Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[NH:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.CN1CCOCC1.O>CN1CCCC1=O>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:28]5[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29]5)[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(Cl)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 120 °C
Yield: 76.2 %

Procedure:
A mixture of 1-[6-chloro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.0876 mmol; 59.7 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.263 mmol; 52.6 mg), and N-Methylmorpholine (0.263 mmol; 26.9 mg; 0.0292 mL) in 1-methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-(trifluoromethyl)-2-pyridyl]-3-piperidyl]carbamate as a white solid (37.0 mg, 65%).
Reaction SMILES: C(OC(=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:36][O:37][C:38](=[O:66])C(C1C=CC(C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=CC=1)C.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:66])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:34])[C:17]=3[CH:16]=2)=[CH:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.108 g, 0.37 mmol), triethyl amine (10 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by work up and flash column chromatography over silica gel (230-400 mesh) using 1%-4% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow amorphous solid (0.148 g, 87%).
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:22])([CH2:14][N:15]2[C:19]([S:20][CH3:21])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.OO.[OH-:25].[Na+].C(O)(=[O:29])C>>[Cl:1][C:2]1([C:5]([OH:22])([CH2:14][N:15]2[C:19]([S:20]([CH3:21])(=[O:29])=[O:25])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)c1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 3.57 g (10 mmol) of 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-(5-methylthio-1,2,4-triazol-1-yl)-propan-2-ol in 40 ml of glacial acetic acid is treated dropwise at 90° C. with stirring with 4 ml of an aqueous hydrogen peroxide solution (35% strength). After the addition has ended, stirring of the reaction mixture is continued at 90° C. for 30 minutes, and the mixture is then cooled to room temperature, treated with ice and rendered alkaline by adding aqueous sodium hydroxide solution. The mixture is extracted repeatedly using ethyl acetate, and the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The slowly crystallizing product which remains is filtered off with suction. In this manner, 2.0 g (51% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methylsulphonyl-1,2,4-triazol-1-yl)-propan-2-ol) are obtained in the form of a solid which melts at 125°-128° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]4[CH:29]=[C:30]([F:34])[C:31]([Cl:33])=[CH:32][C:26]=4[N:25]=3)=[CH:20][C:19]=2[Cl:35])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN(CCCOC2C=CC(C=O)=CC=2Cl)CC1)=O)(C)(C)C.ClC1C=C(N)C(N)=CC=1F>>[Cl:33][C:31]1[C:30]([F:34])=[CH:29][C:27]2[NH:28][C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:19]([Cl:35])[CH:20]=3)=[N:25][C:26]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(-c3nc4cc(Cl)c(F)cc4[nH]3)cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2Cl)CC1
Agent: Nc1cc(F)c(Cl)cc1N
Product: Fc1cc2[nH]c(-c3ccc(OCCCN4CCNCC4)c(Cl)c3)nc2cc1Cl
Yield: 15 %

Procedure:
4-{3-[2-Chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester. This compound was prepared by the method described in Example 1, using 4-[3-(2-chloro-4-formyl-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmol, 1.0 equiv), 4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0 equiv), and Na2S2O5 (648 mg, 3.4 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 256 mg (15%) of the title compound. MS (electrospray): mass calculated for C25H29Cl2FN4O3, 522.16; m/z found, 545.3 [M+Na]+. B. 5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-benzoimidazole. To a suspension of 4-{3-[2-chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (52.7 mg, 0.10 mmol) in dichloromethane (1.0 mL) at rt was added TFA (1.0 mL), and the reaction mixture was stirred for 50 min. The mixture was concentrated under reduced pressure, and the solid residue was washed four times with dichloromethane. The title compound was obtained in quantitative yield as the TFA salt. MS (electrospray): mass calculated for C20H21Cl2FN4O, 422.11; m/z found, 423.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.17 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.7, 2.3 Hz, 1H), 7.81 (d, J=6.4 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.33 (t, J=5.8 Hz, 2H), 3.50-3.47 (m, 4H), 3.36 (br s, 4H), 3.25 (t, J=7.4 Hz, 2H), 2.33-2.26 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](C)[C:10](O)=O)C=[CH:6][C:7]=1[F:8].[C:14](Cl)(=[O:18])[C:15](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:6][C:7]=1[F:8])[C:14](=[O:18])[CH2:10][CH2:9]2
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-difluorophenyl propionic acid (30.45 g; 163.6 mmol) and 2 drops of DMF in CH2Cl2 (200 mL) was added oxalyl chloride (41.4 g, 327 mmol) over 20 min. The resulting solution was stirred for 24 hr and concentrated in vacuo (chased 1×PhMe, ca. 100 mL). The residue was dissolved in CS2 (300 mL), cooled to 0° C. and AlCl3 (76.4 g, 573 mmol) was added over 10 min. The mixture was stirred 30 min at 0° C., then heated under reflux for 4 hr. Upon cooling to room temperature the solution was carefully poured onto crushed ice, the carbon disulfide layer was separated and the aqueous layer extracted with EtOAc. Combined organics were dried over MgSO4 and the concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]2C(OCC)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:10]2)[CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C(=O)OCC)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)CC(=O)C(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 2.74 g ethyl 8-ethoxycarbonyl-2-methyl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate in 10 ml N,N-dimethylformamide, were added 512 mg sodium chloride and 315 μl water, and the mixture was heated with stirring for two hours in an oil bath held at 140°-150° C. The reaction mixture was poured into 30 ml ice water, the resulting mixure was extracted with chloroform, and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent from the dried solution, the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of n-hexane/ethyl acetate (1:1 by volume), giving 1.54 g of 8-ethoxycarbonyl-2-methyl-1-oxa-8-azaspiro[4,5]- decane-3-one as oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([C:13]([O-:15])=[O:14])[C:10]([O-:12])=[O:11])=[O:7])[C@@H:3]([CH3:5])O.[CH3:16][CH:17](OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:30]1COC[CH2:31]1>>[CH2:16]([O:15][C:13]([CH:9]([C:10]([O:12][CH2:30][CH3:31])=[O:11])[N:8]1[CH:3]([CH3:5])[CH:2]([NH2:1])[C:6]1=[O:7])=[O:14])[CH3:17]
Reactant: C1CCOC1
Reactant: C[C@@H](O)[C@H](N)C(=O)NC(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Product: CCOC(=O)C(C(=O)OCC)N1C(=O)C(N)C1C

Procedure:
Ox-L-Threonylaminomalonate (0.45 g, 0.92 mmoles) and TPP (0.26 g, 0.1 mmoles) were dissolved in THF (15 mL). DIAD (0.196 mL, 0.1 mmoles) in THF (15 mL) was added dropwise over 0.5 hour, after which the reaction mixture was evaporated and chromatographed (silica, 9:1 methylene chloride to ether). A mixture (0.32 g) containing the product was eluted. By NMR this mixture contained the desired β-lactam along with the dehydropeptide and the pyrrolidinone. The ratio of products (73%) was roughly 2:1:1. Careful rechromatography (slower gradient) led to the isolation of the β-lactam 50 mg (0.1 mmoles, 11%); M.P. 140°-142° C. NMR (DCCl3): 1.16-1.14 (9H, m); 4.09-4.5 (7H, m); 5.13 (1H, s); 7.23 (5H, s); 7.3-7.66 (5H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[C:23]([F:32])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CO.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[C:23]([F:32])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [4-(2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetate (0.300 g, 0,679 mmol) in 6 ml anhydrous tetrahydrofuran was added by 2 ml methanol and 2 ml water. Lithium hydroxide (81.0 mg, 3.40 mmol) was added, and the mixture stirred at RT overnight. 1 M hydrochloric acid was added and the pH adjusted to 4. The volatiles were removed under reduced pressure, and the aqueous phase extracted with dichloromethane (3×20 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 428.2 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.Cl[C:26]1[C:27]2[C:34]([CH3:35])=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:26]4[C:27]5[C:34]([CH3:35])=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:21][CH2:22]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1cccc(Oc2ccc(F)cc2)c1)C1CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(Oc5ccc(F)cc5)c4)CC3)c12
Temperature: 190 °C
Yield: 68.8 %

Procedure:
A mixture of piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide hydrochloride (2.51 g, 7.16 mmol) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.97 mmol) in iso-propanol (15 mL) was placed in a microwave vessel, followed by addition of triethylamine (2.5 mL, 18 mmol). The microwave vessel was sealed then heated in the microwave at normal absorbance at 190° C. for 60 min. The mixture was concentrated to remove most of the iso-propanol and triethylamine. The residue was washed with methanol (2×15 mL) to afford a brown solid. The solid was washed with water (3×30 mL) and dried overnight to afford 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide (1.83 g, 69%) as a light-brown solid ((M+H)+: 446.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC>CO.O>[CH2:26]([O:16][C:15](=[O:17])[C@@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Yield: 82 %

Procedure:
N-p-Methoxybenzyloxycarbonyl-D-serine (5.39 mg, 2.00 sm:ol; prepared as a colourless solid of m.p. 96°-97° C. in 60% yield by the dissolved in methanol and treated with a solution of potassium carbonate (138 mg, 1.00 mmol) in water (2 ml). The mixture is evaporated by dryness, N,N-dimethyl-forimide (DMF) is added and re-evaporated (2×2 ml), and the solid residue is then dissolved in dry warm DMF, benzyl bromide (248 μl, 2.1 mmol) is added and the solution is warmed in a dry closed flask at 50° C. for 1 hour. The resulting mixture is portioned between ether (10 ml) and water (10 ml) and the aqueous layer is extracted with ether (2×10 ml). The combined ether extracts are washed with saturated sodium bicarbonate (5 ml) and saturated brine (5 ml), dried and evaporated to dryness. The residue is purified on a column of silica gel using 1:1 v/v ethyl acetate:petroleum ether as eluant to yield to title compound as a homogenous oil (590 mg, 82%) which crystallises on standing to give a colourless solid of m.p. 67°-68° C. (from diethyl ether); [α]D20 --6.3° (c 4.0, CHCl3).
Reaction SMILES: CCCCCCCCC.[F:10][C:11]([F:31])([F:30])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=O)[CH:25]3[NH:28][CH:21]([CH2:22][CH2:23][CH2:24]3)[C:20]2=O)=[CH:15][CH:14]=1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1.[OH-].[Na+]>C1COCC1>[F:31][C:11]([F:10])([F:30])[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:26][CH:25]3[NH:28][CH:21]([CH2:22][CH2:23][CH2:24]3)[CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Reaction time: 0.67 h

Procedure:
3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane: A solution of 3-(4-trifluoromethoxyphenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (80 mg, 0.25 mmol) and THF (4 mL) was heated at 70° C. under N2. A solution of BH3—SMe2 (2M in THF, 0.4 mL, 0.8 mmol) was added dropwise. After 40 min, 6N HCl (1.0 mL) was added dropwise (Caution: H2 evolution). After an additional 30 min, the reaction was poured into 1N NaOH (8 mL) and extracted with dichloromethane (30 mL×2). The combined organic extracts were dried, filtered and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: MS (ESI): 287.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[O:9])/[N:4]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:3]=1.[I:25][CH3:26]>C(#N)C>[I-:25].[CH3:26][N+:12]1[CH:13]=[CH:14][N:10]([C:8](/[N:7]=[C:5]2\[S:6][C:2]([CH3:1])=[CH:3][N:4]\2[C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)=[O:9])[CH:11]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2ccnc2)s1
Reactant: CI
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Product: [I-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]-1H-imidazole-1-carboxamide (2.0 g, 5.68 mmol, Example 18A) in acetonitrile (10 mL) was treated with iodomethane (3 mL). The mixture was stirred at room temperature for five days, the solvent was evaporated, and the title product was used directly for the next step.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>O1CCOCC1.O>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:10])[CH:6]=[C:7]([N:12]([CH3:13])[CH3:11])[N:8]=1
Reactant: CNC
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 97.9 %

Procedure:
To a solution of 46 g 2-methylthio-4,6-dichloropyrimidine in 250 ml dioxane, were added at room temperature and over a period of 10 minutes, 65.6 ml of 40% dimethylammonia-solution in water and the mixture was stirred for one hour. The solvent was evaporated and the residue purified on silica gel with toluene as eluent to give 57.0 g (97.9%) of 2-methylthio-4-chloro-6-(N,N-dimethylamino)-pyrimidine of m.p. 102° C.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:31])[C@@:7]12[O:30][CH2:29][O:28][C@@H:8]1[CH2:9][C@@H:10]1[C@:24]2([CH3:25])[CH2:23][C@H:22]([OH:26])[C@H:21]2[C@H:11]1[CH2:12][CH2:13][C:14]1[C@:19]2([CH3:20])[CH:18]=[CH:17][C:16](=[O:27])[CH:15]=1)(=O)C.O.C(=O)([O-])[O-].[Ca+2]>CO>[OH:26][C@H:22]1[CH2:23][C@@:24]2([CH3:25])[C@@H:10]([CH2:9][C@H:8]3[O:28][CH2:29][O:30][C@:7]32[C:6](=[O:31])[CH2:5][OH:4])[C@H:11]2[C@H:21]1[C@:19]1([CH3:20])[C:14]([CH2:13][CH2:12]2)=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]1
Reactant: CC(=O)OCC(=O)[C@@]12OCO[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]12C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@H]1OCO[C@]12C(=O)CO
Yield: 56 %

Procedure:
1.5 g of 21-acetoxy-11β-hydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione is dissolved in 510 ml of methanol and 111 ml of water and refluxed under agitation with 1.5 g of calcium carbonate for 24 hours. The calcium carbonate is removed by vacuum-filtering; the filtrate is concentrated to turbidity and poured on water. After the usual working-up process, the crude product is purified on 115 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone), thus isolating 758 mg of 11β,21-dihydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione, mp 220°-223° C. (decomposition).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH3:23][C:24]1[N:25]([C:2]2[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:6]=2)[CH:26]=[CH:27][N:28]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.33 g), 2-methylimidazole (1.33 g), potassium carbonate (2.00 g) and N-methylpyrrolidone (10 mL) was stirred at 110° C. for 2 h. The reaction mixture was poured into iced water (100 mL), and the precipitated crystals were collected by filtration, washed with water and air-dried to give the title compound as crystals. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals (1.07 g, 71%). melting point: 94-95° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C([Mg]Br)C.C1(C)C=CC=CC=1.[CH2:20]=[O:21]>C1COCC1.CN1CCCN(C)C1=O>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][C:1]=1[CH:20]=[O:21]
Reactant: Cc1ccc(O)cc1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C=O)c1
Yield: 104.4 %

Procedure:
p-Cresol (100 g) in dry THF (100 ml) was added over 30 minutes dropwise to a mechanically stirred, freshly prepared solution of ethyl magnesium bromide [magnesium (25.0 g) and bromoethane (75 ml)] in THF (500 ml) under nitrogen at a rate which maintained a slow reflux. After a further 30 mins toluene (1.21) was added, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (125 ml), and paraformaldehyde (70 g). The mixture was then heated at reflux for 16 h. The mixture was concentrated by distillation and aqueous hydrochloric acid (2M, 600 ml) then added. Water (600 ml) was added and the mixture filtered through "hyflo", dried and concentrated in vacuo to give a brown oil. The oil was steam distilled and the product extracted from the distillate with ether (1 liter). The organic extract was dried and concentrated in vacuo to give a pale yellow slurry which was triturated with ether at -10° C. to give the title compound as colourless needles, (131.4 g).