Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33].C[Al](C)C>>[CH2:31]([NH:34][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:2])[CH2:32][CH3:33]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reactant: CCCN
Agent: C[Al](C)C
Product: CCCNC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a mixture of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (150 mg, 0.37 mmol) and 44 mg of n-propyl amine was added Me3Al (catalytic amount, 2M in toluene) under an argon atmosphere in a seal tube and the mixture was heated at 100° C. for 16 hr. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was then purified by silica gel column chromatography to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid propylamide (30 mg, 18.7% yield) as a white solid. MS calcd. for C26H36N3O3 [(M+H)+] 438.0, obsd. 438.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1.O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A stirred slurry of 21.1 g (0.1 mole) of 5-chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mole) of 4-(N,N-dimethylamino)pyridine in 200 ml of N,N-dimethylformamide was cooled to ice-bath temperature, and then a solution of 16.1 g (0.11 mole) of 2-thenoyl chloride in 50 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 1 liter of water and 75 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and then the solid was collected by filtration. The solid was washed with water and then recrystallized from 1800 ml of acetic acid, to give 26.6 g of the title compound as fluffy, yellow crystals, m.p. 230° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[N:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:27][CH:26]=2)[O:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)C>C(#N)C>[Cl:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:17]2[O:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:16]=2)=[CH:26][CH:27]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of piperidine (90 μl, 0.86 mmol, 1.1 eq) and potassium carbonate (0.43 g, 3 mmol, 4 eq) in acetonitrile (5 ml) is treated dropwise with a solution of ethyl 4-(bromomethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i93 (0.30 g, 0.77 mmol, 1 eq) in acetonitrile (2 ml) and is stirred at room temperature overnight. Diethyl ether is then added and the solution is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 210 mg of crude ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95, used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(Nc2ccc(F)cc2F)nc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (100 mg; 0.35 mmol) in THF (2.2 ml) is treated at −78 C with nBuLi (0.48 ml of a 1.5M solution in hexane; 0.77 mmol). After 10 min at −78 C, 5-bromo-2-methoxybenzaldehyde (75 mg; 0.35 mmol) in THF (0.3 ml) is added and stirring continued for 30 min. at −78 C. The reaction mixture is poured on water/ice and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; TBME/hexanes 3/7) yields the title compound (60 mg; 40%)
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1.CS(C)=O.[C-:25]#[N:26].[Na+].O>[Cl-].[Na+].O>[C:25]([CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1)#[N:26]
Reactant: COC(=O)[C@H]1C[C@@H](CCBr)CCN1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](CCC#N)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 12.95 g (0.031 mol, containing triphenylphosphine oxide) of methyl cis-4-(2-bromoethyl)-N-t-butoxycarbonyl-2-piperidinecarboxylate and 40 ml of DMSO was added 2.30 g (0.047 mol) of sodium cyanide. The mixture was stirred for approximately 30 minutes at 50° C. To the mixture was added 50 ml each of water and brine and the mixture was extracted four times with methylene chloride and once with diethyl ether. The organic extracts were combined, washed twice with water and once with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resultant residue was dissolved in 100 ml of ethyl acetate:hexane (1:3, v:v) and filtered through a one inch pad of silica gel (230-400 mesh) in a 150 ml medium porosity sintered glass funnel. The silica gel pad was washed with an additional 400 ml of ethyl acetate:hexane (1:3, v:v). The filtrate was concentrated under vacuum to afford 7.85 g of methyl cis-4-(2-cyanoethyl)-N-t-butoxycarbonyl-2-piperidinecarboxylate.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
8 g (61.5 mmol) of ethyl acetoacetate were dissolved in 280 ml of CH2Cl2, the solution was cooled at 0° C. and successively were added 6.00 g (63.3 mmol) of anhydrous magnesium chloride, 10 ml (124 mmol) of pyridine and 13.4 g (94.73 mmol) of isonicotinoyl chloride. The yellow suspension was stirred 1 h under ice cooling and 18 h at room temperature. The reaction mixture was poured into crashed ice and extracted twice with CH2Cl2. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography (n-heptane:EtOAc 1:4) to afford the title compound as light yellow oil (6.75 g, 47%). MS: 236.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)c1cc(F)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Intermediate 50 (50 g, 0.217 moles) was taken in a RB flask and to this acetic anhydride (424 ml) and sodium acetate (124 g, 1.51 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as colourless solid (44 g, 80% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87(dd, J=8.3,3.0 Hz, 1H), 7.47-7.35(m,5H), 7.29(m, 2H), 2.32(s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=1.[CH3:32]N(C)C=O.C(O)(=O)C.C(O)(=O)C.C(N)=N>O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:32]=[N:16][NH:15][C:14]3=[O:17])=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])=[CH:20][CH:19]=1
Reactant: NNC(=O)Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Reactant: CN(C)C=O
Agent: N=CN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ncn1-c1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
4-[4-[5-Oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,4H-1,2,4-triazol-1-yl]phenyl]semicarbazide (4.75 g) was added to N,N-dimethylformamide (60 ml). To the mixture were added acetic acid (4 g) and formamidine acetate (6 g), and the resulting mixture was stirred at room temperature for 3 hours and then at 80° C. for 1.5 hours. After cooling, the reaction solution was diluted with water (30 ml). The precipitated crystals were collected by filtration and washed with water (100 ml). The crystals were dried and dissolved in a mixture of tetrahydrofuran (300 ml) and ethyl acetate (600 ml) with warming. The solution thus obtained was dried over anhydrous magnesium sulfate, filtrated and concentrated under reduced pressure. Ethyl acetate (50 ml) was added to the residue and the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran to give 4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,4H-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.4 g, 49%) as a white crystalline powder.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:31](=[O:32])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:23][CH:22]=1)[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. mixture of 9.0 g of product from Example 19, 4.44 g of pyridine and 70 ml of methylene chloride is added, dropwise, 5.28 of phenyl chloroformate. The reaction is stirred at 0° C. for 15 minutes; followed by room temperature for 30 minutes. The mixture is poured into saturated sodium bicarbonate and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 0-5% ethyl acetate/hexane) to give 12.6 g of colorless prisms.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:28][CH3:29])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:32]>>[C:1]1([S:7]([C:10]2[C:11]([S:28][CH3:29])=[N:12][N:13]3[C:18]([Cl:32])=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(O)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A suspension of 4.0 g (9 mmol) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 100 ml of POCl3 was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 150 ml of CH2Cl2 and the organic phases were dried (MgSO4), filtered and evaporated. Chroma-tography (SiO2CH2Cl2/MeOH 10:1) of the residue yielded 4.0 g (98%) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as a pale brown powder, m.p. 113-116°.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH2:23]([C@H:25]1[O:27][CH2:26]1)[Cl:24]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].O>[C:2]([O:6][C:7](=[O:22])[C@@H:8]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:26][C@H:25]([OH:27])[CH2:23][Cl:24])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reactant: ClC[C@@H]1CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCl)C(=O)OC(C)(C)C
Yield: 39 %

Procedure:
A solution of 3 (4.83 g, 14.3 mmol) in chloroform (100 mL) was extracted with saturated NaHCO3 solution (2×100 mL) and water (100 mL). The organic layer was dried, concentrated, and further dried in vacuo. The resulting oil was dissolved in cyclohexane (26 mL), and (S)-(+)-epichlorohydrin (1.58 g, 17.1 mmol) was added under an Ar atmosphere. The precipitated product was filtered after 27 h, washed with cold cyclohexane, and dried in vacuo to give 12a (2.20 g, 39%) as a fine, white powder: mp 87-88° C.; 1H NMR δ 1.30-1.83 (m, 6H), 1.44 (s, 9H), 1.46 (s, 9H), 2.57-2.66 (m, 3H), 2.77 (dd, 1H, J=12.2, 3.9), 3.51 (dd, 1H, J=11.2, 5.7), 3.56 (dd, 1H, J=11.2, 5.2), 3.84-3.91 (m, 1H), 3.94 (dd, 1H, J=8.6, 5.3); 13C NMR 6 24.6, 28.3, 28.7, 30.0, 32.6, 48.2, 50.3, 53.5, 55.8, 71.1, 80.4, 82.5, 158.1, 173.8; HRMS m/z calcd for C18H36ClN2O5 395.2313, found 395.2303. Anal. calcd. for C18H35ClN2O5: C54.74, H 8.93, Cl 8.98, N 7.09. Found: C 54.80, H. 8.99, Cl 9.02, N 7.08 [α]22D−26.1° (c 1.00, CH3OH).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of 1.53 g (5 mmol) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was added 20 mL (20 mmol) of 1M BBr3 in methylene chloride and the mixture stirred for 3 hours. Water was added and the mixture extracted with EtOAc. The EtOAc solution was washed with a NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica and the product eluted with 5% MeOH/methylene chloride to give 658 mg (45% yield) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 174°-179° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:51])[N:29]([C@H:31]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35]1)=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:44]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:51])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:42])[CH3:43])[CH2:35]1)=[O:33])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@@H](CN(C)C)C1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.7 %

Procedure:
At 0° C., trifluoroacetic acid (20 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (1.189, 1.92 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 50 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (80 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 788 mg of (2R)-N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)m ethyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [C:1]([Sn:5]([Cl:11])(F)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:17]([Li])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC>[C:1]([Sn:5]([Cl:11])([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Sn](F)(Cl)C(C)(C)C
Solvent: CCCCCCC
Solvent: CCCCC
Product: CC(C)(C)[Sn](Cl)(C(C)(C)C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A suspension of di-t-butyltin chloride fluoride (5.0 g., 0.017 mole) in heptane (100 ml.) was cooled to -78° C., and a pentane solution of t-butyl-lithium (20 ml., 1.95 M) was added dropwise. After the addition was completed, stirring was continued for 2 hrs., the cooling bath was removed, and the mixture was allowed to warm to room temperature with stirring for 6 more hrs. The resulting pale yellow mixture was worked up to give a thick, pale yellow oil which was chromatographed with pentane. Evaporation of the solvent left a clear oil which solidified spontaneously (5.0 g., 88.3%), m.p. 31-32; (b.p. 122°-123°/5 mm. (Found: C, 44.15; H, 8.15; Cl, 10.95. C12H27ClSn requires C, 44.3; H, 8.35; Cl, 10.9%); n.m.r. 61.35 (s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[S:12]([O:19]S(C(F)(F)F)(=O)=O)([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]>N1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[S:12]([OH:19])(=[O:14])=[O:13].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Oc1ccc2ccncc2c1
Solvent: c1ccncc1
Product: O=S(=O)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.5 g (0.0103 mol) of 7-hydroxyisoquinoline and 5.3 ml of pyridine are cooled to 0° C. 1.86 ml of triflic anhydride are added dropwise thereto. The mixture is stirred for 1 hour at 0° C. and then for 2 hours at room temperature. The resulting mixture is poured into a water/ice mixture and extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a column of silica gel, eluting with a 7/3 cyclohexane/ethyl acetate mixture. 7-Hydroxyisoquinoline trifluoromethanesulphonate is obtained in the form of an oil. 1.65 g of this product are mixed with 27.5 ml of anhydrous dimethylformamide, 41 mg of palladium acetate, 1.65 ml of anhydrous triethylamine and 1.38 g of N,N-diethylethanolamine vinyl ether, under argon. This mixture is heated at 80° C. for 36 hours. The resulting mixture is poured into a water/ethyl acetate mixture, the two phases are separated, the organic phase is washed with water and dried, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a 9/1 ethyl acetate/methanol mixture. 2-[2-(7-Isoquinolyl(ethenyl)oxy)]-N,N-diethyl-1-ethanamine is obtained. 1.5 g of this product are treated with 130 ml of water and 13 ml of 96% sulphuric acid. This mixture is heated for 4.5 hours at 60° C. and poured into ice, saturated aqueous NaHCO3 solution is added thereto and the mixture is extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated off under reduced pressure. The title compound is obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28]C(=O)C)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([OH:28])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
IN 2 ml of methanol was dissolved 73 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carbaldehyde, followed by addition of 5 mg of potassium carbonate. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with diethyl ether, and the extract was washed with aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was recrystallized from ether to give 49 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde which showed the same 1H NMR spectrum as the 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde obtained in Reference Example 2.
Reaction SMILES: Cl.[C:2](=[N:10][OH:11])(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.I[C:13]([CH:15]1[CH2:17][CH2:16]1)=[CH2:14].C(N(CC)CC)C>C(O)C>[CH:15]1([C:13]2[O:11][N:10]=[C:2]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=2)[CH2:17][CH2:16]1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C=C(I)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cncc(-c2cc(C3CC3)on2)c1
Reaction time: 1 h

Procedure:
To a stirred mixture containing 1.35 g. of nicotinoyl chloride oxime hydrochloride and 2.6 g. of 1-iodovinylcyclopropane in 50 ml. of ethanol is added dropwise over a 1 hour period, a solution of 4.27 g. of triethylamine in 40 ml. of ethanol. The reaction is stirred for 1 hour and then the solvent is removed under reduced pressure. The residue is dissolved in water and ether and the ether layer is separated. The water layer is extracted twice with ether and then the combined ether layers are dried over sodium sulfate. Filtration and removal of the solvent under reduced pressure gives an orange-yellow solid. This material is recrystallized from isopropyl alcohol to give white crystals, melting point 74°-75°C., nmr spectrum δ6.82 (DMSO-d6, s, 4-isoxazolyl H).