Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:26]([CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2COS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of methyl 4-(2-mesyloxymethyl-5-chlorophenoxymethyl)benzoate (628 mg; prepared in Reference Example 48.) in DMF (5.0 ml), sodium azide (530 mg) was added in a stream of argon. The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate. The impurity was filtered with celite. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt =10:1) to give the title compound (404 mg) having the following physical data.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[Cl:17][CH:18]([F:33])[C:19]([F:32])([F:31])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:17][CH:18]([F:33])[C:19]([F:31])([F:32])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCOc1ccc(OC(F)(F)C(F)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(OC(F)(F)C(F)Cl)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.71 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-[4-(2-chloro-1,1,2-trifluoroethoxy)phenoxy]ethylamine (1.08 g) and triethylamine (0.40 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O.[Na+].[Cl-]>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Yield: 87242 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowly added drop-wise over 15 min to a cold (0-5° C.), stirring slurry of sodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol) in DMF (250 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The gray slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30 min. The resulting dark-brown mixture was allowed to stir and warm to ambient temperature over 16 h. Water (500 mL) was added and the mixture was divided into equal parts. Each half was diluted with saturated NaCl solution (200 mL) and extracted with ether (5×200 mL). All ether extracts were combined and concentrated to give 55.1 g (87.3%) of a dark-brown oil.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:34]([O:33][C:31](=[O:32])[NH:30][CH2:29][CH2:28][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17]2)[CH2:13]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydro-chloride (see Preparation B(iv) above; 10 g, 34 mmol) in water (25 mL) was added slowly to a solution of sodium bicarbonate (10 g, 119 mmol) in water 10 mL). More water (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. A solution of 2-(tert-butyloxycarbonylamino)ethyl tosylate (see Preparation A above; 11.92 g, 37 mmol) in toluene (40 mL) was added. This mixture was then heated at 65–70° C. for 7 hours before stirring at room temperature overnight. The reaction was reheated to 50° C. and the phases were separated. The aqueous layer was extracted with toluene (40 mL) at 50° C. The combined organic layers were washed with saturated sodium bicarbonate (25 mL). The solvents were evaporated under reduced pressure to yield a mixture of oil and solid (13 g, >100%). Ethyl acetate (50 mL) and citric acid (10%, 25 mL) were added to a portion of the oily solid (5 g, 138 mmol). The aqueous layer was separated and the organic layer washed again with citric acid (10%, 20 mL). The aqueous layers were combined and treated with solid sodium bicarbonate until neutral. The aqueous phase was extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound as a colourless semi-solid, which solidified fully when stored in the refrigerator (4.68 g, 93%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CN(C)C=O.[I-].C[N+](C)(C)[CH2:17][C:18]([C:20]1[C:29]2[CH:28]=[N:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=2[CH2:23][CH2:22][CH:21]=1)=[CH2:19]>C(N(CC)CC)C>[CH3:31][O:30][C:26]1[N:27]=[CH:28][C:29]2[C:20]([C:18]([CH2:17][C:2]3([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[CH2:19])=[CH:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: CC1C(=O)CCC1=O
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ncc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ncc21
Temperature: 25 °C

Procedure:
A solution containing 0.75 parts of 2-methylcyclopentane-1,3-dione in 19 parts of dimethylformamide is treated sequentially with 1.0 part by volume of triethylamine and 1.9 parts of N,N,N-trimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)ammonium iodide. The resulting homogeneous solution is heated at about 135° for 4 3/4 hours. It is allowed to cool to room temperature and solvent is removed under reduced pressure. The remaining material is diluted with water-ether and enough 5% sodium hydroxide solution is added to bring the pH to 10. The aqueous and organic layers are separated and the aqueous layer is extracted with ether. The extracts are washed sequentially with 5% sodium hydroxide solution, 2.5% aqueous formic acid and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. Upon solvent removal, an oil remains which is taken into ether. Then n-hexane is added until the solution becomes turbid. Charcoal is added and the mixture is filtered. Solvent is removed under reduced pressure to yield an oil which crystallizes upon standing. Recrystallization from acetone-water gives pure 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline, which is identical to the product obtained in Example 9 A.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:29][C:28]4[CH:30]=[CH:31][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 ml microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.105 g).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:51])[NH:5][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:18]=1)=[O:14])=[N:7]2.[OH:52][CH2:53][CH2:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1.[H-].[Na+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(N(C)C)=O.ClCCl.O>[F:12][C:11]1[C:2]([O:52][CH2:53][CH2:54][C:55]2[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:18]=1)=[O:14])[NH:5][C:4]2=[O:51]
Reactant: O=C(NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Reactant: O=C(O)c1ccc(CCO)cc1
Agent: CC[SiH](CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCOc2c(F)ccc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
A solution of 5,6-difluoro-4-oxo-N-({3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Step 1 of Example 44 (150 mg, 0.219 mmol) and 4-(2-hydroxyethyl)benzoic acid (40 mg, 0.241 mmol) in DMA (4 mL) was added dropwise to a suspension of 60% sodium hydride (oil dispersion, 0.031 mg, 0.767 mmol) in DMA (2 mL) at room temperature, and the mixture was stirred at room temperature for 20 min, and then stirred at 80° C. under heating for 3 hr. After the reaction mixture was allowed to cool to room temperature, water (50 mL) was added thereto, and the mixture was washed with ethyl acetate (50 mL×2) The aqueous layer was neutralized with 0.1N hydrochloric acid, and the objective compound was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in dichloromethane (2 mL) were added trifluoroacetic acid (0.47 mL) and triethylsilane (0.037 mL, 0.235 mmol) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mm×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from ethanol-diethyl ether to give the title compound as a yellow powder (36 mg, 28% in two steps).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH3:17])[C:4]=2[N:3]=1.[C:18]1([CH2:24][C:25]2[N:29]=[C:28]([CH2:30][CH2:31][CH2:32]O)[O:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:32][CH2:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([CH2:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:29]=3)[C:6](=[O:15])[N:5]([CH2:16][CH3:17])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Reactant: OCCCc1nc(Cc2ccccc2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCn1c(=O)n(CCCc2nc(Cc3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A solution of 8-chloro-3-ethyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.59 mmol) in anhydrous THF (4 ml) was treated with 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-propanol (154 mg, 0.71 mmol) and triphenylphosphine (200 mg, 0.76 mmol). DBAD (162 mg, 0.71 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was degassed by high vacuum then Pd(PPh3)4 (68 mg, 0.059 mmol) and morpholine (515 μl, 5.9 mmol) were added. The mixture was left to stir at rt, under nitrogen, for 3 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude material was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities, then with 2% AcOH/MeOH to elute the compound. The UV active fractions were combined and concentrated by high vacuum. The product was further purified by MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (61 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24]([Br:33])[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].BrC1C=C(C=C(OCCCCCCC2C=CC=C(OCCCC(OCC)=O)C=2CCC(OCC)=O)C=1)C(O)=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[F:106][C:107]1([F:112])CCN[CH2:108]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]([N:29]3[CH2:30][CH2:108][C:107]([F:112])([F:106])[CH2:31]3)=[O:32])[CH:25]=[C:24]([Br:33])[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: FC1(F)CCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)O)c2)c1CCC(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N3CCC(F)(F)C3)c2)c1CCC(=O)OCC
Yield: 92 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid (550 mg, 0.905 mmol), PyBroP (508 mg, 1.09 mmol), 3,3-difluoropyrrolidine hydrochloride salt (156 mg, 1.09 mmol) and DIPEA (473 uL, 2.72 mmol) in dichloromethane (15 mL) to obtain 4-[3-{6-[3-bromo-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (580 mg, 92%) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:23])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C)=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2].O1CCCC1.N.[Li]>C(O)(C)(C)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:23])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.0 g. of 16β-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol in 40 ml. of tetrahydrofuran and 4 ml. of tert.-butanol is added dropwise at -40° C. to 80 ml. of ammonia. After the incremental introduction of 1.2 g. of lithium, the mixture is stirred for 2 hours at -40° C.; then the ammonia is allowed to evaporate, the residue is poured into about 200 ml. of water, and the mixture is extracted with ethyl acetate. The crude product is taken up in 40 ml. of methanol and 4 ml. of 4 N hydrochloric acid and agitated for 15 minutes at 50° C. Thereafter, the mixture is poured into water and extracted with methylene chloride. After recrystallizing the crude product from ethyl acetate/ether, 1.7 g. of 16β-ethyl-17β-hydroxy-4-estren-3-one is produced, m.p. 150°-152° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].Cl>O1CCCC1.O>[OH:22][CH:21]([CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]#[N:24]
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 5.2 g of crude 1,4-dibenzyl-2-formylpiperazine in a mixture of 30 ml of tetrahydrofuran and 10 ml of water are added 2.2 g (33.8 mmoles) of potassium cyanide and 3.4 ml of concentrated hydrochloric acid under ice-cooling, and the mixture is stirred for 30 minutes, mixed with water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 5.70 g of crude oily 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetonitrile.
Reaction SMILES: CO.[Li+].[BH4-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:23])([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11](OCC)=[O:12].[NH4+].[Cl-]>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:23])([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:11][OH:12]
Reactant: CCOC(=O)C(C)(CCCCBr)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(C)(CO)CCCCBr)cc1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
Methanol (3.14 g, 98.22 mmol) was added drop-wise to a stirred suspension of LiBH4 (2.19 g, 101 mmol) in anhydrous CH2Cl2 (50 mL) under N2 atmosphere. After the addition of ethyl 6-bromo-2-methyl-2-p-tolyl-hexanoate (22 g, 67.28 mmol), the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 5° C. and hydrolized with ice (ca. 40 g) and saturated NH4Cl solution (150 mL) for 1 h. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with saturated NH4Cl solution (3×150 mL), dried over anhydrous MgSO4 and concentrated in vacuo to furnish 6-bromo-2-methyl-2-p-tolyl-hexan-1-ol (18.44 g, 96.2%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.24-7.00 (m, 4H), 3.68-3.50 (m, 1H), 3.49-3.35 (m, 1H), 3.34-3.21 (t, J=6.9 Hz, 2H), 2.31 (s, 3H), 1.88-1.51 (m, 4H), 1.51-1.40 (m, 2H), 1.31 (s, 3H), 1.20-1.00 (m, 1H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 141.49, 135.74, 129.47, 126.63, 72.54, 43.03, 37.53, 33.69, 33.51, 22.66, 21.58, 20.98. HRMS (LSIMS, nba): Calcd. for C14H20Br (MH+—H2O): 267.0748, found: 267.0750.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)([N:15]=[C:16]=[O:17])=[O:14]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]1([CH:7]2[C:8]3[O:12][C:16](=[O:17])[NH:15][C:13](=[O:14])[C:9]=3[CH2:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC1c1ccccc1
Reactant: O=C=NC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CC2
Yield: 13.1 %

Procedure:
A solution of 2-phenylcyclopentanone (19.995 g, 125 mmol) and carbonisocyanatidic chloride (23.70 g, 225 mmol) was stirred at 58° C. for 1 h and at 130° C. for 45 min. The resulting tar was dissolved in ethyl acetate and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The product was purified by column chromatography on silica gel to give 7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g, 16.36 mmol, 13% yield) as a brownish solid. LC-MS (M+H)+=230.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18 (2H, d, J=7.3 Hz), 4.20 (1H, t, J=7.6 Hz), 2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:25](N[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)CC)(C)C.C(N)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:28]([O:27][C:25](=[O:26])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C:6]([CH3:7])([CH3:9])[CH3:8])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The Preparation of (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Ia) ##STR26## Step i: N-Boc-O-Benzyl-tyrosine (20.0 g, 53.9 mmol) was dissolved in DMF (270 mL) and treated with diisopropylethylamine (19 mL, 108 mmol), tert-butylamine (5.7 mL. 53.9 mmol), and HBTU (13.9 g, 53.9 mmol). The reaction was stirred for 15 minutes and then diluted with EtOAc (1 L), washed with saturated bicarbonate solution (2×1 L) and brine (1 L), dried over Na2SO4 and concentrated to give 22.1 g (92%) of (S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].F[P-](F)(F)(F)(F)F.C[N+:28](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[NH2:28][C:12]([CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (from Activate Scientific. 0.25 g, 1.2 mmol), ammonium acetate (0.14 g, 1.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.71 g, 1.9 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.43 mL, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.156 g, 63%). LCMS calculated for C9H16N2O3Na (M+Na)+: m/z=223.1. Found: 223.0.