Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[OH:11]O.[OH-].[Na+:14]>CO>[Na+:14].[N+:1]([C:4]1[C:8]([C:9]([NH-:10])=[O:11])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1c[nH]nc1[N+](=O)[O-]
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c[nH]nc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution was made of 8 gm. of 1-sodium salt of 3-nitro-4-pyrazolecarbonitrile in methanol, and 75 ml. of 15% H2O2 was added, followed by 5 ml. of 6N NaOH. The reaction mixture was heated to 45° C., at which point external cooling was needed to maintain the mixture at 45°-50° C. After the exothermic reaction had subsided, the mixture was held at 45°-50° C. and stirred for 4 hours. Then the mixture was cooled and the methanol was evaporated under vacuum. The liquid remaining was cooled in an ice bath and the product was separated by filtration and dried under vacuum. The dry product was determined to be 8 gm. of 3-nitro-4-pyrazolecarboxamide sodium salt, m.p. >300° C.
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: II
Reactant: CC(C)(C)OC(=O)NC[C@H](F)CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Imidazole (19.8 g, 0.29 mol) was dissolved in methylene chloride (900 mL) at room temperature. Iodine (73.9 g, 0.29 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (76.3 g, 0.29 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2S)-2-fluoro-3-hydroxypropylcarbamate (45.0 g, 0.23 mol) in methylene chloride (300 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 h. The reaction mixture was filtered through a pad of Celite® and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2S)-2-fluoro-3-iodopropylcarbamate as a colorless oil (42.5 g, 62%). 1H NMR (300 MHz, CDCl3) δ 4.80–5.10 (br s, 1H), 4.58–4.72 (m, 0.5H), 4.42–4.56 (m, 0.5 H), 3.48–3.70 (m, 1H), 3.20–3.46 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].N1C=CC=CC=1.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:34])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(NC(=O)C2CCCC2)cc1
Reaction time: 2 h
Yield: 74 %

Procedure:
2.8 g (9 mmol) of 2-methoxy-N-(4-aminophenylsulfonyl)benzamide are suspended in 100 ml of dioxane, 0.72 g (9 mmol) of pyridine and 1.21 g (9 mmol) of cyclopentan-ecarbonyl chloride are added at 0° C., and the mixture is stirred for 2 hours at this temperature. The reaction mixture is subsequently transferred into water, and the resulting precipitate is filtered off with suction. After drying, 2.68 g (73%) of N—[4-(2-methoxy-benzoylsulfamoyl)phenyl]cyclopentanecarboxamide of melting point 202-206° C. are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)-phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:9]([OH:11])[CH3:10].Cl>C(OCC)C>[NH2:2][C:1]([O:11][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C=C(N)OCC
Yield: 53.8 %

Procedure:
In an oven-dried flask were placed 113.1 g of redistilled ethyl cyanoacetate, 46 g of ethanol (distilled from calcium hydride), and 500 ml of anhydrous diethyl ether. The solution was cooled to 0°, 36.5 g of hydrogen chloride gas were added and the flask was sealed. The mixture was refrigerated for several days until precipitation of white solid was observed. The white precipitate was collected by filtration and immediately resuspended in approximately 300 ml of diethyl ether. The ether-suspension was mixed with 1000 ml of a 40% aqueous solution of potassium carbonate (previously cooled to 0°). The ether layer was separated and placed over 30 g of anhydrous potassium carbonate. The aqueous phase was washed three times with 150 ml portions of diethyl ether. The washings were added to the ether phase over potassium carbonate. The combined ether phase and washings were decanted onto approximately 80 g of fresh anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the ether was removed by evaporation under reduced pressure. The residue was distilled at 0.25 mm hg. The fraction distilling at 60° was collected to yield 85.5 g of ethyl 3-amino-3-ethoxyacrylate, nD25 = 1.4808. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.Cl.[N:20]([O-])=O.[Na+].[Cl:24][Sn]Cl>O>[ClH:24].[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][NH2:20])=[CH:9][CH:8]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
25.3 parts by weight of 4-(3'-trifluoromethylphenoxy)-aniline suspended in 230 parts by volume of concentrated hydrochloric acid are diazotized with 6.9 parts by weight of NaNO2 in 30 parts by volume of H2O at 0° C., and the product is then reduced with 45 parts by weight of SnCl2 to give 4-(3'-trifluoromethylphenoxy)-phenylhydrazine hydrochloride. The hydrochloride is suspended in 400 parts by volume of 2 N hydrochloric acid, 16.7 parts by weight of mucochloric acid are added and the mixture is kept for 1 hour at 90° C. When it has cooled, the hydrochloric acid is separated from the organic phase, 160 parts by volume of glacial acetic acid are added to the latter, and this mixture is stirred for 10 minutes after reflux. It is then cooled and water is then added to the reaction mixture. The 1-[4'-(3"-trifluoromethyl-phenoxy)]-phenyl-4,5-dichloro-pyridaz-6-one formed is filtered off and recrystallized from methanol (No. 1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:7]=2[CH:14]=1)#[N:2].[CH3:15][C:16](=[O:20])[C:17](=O)[CH3:18].[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][N:8]([C:18]3[CH:17]=[C:16]([CH3:15])[O:20][C:21]=3[CH3:22])[C:7]=2[CH:14]=1)#[N:2]
Reactant: CC1(C)CNc2cc(C#N)ccc2O1
Reactant: CC(=O)C(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CC(C)(C)Oc3ccc(C#N)cc32)c(C)o1

Procedure:
In 2 ml of toluene were dissolved 0.5 g of 6-cyano3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 1.2 ml of 2,3-butanedione and a catalytic amount of p-toluenesulfonic acid and the mixture was stirred at 100° C. for 2 days. The solvent was then distilled off under reduced pressure and the residue was re-dissolved in toluene, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography to give 0.15 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2,5-dimethyl-3-furyl)-2H-1,4-benzoxazine.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:29])[O:11][CH:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:2]2.[Cl:30][CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>C(OCC)(=O)C.C(#N)C>[Cl-:30].[O:33]=[C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[CH2:31][N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([O:11][CH:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=1)=[O:29])[CH2:2]2
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3cccs3)CCC1CC2)OC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
Phenyl(4-(trifluoromethyl)phenyl)methyl(R)-quinuclidin-3-ylcarbamate (56.0 mg, 0.14 mmol) was dissolved in ethyl acetate (1 ml) and acetonitrile (0.5 ml). The resulting solution was treated with 2-chloro-1-(thiophen-2-yl)ethanone (24.0 mg, 0.15 mmol) and stirred at room temperature overnight. The solvent was evaporated, and the crude was first purified by flash chromatography (DCM/MeOH=95/5) and then by preparative HPLC(CH3CN/H2O) to afford (3R)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-3-((phenyl(4-(trifluoromethyl)phenyl)methoxy)carbonylamino)-1-azoniabicyclo[2.2.2]-octane chloride (30.0 mg, mixture of diastereoisomers).
Reaction SMILES: Cl[C:2]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3].N1C=CC=CC=1.[CH3:15][OH:16]>C(Cl)Cl>[NH:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:2]([O:16][CH3:15])=[O:3]
Reactant: CO
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc[nH]1

Procedure:
40 ml of a solution of 45 (mmoles) of 2-chlorocarbonyl-1H-pyrrole in methylene chloride were added dropwise to a cold mixture of 4.3 ml of pyridine and 3.5 ml of methanol and the mixture was washed with water, then with 6 ml of N sodium hydroxide, and was extracted with methylene chloride. The organic phases were dried and concentrated to dryness and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 4.014 g of methyl 1H-pyrrole-2-carboxylate melting at ≃74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24](O)=[O:25])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:18])([F:20])[F:19])[N:14]3[N:21]=[C:22]([C:24]([N:30]4[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]4)=[O:25])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(C(=O)O)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3N2)cc1OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
A 5 mL microwave vial was charged with 5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (50 mg, 0.135 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.404 mmol), HATU (205 mg, 0.539 mmol), N,N-diisopropylethylamine (0.059 mL, 0.337 mmol) and DMF (1.0 mL, 12.915 mmol). The vial was capped and the mixture was stirred for 6 hours at 40° C. The mixture was diluted with Ethyl acetate (5 mL), washed 2× with water (2 mL), washed with 0.1N aqueous HCl (2 mL), washed with saturated aqueous sodium bicarbonate (2 mL), washed with brine (2 mL), dried with sodium sulfate, filtered and concentrated. Compound was purified by chromatography on Biotage SP4 (Column Interchim 25 g, 30 μM) using 12-100% EtOAc/Heptane as eluent to afford intermediate tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carbonyl)piperazine-1-carboxylate (38 mg, 0.070 mmol, 52.3% yield).
Reaction SMILES: [C-]#N.[K+].[CH:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:12]1C(C)=CC=C[C:13]=1C.O.[CH3:21][C:22]([O:24]C(C)=O)=O>C(Cl)Cl>[C:22]([O:11][C@@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:13]#[N:12])(=[O:24])[CH3:21]
Reactant: Cc1cccc(C)n1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@H](C#N)c1ccccc1
Temperature: -30 °C
Reaction time: 10 h
Yield: 642.2 %

Procedure:
To a mixture of KCN (5.0 g, 77 mmol) and catalyst 1a (R1=R2=tBu)(0.3 g, 0.25 mmol) in CH2Cl2 (60 ml) were added with stirring benzaldehyde (2.5 ml, 25 mmol), 2,6-lutidine (0.28 ml, 2.4 mmol) and water (0.4 ml, 24 mmol). The reaction mixture was cooled to −30° C. and Ac2O (5 ml, 53 mmol) was added. The reaction mixture was stirred for 10 hours at −30° C. and then filtered, passed through a SiO2 column (1 cm×10 cm) in a mixture of hexane/AcOEt 10:1 to remove the catalyst. The filtrate was evaporated and distilled in vacuo to give 2.7 g (63%) of O-Acetyl (S)-mandelonitrile with 87% enantiomeric excess as determined by chiral gas chromatography.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[C@H:4]1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([Cl:32])=[O:31])=[CH:28][CH:27]=1>CCOCC>[ClH:32].[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:2]([CH3:1])[C@@H:3]2[CH2:12][CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[C@H:4]2[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN[C@@H]1CCCC2(OCCO2)[C@H]1N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCCC2(OCCO2)[C@H]1N1CCCC1
Product: Cl
Yield: 12.2 %

Procedure:
To a stirred solution of 7.2 g (0.03 mole) of trans-(±)-1-[7-(methylamino)-1,4-dioxaspiro[4.5]dec-6-yl]pyrrolidine in 200 ml Et2O and 3.64 g (0.036 mole) of triethylamine was added a solution of 7.9 g (0.036 mole) of 4-bromobenzoyl chloride in 50 ml Et2O over thirty minutes under N2. After two hours the slurry was filtered and the salt washed with Et2O. The combined ethereal layers were washed with H2O, 10% NaOH, H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was treated with Et2O/HCl and the resultant precipitate recrystallized from MeOH/EtOAc to give 7.0 g, mp 218°-219° and 1.68 g, mp 212°-214° (56%) of the titled amide: mp 219-220.5. The nmr and ir spectra were in accord with the titled amino amide ketal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[OH:25]O.[OH-].[K+].Cl>CO.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([NH2:18])=[O:25])=[C:9]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: N#Cc1c(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1c(-c2ccccc2)n(-c2ccc(O)cc2)c2ccccc12

Procedure:
1-(4-Hydroxy-phenyl)-2-phenyl-1H-indole-3-carbonitrile (Example 46, 10 mg, 0.03 mmol) was dissolved in 1 ml of MeOH. H2O2 (1 ml, 35% by weight in H2O) and 2M KOH (0.5 ml) were added and the reaction mixture was heated to reflux over night. The mixture was acidified with 1M HCl and EtOAc was added. The phases were separated and the organic solvents were evaporated. The crude product was purified by reversed phase preparative HPLC to give the title amide. ES/MS m/z: 329.1 (M+H), 327.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.34 (m, 1H), 7.46 (m, 2H), 7.40-7.37 (m, 3H), 7.24-7.18 (m, 2H), 7.12 (m, 2H), 7.07 (m, 1H) and 6.85 (m, 2H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH2:15][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:6]=[CH:5][C:4]1=2.[H-].[Na+].[CH3:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=1)=O.[CH3:49]S(C)=O>>[CH3:15][C:7]1[C:6]([CH:39]([C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)[CH:38]=[CH2:49])=[CH:5][C:4]2[C:3]([CH3:35])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:8]=1
Reactant: CS(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methyl-triphenyl-phosphonium bromide (6.25 g, 11.5 mmol) and NaH (10.5 mmol), coming from 0.42 g of a dispersion of 60% NaH in oil, in 35 ml of anhydrous DMSO is agitated under argon for 20 minutes, during which a solution of 4-cyanoacetophenone (1.45 g, 10.0 mmol) in 15 ml of DMSO is added. The solution is agitated for 6 hours at ambient temperature then poured over ice (150 g). This was then extracted with ether (125 ml, 3×50 ml). The raw product is then purified by three successive flash chromatographies on silica (1st eluent hexane:acetone=5:95, 2nd eluent hexane:acetone=4:96, 3rd eluent hexane:acetone=2.5:97.5) so as to separate the (E) and the (Z) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzonitriles. In order to obtain the pure (Z) isomer (less polar than the (E)isomer), the different fractions are verified by HPLC. The (E)isomer crystallises in the fractions coming from the flash chromatography. It is filtered, washed with hexane and dried at the palette pump. Its purity is determined by HPLC analysis.
Reaction SMILES: [NH3:1].CO.[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([O:25]CC)=O)=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1>C1COCC1>[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([NH2:1])=[O:25])=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A 2 M ammonia-methanol solution (3 ml) was added to a solution of ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (150 mg) in THF (0.5 ml), and then the reaction solution was stirred in a microwave reactor at 130° C. for 30 minutes. The precipitate was filtrated to obtain 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxamide as a crude white solid.
Reaction SMILES: O[C@@H]1C[C@@]2(C)[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.Cl[C:24](Cl)(Cl)[C:25]([C:27]([Cl:30])(Cl)Cl)=O.[C:33]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:30][C@H:27]1[CH2:25][C@@:24]2([CH3:33])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@H]2O
Solvent: ClCCl
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 800 mg of 11α-hydroxy-7α-methylestr-4-ene-3,17-dione (F) in 8 ml of dichloromethane was mixed at 0° C. with 1.21 ml of hexachloroacetone and 764 mg of triphenylphosphine and stirred at room temperature for 4 hours. Then, it was diluted with dichloromethane, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 430 mg of pure 11β-chloro-7α-methyl-estr-4-ene-3,17-dione (F′) with a melting point of 215.1° C. was obtained ([α]D20=+182.7° (c=0.5% in chloroform)).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:48]CCCl>>[ClH:48].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][NH:22][CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCOCC1
Reactant: NCCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: O=S(=O)(c1ccccc1)n1ccc2c(OCCNC3CCOCC3)cccc21
Reaction time: 18 h

Procedure:
A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine (0.316 g, 1.0 mmol), tetrahydro-4H-pyran-4-one (0.09 ml, 1.00 mmol) and sodium triacetoxyborohydride (0.312 g, 1.4 mmol) in 1,2-dichloroethane is treated with acetic acid (0.06 ml) at room temperature, stirred under nitrogen for 18 hr, quenched with concentrated aqueous NH4OH and diluted with methylene chloride and water. The aqueous layer is separated and extracted with methylene chloride. The organic layer and extracts are combined, washed with saturated NaCl, dried over Na2SO4, and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 9/1/0.05) to afford the free amine of the title product as a clear oil, 0.36 g (90%).
Reaction SMILES: C([C:9]1[CH:13]=[C:12]([C:14](=O)[CH2:15]C)O[N:10]=1)(=O)C1C=CC=CC=1.[C:18]([C:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][N:23]=1)(=[O:21])[CH2:19][CH3:20].[ClH:33].N1CCCC[CH2:35]1.C=O.Cl>C(OCC)C.O1CCOCC1>[ClH:33].[CH3:20][CH:19]([CH2:35][N:10]1[CH2:15][CH2:14][CH2:12][CH2:13][CH2:9]1)[C:18]([C:22]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][N:23]=1)=[O:21]
Reactant: CCC(=O)c1cc(-c2ccccc2)on1
Reactant: CCC(=O)c1cc(C(=O)c2ccccc2)no1
Reactant: C1CCNCC1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(CN1CCCCC1)C(=O)c1cc(-c2ccccc2)on1

Procedure:
To a mixture consisting of 1.5 g (7.5 mmol) of the ketone derivative, i.e., (3-propionyl-5-phenylisoxazole) prepared above in the procedure (3), 0.99 g (8.2 mmol) of piperidine hydrochloride, 0.36 g of paraformaldehyde and 3 ml of dioxane, 0.03 ml of 12N-hydrochloric acid was added. The resultant mixture was heated under reflux for 2 hours. After completion of the reaction, ethyl ether was added. Colorless crystals thus formed were collected by filtration and added to a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with ethyl ether. The solvent was distilled off so that 3-(2-methyl-3-piperidinopropionyl) -5-phenylisoxazole was obtained as colorless crystals. Analytical results of the crystals obtained: Yield: 1.2 g (48.1%). Melting point: 87°-89° C.