Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:38])[NH:14][C:15]2[CH:20]=[CH:19][C:18]3=[N:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=4)=[CH:23][N:17]3[N:16]=2)[CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([NH:31][C:26]1[CH:25]=[C:24]([C:22]2[N:21]=[C:18]3[N:17]([CH:23]=2)[N:16]=[C:15]([NH:14][C:13]([C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:39])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[O:38])[CH:20]=[CH:19]3)[CH:29]=[CH:28][C:27]=1[CH3:30])=[O:37]
Reactant: CCOC(=O)C=Cc1cccc(C(=O)Nc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)O)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 20-mL vial is charged with ethyl-3-[3-[[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]carbamoyl]phenyl]prop-2-enoate (0.042 g, 0.08 mmol) and a solution of THF-MeOH (1 mL, 1:1). To this mixture is added aqueous NaOH (1 mL, 1 M), then stirred at 50° C. for 1 hour. The mixture is concentrated to remove the organics and extracted with EtOAc once. Aqueous HCl (1M) is added to lower the pH to 2 and the resulting solids are filtered to give the title compound (0.025 g), which is used without further purification. LCMS (m/z)=498.5 [M+H]+, tR=2.47 min.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:3].C(N(CC)CC)C.[N+:25]([C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(Cl)Cl>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:33]([C:31]3[S:32][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)(=[O:35])=[O:34])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH3:1]
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 3-(1-methylethyl)-4-((2R)-2-piperazinylmethyl)-2-piperazinone (186 mg, 0.774 mmol) and triethylamine (324 μL, 2.32 mmol) in CH2Cl2 (5.00 mL) was added a solution of 5-nitrothiophene-2-sulfonyl chloride (190 mg, 0.836 mmol, Enamine, Kiev, Ukraine) in CH2Cl2 (1 mL) drop-wise at room temperature. The solution was stirred for 30 min and then the mixture was concentrated. The residue was dissolved in CH2Cl2, the organics were washed with water followed by brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH to give 3-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-2-piperazinone (263 mg).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:32](=[O:37])[CH:33]([Cl:36])[CH2:34][CH3:35]>O>[CH2:1]([N:7]([CH2:8][CH2:9][CH:10]1[O:11][C:12]([CH3:17])([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14]1)[C:32](=[O:37])[CH:33]([Cl:36])[CH2:34][CH3:35])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: CC=CCCCNCCC1OC(C)(C)C(C)(C)O1
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC=CCCCN(CCC1OC(C)(C)C(C)(C)O1)C(=O)C(Cl)CC

Procedure:
N-Hex-4-enyl-N-(4,4,5,5-tetramethyl-1,3-dioxolan-2-ylethyl)-amine (10 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 5° to 10° C. and α-chlorobutanoyl chloride (7 grams) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-hex-4-enyl-N-(4,4,5,5-tetramethyl-1,3-dioxolan-2-ylethyl)-α-chlorobutanamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[CH:22][CH:21]=1>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:30][CH:29]=3)[CH2:26]2)[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(OC2CN(c3cccc(Br)n3)C2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
To 2-bromo-6-fluoropyridine (150.0 mg, 0.852 mmol) in 2-propanol (3.00 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.445 mL, 2.56 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (174 mg, 0.852 mmol). The resulting reaction mixture was stirred at RT for 3.5 h, then heated to 70° C. for 24 h, cooled to RT and concentrated. Purification of the crude product using MPLC (5 g cartridge, 12 g column, 0 to 60% EtOAc-hexanes) gave 2-bromo-6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (211.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[N:25][CH:24]=[CH:23]2)=[CH:18][CH:17]=1)=[O:15]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([OH:11])([CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:20][CH:21]=1)=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:10]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Solvent: CCO
Product: CCOC(=O)C(O)(CC(=O)c1ccc(-n2ccnc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of diethylketomalonate (87.08 g, 0.50 mole) and 4-(imidazol-1-yl)acetophenone (93.1 g, 0.50 mole) is warmed to 95°-100° C. with stirring for three hours. During this time, the original tan slurry is transformed into a black syrup. At the end of three hours, anhydrous ethanol (130 ml) is added with stirring, resulting in a black solution. This solution is cooled to room temperature, an aliquot is removed and scratched to induce crystallization, and the crystals thus obtained returned to the cool solution. Upon standing overnight at 8° C., the solution forms a solid mass, which is suspended in absolute ethanol (100 ml) and filtered to obtain a brownish solid, which is dried at 43° in a vacuum oven for four hours to yield 67 g hydroxy [2-[4-(1H-imidazol-1-yl)-phenyl]-2-oxoethyl]propanedioic acid diethyl ester. Material thus obtained is suitable for use without additional purification, however, it can be recrystallized from methanol to give pure product, mp 155°-156° C.
Reaction SMILES: [NH:1]([C:26]([CH3:28])=[O:27])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23](O)=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(OC([NH:35][CH:36]([C:45](=[O:56])[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=O)C=C>>[C:26]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([CH:37]([C@H:36]([NH2:35])[C:45](=[O:56])[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])[C:38]([OH:40])=[O:39])=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)(=[O:27])[CH3:28]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)C(C(=O)O)[C@H](N)C(=O)COCc1ccccc1Cl)C(C)C

Procedure:
N-Acetyl-(S)-tyrosinyl-(S)-valinyl-(S)-alaninyl-3(S)-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (89) was prepared from Ac-Tyr-Val-Ala-OH and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenyl-methoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.5 (d, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.55-7.3 (m, 4H), 7.0 (d, 1H), 6.6 (d, 2H), 4.6-4.3 (m, 6H), 4.3-4.1 (m, 2H), 2.9 (d, 1H), 2.76 (dd, 1H), 2.7-2.5 (m, 2H), 1.95 (m, 1H), 1.75 (s, 3H), 1.2 (d, 3H), 0.9-0.7 (dd, 6H)
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[O:22])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2].S([O-])(O)=O.[Na+].C(OCC)(=O)C.[C-:45]#[N:46].[K+]>O>[C:1]([N:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]([NH:19][C@@H:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]([OH:22])[C:45]#[N:46])=[O:18])[C:6](=[O:30])[CH:5]1[CH:31]([CH3:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](C=O)Cc2ccccc2)C(=O)C1C(C)C
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C#N)C(=O)C1C(C)C
Reaction time: 0.5 h

Procedure:
(2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal (630 mg, Compound No. 7-1) is suspended in water (6 ml). Sodium hydrogensulfite (160 mg), water (6 ml) and ethyl acetate (18 ml) are added to the suspension, and the mixture is stirred for 30 minutes. Potassium cyanide (105 mg) is added to the mixture, and the whole is stirred for one day. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (624 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2
Reactant: NCc1ccccn1
Reactant: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccc2nc(-c3cncnc3)nc(NCc3ccccn3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To a stirred suspension of 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (2.0 g, 6.5 mmol) in DMF (20 mL) was added diisopropylethyl amine (3.4 ml, 19 mmol) followed by PyBroP (3.7 g, 7.9 mmol). After 5 min stirring at room temperature, 2-aminomethylpyridine (1.0 mL, 9.8 mmol) was added to the reaction. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 2 h (during which time reaction became a clear solution). At the conclusion of this period, the reaction mixture was quenched by the addition of cold water and then extracted into 50% ethyl acetate and hexane mixture (200 mL). The organic extracts were dried, concentrated, purified by column chromatography using ethyl acetate and hexanes as eluent to yield the crude produce. The crude product was further purified by trituration with ethyl acetate and hexane to yield 5-bromo-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (0.5 g, 20% yield). 1H NMR (400 MHz, CDCl3, δ): 5.07 (d, J=4.4 Hz, 2H); 7.26 (m, 1H); 7.41 (d, J=7.6 Hz, 1H); 7.53 (t, J=8 Hz, 1H); 7.71-7.73 (m, 2H); 7.86 (dd, J=0.8 Hz, 8.4 Hz, 1H); 8.65 (d, J=4 Hz, 1H); 9.30 (s, 1H); 9.38 (br s, 1H); 9.75 (s, 2H). ES-MS: [M++1]=393 and [M++3]=395.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:25][CH:26]([CH2:36][CH2:37][C:38]([NH:40][CH3:41])=[O:39])[C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28]>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:25][CH:26]([CH2:36][CH2:37][C:38]([NH:40][CH3:41])=[O:39])[C:27]([N:29]([CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH3:35])=[O:28])=[O:10]
Reactant: O=C(O)C=Cc1ccco1
Reactant: CCCN(CCC)C(=O)C(N)CCC(=O)NC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)C(CCC(=O)NC)NC(=O)C=Cc1ccco1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 75 ml of methylene chloride was dissolved 1.5 g of β-(2-furyl)acrylic acid, and 2.7 g of triethylamine and 1.3 g of ethyl chlorocarbonate were successively added thereto dropwise at -25° C. to -20° C. After 30 minutes, 3 g of the DL-2-amino-N5 -methyl-N1,N1 -di(n-propyl)-pentane-1,5-diamide hydrochloride was added to the above solution, and the resulting mixture was subjected to reaction at the same temperature for 30 minutes and at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was washed successively with 30 ml of a 5% aqueous sodium hydroxide solution, 30 ml of diluted hydrochloric acid and 30 ml of water and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 3.1 g (yield 80%) of DL-2-[β-(2-furyl)acrylamido]-N5 -methyl-N1,N1 -di(n-propyl)pentane-1,5-diamide having a melting point of 112°-113° C.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH3:6])#[N:2].[C:10]([C:12]1[CH:25]=[CH:24][C:15]2[O:16][C:17]([CH3:23])([CH3:22])[C@@H:18]([OH:21])[C@H:19]([NH2:20])[C:14]=2[CH:13]=1)#[N:11]>C(OCC)(=O)C>[C:10]([C:12]1[CH:25]=[CH:24][C:15]2[O:16][C:17]([CH3:23])([CH3:22])[C@@H:18]([OH:21])[C@H:19]([NH:20][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH3:6])[C:14]=2[CH:13]=1)#[N:11]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(CC)=NC#N
Solvent: CCOC(C)=O
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 1.39 g of ethyl N-cyanopropionimidate, 2.17 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate Then, ethyl acetate was distilled off under reduced pressure The residual oily substance was purified by silica gel column chromatography to obtain 1.48 g of the above identified compound in the form of crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=O)(=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCN(CC)CC.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](Cl)=[S:29])[CH3:26]>CCOC(C)=O>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](=[S:29])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:26]
Reactant: CCN(CC)C(=S)Cl
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=S)Oc1ccc2c(c1)Oc1ccccc1S2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 3-hydroxyphenoxathiin (310 mg, 1.43 mmol) (Example 7), Et3N (0.30 ml, 2.15 mmol) and N,N-diethylthiocarbamoyl chloride (238 mg, 1.57 mmol) in EtOAc (25 mL) was refluxed for 3 h, cooled to room temperature and the precipitated hydrochloride salt filtered. The filtrate was washed with 10% aqueous HCl (30 mL), saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated in vacuo to an orange oil (479 mg). The crude product was purified by radial chromatography (EtOAc/hexane 10:90) to give 282 mg (66%) of the title compound as a white solid: mp 121-123° (EtOAc); TLC (EtOAc/hexane, 15:85) Rf =0.43; 1H-NMR (CDCl3) δ 1.32 (=7Hz, 6H), δ 3.68 (q. J=7 Hz, 2 H), δ 3.90 (q, J=7 Hz, 2 H), δ 6.75 (d, J=6 Hz, 1 H, C2 -H), δ 6.78 (s, 1 H, C4 -H), δ 6.95-7.13 (m, 5H): MS m/e (relative intensity) 332 (MH+, 100), 116 (22).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[C:32]([CH:33]=O)=[CH:31][CH:30]=[C:29]1[C:35]([O:37][CH3:38])=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:38][O:37][C:35]([C:29]1[N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:32]([CH2:33][N:18]2[CH2:19][CH2:20][CH:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:16][CH2:17]2)=[CH:31][CH:30]=1)=[O:36]
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C=O)n1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 100-mL three-neck flask, 1.1 g (4.0 mmol) of 4-benzhydryloxypiperidine synthesized in Production Example 1, 1.0 g (4.0 mmol) of methyl N-tert-butoxycarbonyl-5-formylpyrrole-2-carboxylate, and 20 mL of dichloromethane were fed under an argon atmosphere, and the internal temperature was cooled to 0° C. Thereinto, 1.3 g (6.1 mmol, 1.5 eq.) of sodium triacetoxyborohydride was added at an internal temperature of not higher than −5° C., and the mixture was stirred for 5 minutes at the same temperature. Then, the mixture was heated to a room temperature and stirred overnight.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(CC)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-ethyl aniline (10.00 g) in acetic acid (20 mL) was added ethyl acrylate (8.26). The mixture was heated to 70° for 3.5 hours. The mixture was allowed to cool to room temperature. The mixture was partitioned between dichloromethane and water, and was extracted three times. The combined organics were washed once with brine, dried with sodium sulfate, filtered, and concentrated. The mixture was taken on to the next step. MS (ESI+) for C13H19NO2 m/z 223.1 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.C(Cl)(=O)C>[CH3:22][C:21]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (1) (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C(Br)(Br)(Br)[Br:18].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:18])=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: OCc1ccc(Br)c(OC2CCCCO2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCc1ccc(Br)c(OC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
The title compound was prepared adapting the method reported by Wada et al.[Wada, 1979] with the following modifications. To a solution of 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl alcohol (3.0 g, 10.45 mmol), carbon tetrabromide (6.93 g, 20.90 mmol) and anhydrous pyridine (0.85 mL, 10.45 mmol) in anhydrous Et2O (50 mL) at 0° C. was added dropwise a solution of triphenylphosphine (5.48 g, 20.90 mmol) in anhydrous Et2O (10 mL). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was removed in vacuo and the residue suspended in n-hexane and filtered. The filtered solid was washed with n-hexane and the combined filtrates concentrated in vacuo to ca. 10 mL. The residue was purified by flash column chromatography [SiO2, EtOAc/n-hexane (5:95)] to give 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl bromide as a pale yellow oil (2.82 g, 77%) which slowly darkened on exposure to light and air; ¤H (270 MHz, CDCl3) 1.58-2.12 (m, 6H), 3.58-3.65 (m, 1H), 3.83-3.92 (m, 1H), 4.41 (d, J=12.6, 2H), 5.53 (m, 1H), 6.89 (dd, J=7.9, 2.0, 1H), 7.16 (d, J=2.2, 1H), 7.48 (d, J=8.2, 1H); LC-MS (APCI−): tR=4.71 min, m/z 266.95 (48, C12H1481Br2O4—C5H8O—H), 264.93 (100, C12H14Br2O4—C5H8O—H), 262.92 (50, C12H1479Br2O4—C5H8O—H); HPLC: tR=3.91 min (94%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20][O:21]C1C=CC=C2C=1NC=C2>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COc1cccc2cc[nH]c12
Product: COc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methoxy-1H-indole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C@H:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][N:10]=2)=[CH:5][CH:4]=1)#[N:2].[C:18](OC(=N)N(C(C)C)C(C)C)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.Cl[Cu]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][C@H:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[O:11][N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: N#Cc1ccc(C2=NO[C@@H](CC(=O)O)C2)cc1
Agent: Cl[Cu]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC(c2ccc(C#N)cc2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a suspension of [3-(4-cyanophenyl)isoxazolin-5(R)-yl]acetic acid(500 mg, 2.17 mmol) in CH2Cl2 (20 ml) cooled in an ice-water bath was added a 1.6M solution of O-tert-butyl-N, N-diisopropylisourea, cat. CuCl(4 ml). The resulting mixture was stirred at rt for 48 hrs and then filted. The fitrate was concentrated and the residue dissolved in EtOAc. The EtOAc solution was washed with brine and then dried over Na2SO4. After concentration, the residue was chromatographed with a mixture of EtOAc and hexane to afford 600 mg of the product as a white solid(96%). 1H NMR(300 MHz, CDCl3) δ1.48(s, 9H), 2.60(dd, 1H), 2.60(dd, 1H), 3.16(dd, 1H), 3.52(dd, 1H), 5.169m, 1H0, 7.70(d, 2H), 7.78(d, 2H); MS(ESI) Calc. for (M−1)+: 285. Found: 285.