48: 2111 (1983)) to form the 5-hydroxy-3-oxo-6-heptenoic acid-ethyl ester, 10.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17].Cl.Cl[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 14 h

Procedure:
112 g (0.81 mol) of potassium carbonate are added to a solution of 35 g (0.202 mol) of 2-chloro-4-nitrophenol in 350 mL of DMF. Then the reaction mixture is combined with 35 g (0.203 mol) of (2-chloroethyl)diethylamine hydrochloride and stirred for 3 hours at 80° C. and 14 hours at ambient temperature. The reaction mixture is evaporated down and the residue is poured onto 1000 mL of water and this mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the desiccant is filtered off and the filtrate is evaporated down. Yield: 49.6 g (90% of theory); C12H17ClN2O3 (M=272.73); calc.: molecular ion peak (M+H)+: 273; found: molecular ion peak (M+H)+: 273; Rf value: 0.36 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[OH:26])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7].Cl>O.C(O)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@@H:25]([OH:26])[CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:16]2[CH:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.36 %

Procedure:
A solution of 10% lithium hydroxide monohydrate in water (2 mL) was added to a solution of (R)-3′-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-ethylamino}-biphenyl-3-carboxylic acid methyl ester (50 mg, 0.12 mmol, 1.00 equiv) in ethanol (4 mL). The solution was stirred at ambient temperature for about 16 hours, and then the pH value of the solution was adjusted to 7-8 with concentrated hydrogen chloride. After concentrating the solution in vacuo, the resulting crude residue was purified by prep-HPLC to give the title product of as a white solid (20 mg; yield=41.36%). LC-MS: m/z=411 (MH)+. Retention time: 1.69 minute. [α]20.4D −20° (c=0.075, MeOH). [a]=−20° (c=0.075 g/100 ml in methanol, T=20.4). 1H NMR (300 MHz, CD3OD) δ: 8.22 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.29-7.38 (m, 4H), 7.20 (t, J=8.1 Hz, 1H), 6.97 (m, 2H), 6.68 (d, J=1.5 Hz, 1H), 5.00 (m, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.23-3.33 (m, 3H), 3.12 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:7][CH2:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cccc1CCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
10 ml of a saturated potassium carbonate solution are added to a solution of 4.96 g of 2-(2-aminoethyl)-1-methylpyrrole in 20 ml of dioxane, with stirring. Then at 0° C. a solution of 10.1 g of p-chlorobenzene sulphonylchloride in 30 ml of dioxane is added dropwise. The mixture is then stirred for 3 hours at ambient temperature, the precipitate is removed by suction filtering, washed with ether and the organic phase is separated off. After drying over sodium sulphate 10 g of crude product are obtained which is chromatographed over a silica gel column with methylene chloride/cyclohexane (9:1).
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C@@H:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@H:2]12.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[O:7]=[C:5]1[CH2:6][O:1][C@H:2]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C@H:3]2[N:4]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C1CO[C@H]2Cc3ccccc3[C@H]2N1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)CO[C@H]2Cc3ccccc3[C@H]21
Reaction time: 0.17 h

Procedure:
To a solution of (4aR,9aS)-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one from Step B (600 mg, 3.17 mmol) in DMF (15 mL) at 0° C. was added NaH (228 mg of a 60% dispersion in oil, 5.71 mmol) and the resulting mixture was stirred for 10 min. Ethyl bromoacetate (0.288 mL, 3.5 mmol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and then extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc 80:20 to 0:100, to give the title compound. MS: m/z=276 (M+1)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])N)=[CH:5][CH:4]=1.CC[O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([OH:25])=[O:23])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(C)c1ccccc1N(N)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CC(C)c1cccc2c3c(n(Cc4ccc(Cl)cc4)c12)C(CC(=O)O)CCC3

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-isopropylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:20][N:2]([CH3:1])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(Cc2ccc(N)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1
Yield: 164.4 %

Procedure:
A mixture of 4-(4-dimethylaminosulfonylbenzyl)-phenylamine (288 mg) and 2-chloro-imidazoline sulfate (110 mg) in 2-propanol was heated under reflux for 1 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaporated to give 2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline as a solid (320 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH2:9][C:10]([C:26]([O:28]CC)=[O:27])=[CH:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:13]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([C:8]1[CH2:9][C:10]([C:26]([OH:28])=[O:27])=[CH:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])=[CH:15][C:13]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1=Nc2cc(C(F)(F)C(F)(F)F)ccc2C=C(C(=O)O)C1
Reaction time: 4 h

Procedure:
To a solution of (1E,4E)-ethyl 2-(tert-butoxycarbonyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate in THF/H2O (4:1, 10 mL) was added LiOH.H2O (42 mg, 1.00 mmol). After 4 hours the mixture was made acidic (pH 4) with 10% citric acid and extracted with CH2Cl2 (2×100 mL). The combined organics were dried and concentrated. The material was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:38])[NH:33][CH2:34][CH2:35][CH2:36]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:38])[NH:33][CH2:34][CH2:35][CH2:36][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCI
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of triphenylphosphine (28.5 g, 108.6 mmol) and imidazole (7.39 g, 108.6 mmol) in CH2Cl2 (400 mL) at RT, is added iodine (28.92 g, 113.95 mmol) portionwise. To this solution is added a solution of (3-hydroxypropyl)-carbamic acid tert-butyl ester (18.66 g, 106.49 mmol) (Synthesis 1990, 366) in CH2Cl2 (75 mL) dropwise and the mixture allowed to stir at RT for 14 h. The mixture is then filtered and the filtrate concentrated to a crude red oil, which is partitioned between ether and sat. sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 200 mL and then filtered through a plug of silica, eluting with ether. Evaporation of solvent affords the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:30][CH2:31][CH2:32][OH:33])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: NCCO
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NCCO)cc1F
Yield: 24 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) was reacted with 2-aminoethanol (excess) to give the title compound (10 mg, 24%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>C1COCC1>[F:30][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1F)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.77 g, 10.8 mmol) (see Example 5) in THF (40 mL) at −78° C. was slowly added n-butyllithium (5.56 ml, 2.5M). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-fluorobenzenesulfonimide (4.11 g, 13.0 mmol) in THF (40 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL), and extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography (2% ethyl acetate/heptanes) afforded 1.40 g of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][N:4]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
A solution of tert-butyl 4-{1-[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (750 mg; compound B4) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-proline.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:6]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](C(OC(C)(C)C)=O)[CH:27]=[CH:28][C:21]=34)[CH:18]=[N:19][C:5]=2[NH:4][CH2:3]1>Cl>[NH:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:17]3[N:16]=[C:6]4[N:7]([CH2:8][CH2:9][CH:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[C:2](=[O:1])[CH2:3][NH:4][C:5]4=[N:19][CH:18]=3)=[C:21]2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cnc4c(n3)N(CCC3CCOCC3)C(=O)CN4)ccnc21
Agent: Cl
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Yield: 63 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibezylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2 [M+1]+.
Reaction SMILES: [O:1]([CH:9]([C:36]([F:41])([F:40])[CH2:37][CH2:38][CH3:39])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:41][C:36]([F:40])([CH2:37][CH2:38][CH3:39])[CH:9]([OH:1])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1

Procedure:
To a solution of methyl (Z)-7-[(1R)-(2R,3R,5S)-2-{4(RS)-t-butyldimethylsiloxy-5,5-difluorooctyl}-5-hydroxy-3-tetrahydropyranyloxycyclopentyl]hept-5-enoate (17) (1.90 g) in tetrahydrofuran was added tetrabutylammonium fluoride in tetrahydrofuran (1.0M, 15.7 ml). The resultant mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the obtained residue was subjected to silicagel column chromatography to give the titled compound (18).
Reaction SMILES: [CH3:1][N:2]([CH2:5][CH2:6][CH:7]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)OC.[CH3:24]O>[Ni]>[CH3:1][NH:2][CH2:5][CH2:6][C@:7]([CH3:24])([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: CO
Reactant: CON(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: [Ni]
Product: CNCC[C@](C)(Oc1cccc2ccccc12)c1cccs1
Reaction time: 12 h

Procedure:
N-methyl-N-methoxyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine obtained in example 3 was dissolved in 15 mL of methanol with 0.67 g of Raney-nickel charged in a glass autoclave. The resulting solution was hydrogenated at 50□ for 12 hours. Upon completion of hydrogenation, the reaction mixture was filtered and solvent is removed under reduced pressure, and then the desired compound is obtained as an oily compound (12.0 g, 96.4% by HPLC assay). 1H NMR (400 MHz, CDCl3) δ (ppm)=2.2 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.8 (m, 2H), 5.8 (m, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 7.5 (m, 2H), 7.8 (m, 1H), 8.3 (m, 1H).
Reaction SMILES: C(O[C@:9]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:10](=[O:12])[CH3:11])(=O)CCCCC.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:11][C:10](=[O:12])[C:9]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1
Reactant: CCCCCC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.3 %

Procedure:
One gram of 17α-hexanoyloxy-4pregnene-3,20-dione is heated analogously to Example 1 in "Dowtherm" for 80 minutes to 285° C., worked up, separated, and combined. Recrystallization from ethanol yields 600 mg of 4,16-pregnadiene-3,20-dione (83% of theory), m.p. 185°-190° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>CN(C=O)C>[CH2:41]([O:14][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)C(=O)O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-2-carboxyethyl]disulfanyl}propanoic acid LXVI (5.6 g; 11 mmol) and anhydrous potassium carbonate (6.08 g; 44.0 mmol) in DMF (50 mL) cooled to 0° C. was added benzyl bromide (7.8 mL; 66.0 mmol). The mixture was stirred overnight at r.t. Water (150 mL) was added, and solution was extracted once with DCM (40 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in diethyl ether (60 mL). The ether was washed with 10% aq Na2S2O3 until all the DMF was removed and once with water. The organic phase was dried over anhydrous MgSO4, evaporated and the residue purified on a silica gel column (100% CHCl3→200:3 CHCl3:MeOH). Benzyl (2S)-3-{[(2S)-3-(benzyloxy)-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl]disulfanyl}-2-{[(benzyloxy)carbonyl]amino}propanoate LXVII was obtained as a light-green viscous oil (5.9 g; 8.56 mmol; 77.8% yield). 1H NMR (CDCl3) 3.04-3.18 (m, 4H), 4.62-4.76 (m, 2H), 5.12 (s, 2H), 5.17 (s, 2H), 5.62-5.76 (m, 2H), 7.28-7.40 (m, 20H); ESIMS found for C36H36N2O8S2 m/z 689.5 (M+H).