Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([S:13][CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.CO>[C:7]1([S:13]([CH:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[O:29][CH3:30])[CH2:15][NH:16][CH:17]=[O:18])=[O:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc2ccccc2c1C(CNC=O)Sc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2ccccc2c1C(CNC=O)S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A concentrated solution of sodium metaperiodate (2139 mg. 10 mmol) in water is added dropwise at 0° C. under cooling to a solution of 1-(1-phenylthio-2-formylaminoethyl)-2-methoxy-naphthalene (3374 mg, 10 mmol) in methanol (100 ml). The reaction is then stirred at room temperature for 24 h. The solids are filtered off and washed several times with ethyl acetate (1000 ml). The filtrate and washings are combined and then evaporated under vacuum to yield crude title compound in about 100% yield (3534 mg ) which is used in the next step without further purification.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:33])[C@@H:10]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[C:24]=1[CH3:32])[C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:31][C:25]1[C:24]([CH3:32])=[C:23]([NH:22][C@@H:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)propyl amino)-2-chloro-3-methylbenzonitrile (425 mg, 0.85 mmol) was deprotected using tetrabutylammonium fluoride (1.0 M solution in THF, 1.7 mL, 1.7 mmol) in a procedure analogous to that used for the preparation of example 7. After column chromatography (50% EtOAc/hexanes) the title compound was isolated as a white solid (225 mg, 69%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.94 (m, 2H), 7.51 (m, 4H), 6.81 (d, J=8.7 Hz, 1H), 5.88 (d, J=7.1 Hz, 1H), 5.13 (dd, J=3.5, 7.2 Hz, 1H), 5.02 (br s, 1H), 4.48 (m, 1H), 2.39 (s, 3H), 1.41 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([CH2:30][O:31]C)[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1.B(Br)(Br)Br>C(Cl)Cl.C(OCC)C>[F:34][C:2]([F:1])([F:33])[CH:3]([CH2:30][OH:31])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16][N:17]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:9][CH:10]=1
Reactant: COCC(Oc1ccc(NC(=O)C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Nc3ccc(OC(CO)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (rac)-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-(2,2,2-trifluoro-1-methoxymethyl-ethoxy)-phenyl]-amide (240 mg), product of example 54) in methylene chloride was treated at RT and under an argon atmosphere with BBr3 (0.5 molar in methylene chloride, 2 ml) and stirred 2 h at RT. The reaction mixture was then taken up in diethyl ether, washed with aqueous 1N HCl, the layers were separated, the organic layer dried over sodium sulfate and evaporated off to give the desired (rac)-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid [4-(2,2,2-trifluoro-1-hydroxymethyl-ethoxy)-phenyl]-amide crystalline light red solid. MS (ESI): 487.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:21])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:13]1[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][C@H:9]([CH3:21])[C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[C:14]1=[O:15]
Reactant: C[C@H]1Oc2ccc(F)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)Oc2ccc(F)cc21
Yield: 99.8 %

Procedure:
0.30 g (0.97 mmol) ((6R,7S)-2-Fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 8 ml dimethylformamide were stirred with 0.14 ml (1.45 mmol) methyl bromoacetate and 0.48 g (1.45 mmol) cesium carbonate overnight. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane 1:4 yielded 0.37 g (quant.) ((6R,7S)-7-tert-butoxycarbonylamino-2-fluoro-6-methyl-8-oxo-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetic acid methyl ester, MS m/e (%): 383.1 (M+H+, 14), 327.3 (24), 283.4 (199).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[CH3:29]>C(O)CO.O>[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][CH2:27][CH2:26][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:31]1)[CH3:29]
Reactant: CCN1CC[C@@H](N)C1
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Solvent: OCCO
Solvent: O
Product: CCN1CC[C@@H](NCCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Yield: 2.6 %

Procedure:
A solution of (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (Intermediate 74, 0.150 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 0.25 g) in ethylene glycol (1 ml) was irradiated in the microwave at 200° C. for 30 minutes. After cooling, the mixture was diluted with water and loaded onto a SCX-2 SPE cartridge then washed with water, methanol and 2M ammonia in methanol. The basic fractions were combined and evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% ammonia, with a gradient of 10-98%. Then further purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-60% to give (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (0.005 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][CH:17]1[O:19][CH2:18]1.[OH-].[Na+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COc1cccc(OCC2CO2)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCNCC(O)COc1cccc(OC)c1

Procedure:
This compound was prepared in accordance with Example 1 using 7.6 g of the hydrochloride of ethyl 3-aminopropanoate, 4.5 g of 3-(3-methoxyphenoxy)-1,2-epoxypropane, and 2.0 g of NaOH. The crude product was washed with 150 ml of water and dissolved in 100 ml of water and 10 ml of 2-n HCl. This solution was extracted with ethyl acetate, treated with NaHCO3, and extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and evaporated. Ethyl N-[3-(2-cyano-4-methoxyphenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 1.2 g. Melting point 72° C. (base). The structure was determined by NMR.
Reaction SMILES: Br[CH2:2][C:3]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:6]=1[O:13][CH3:14].[CH2:32]([SH:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:12][C:7]1[C:6]([O:13][CH3:14])=[C:5]([CH:4]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[C:3]([CH2:2][S:34][CH2:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: COc1c(F)cc(F)cc1C(Nc1cccc2nc(C)ccc12)C(O)(CBr)C(F)(F)F
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1cc(F)cc(F)c1OC)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.24 mmol) {[3,5-difluoro-2-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine (example 14) are reacted with 0.25 ml of the 1 M ethanthiol solution under the presence of 148 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 49 mg of the title compound after preparative thin layer chromatography on silica gel (acetone in hexane 50%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][C:6]1[C:16]([O:17][CH3:18])=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[C:7]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:4][O:5][C:6]1[C:16]([O:17][CH3:18])=[CH:15][C:9]2[CH2:10][CH2:11][N:12]([CH2:1][CH2:2][OH:3])[CH2:13][CH2:14][C:8]=2[C:7]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCNCC2
Reactant: C1CO1
Solvent: CO
Product: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(CCO)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylene oxide (0.5 ml., 0.44 g., 0.010 mole) is added to a stirred solution of 1.58 g. (0.005 mole) of 7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml. of methanol at 0° C. The mixture is stirred at this temperature for 2 hours and then allowed to warm to room temperature. Concentration of the mixture in vacuo gives 7,8-dimethoxy-3-(2-hydroxyethyl)-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1ccc2ccccc2c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2ccccc2c1N

Procedure:
1-nitro-2-methoxynaphthalene (1 g.) is hydrogenated in absolute ethanol (200 ml.) over Raney nickel catalyst (1 g.) at 25° C and an initial pressure of 40 psi until the theoretical amount of hydrogen is absorbed. The catalyst is removed, the filtrate concentrated to dryness under vacuum, and the residue recrystallized from methanol to yield 1-amino-2-methoxynaphthalene.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[NH:38]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:37]3[NH:38][C:39]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[C:32]([CH3:31])[CH:40]=4)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Reactant: Brc1cnc2c(n1)c(I)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncc(Br)nc34)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of 2-bromo-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine (6) (100 mg, 0.1766 mmol), 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (7) (47 mg, 0.1766 mmol) in acetonitrile (5 mL) was added cesium carbonate (115.74 mg, 0.3532 mmol). The resulting reaction mixture was degassed, purged with nitrogen for 10 min followed by the addition of Pd(PPh3) Cl2.DCM (7.06 mg, 0.0088 mmol) to the reaction mixture, which was again degassed, purged with nitrogen for another 15 min. The final reaction mixture was stirred for 2 h at 90° C. in a seal tube. After completion of the reaction, the contents were allowed to cool to RT and was diluted with DCM (25 mL) and filtered through Celite bed. The organic layer was concentrated to get the crude. The resulting oil was purified by flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 27% ethyl acetate in hexane to afford pale yellow solid (30 mg) of compound 2-bromo-7-(6-methyl-1H-indol-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine (8).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].[CH3:28][C:29]1(B(O)O)[CH:33]=[C:32]([CH3:34])[O:31][NH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].O1CCOCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]4[C:29]([CH3:28])=[N:30][O:31][C:32]=4[CH3:34])=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4]
Reactant: CC1=CC(C)(B(O)O)NO1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Br)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc2[nH]c(-c3ccc(-c4c(C)noc4C)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 42 mg (0.1 mmol) of 5-(4-bromo-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester, 21 mg (0.15 mmol) of 3,5-dimethyl-isoxazoleboronic acid, 7.3 mg (0.01 mmol) of Pd catalyst, and 63 mg (0.3 mmol) of potassium phosphate in 1 mL of 1,4-dioxane was shaken at 95° C. in a sandbath overnight. The reaction mixture was then diluted with dichloromethane, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a residue, which was purified via reverse-phase chromatography (Gilson) to afford desired 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C25H26N4O4 [M++H]+: 447.19, found: 447.3. This material was then converted to 6-cyclohexyl-5-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (591) via the well known LiOH saponification protocol (37% yield over 2 steps); LC-MS—calcd for C24H24N4O4 [M++H]+: 433.18, found: 433.1.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:56]1[N:60]2[CH:61]=[CH:62][CH:63]=[N:64][C:59]2=[C:58]([C:65](O)=[O:66])[CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:5][CH2:6][N:7]1[C:65]([C:58]1[CH:57]=[N:56][N:60]2[CH:61]=[CH:62][CH:63]=[N:64][C:59]=12)=[O:66]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of (3S)-3-methyl-1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Description 13) (300 mg, 0.925 mmol), HOBt (142 mg, 0.925 mmol), HBTU (351 mg, 0.925 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (151 mg, 0.925 mmol) in DMF (50 ml) was added DIPEA (0.485 ml, 2.78 mmol) and the resulting mixture stirred at room temperature overnight, then concentrated under vacuum. The residue was redissolved in EtOAc, washed with aqueous NaHCO3 and brine, then concentrated under vacuum. Flash chromatography (silica; EtOAc) and concentration of the desired fractions gave the title compound (157 mg).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>CN(C)C=O>[C:19]1([NH:18][C:16]([CH2:15][N:4]2[C:5](=[O:6])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:1]2(=[O:2])=[O:3])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2S1(=O)=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A solution of 22.6g (0.11 mole) of sodium saccharin and 16.7g (0.1 mole) of N-chloroacetylaniline in 150ml of dimethylformamide is heated on a steam bath for one hour, allowed to stir at room temperature for 16 hrs. and poured into ice-water. The resulting precipitate is collected and dissolved in dichloromethane. This solution is dried over magnesium sulfate, and the solvent is evaporated. The residue is recrystallized from methanol to give 19.9g of product, mp. 180°-182° C. EXAMPLE 2 ##STR5##
Reaction SMILES: [CH2:1]([C:3]([CH3:9])([CH2:7][CH3:8])[C:4](O)=O)[CH3:2].[NH2:10][NH:11][C:12]([NH2:14])=[S:13].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O1CCOCC1>[NH2:14][C:12]1[S:13][C:4]([C:3]([CH2:7][CH3:8])([CH3:9])[CH2:1][CH3:2])=[N:10][N:11]=1
Reactant: NNC(N)=S
Reactant: CCC(C)(CC)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)(CC)c1nnc(N)s1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
A solution containing 13.0 g of 2-ethyl-2-methylbutyric acid and 9.1 g of thiosemicarbazide in 125 ml of dioxane was stirred and heated to 90° C. To the stirred reaction mixture was added dropwise over thirty minutes 15.3 g of phosphorous oxychloride. Following complete addition, the reaction mixture was heated at 90° C. for six hours. The mixture was then cooled to about 30° C. and added to 100 g of ice. The aqueous mixture was made alkaline by the addition of ammonium hydroxide, and the alkaline solution was extracted several times with ethyl acetate. The extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].Br[C:14]1[S:18][C:17]([C:19]([O:21]CC)=[O:20])=[N:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]#[N:32])[CH:25]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:26]1[CH:25]=[C:24]([C:15]2[N:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=2[C:5]2[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:29]=[CH:28][C:27]=1[F:30])#[N:32]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(F)cc(-c2sc(C(=O)O)nc2-c2ccc(F)c(C#N)c2)c1

Procedure:
At room temperature, 244 mg (1.48 mmol) of the boronic acid from Example 22A are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under, reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 97.6 mg (16% of theory) of the title compound having a purity of 61% are obtained.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=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][CH2:14][CH2:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>[H-].[Na+].O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:23])=[CH:25][CH:26]=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][CH2:14][CH2:15][CH3:16]
Reactant: Oc1cccnc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Oc2cccnc2)cc1

Procedure:
A 6 g. (16.6 m moles) sample of 4-(hexadecylamino)benzoic acid and 2.7 g. (16.6 m moles) 1,1'-carbonyldiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2 hours. Then, 1.58 g. (16.6 m moles) 3-hydroxypyridine and a trace of sodium hydride catalyst is added and the reaction is refluxed for 3 hours. The solution is cooled, filtered, and evaporated. The product is crystallized from isopropanol.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([F:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[CH:14]=1>>[F:11][C:10]1[C:3]2[C:2]([NH:12][C:13]3[C:22]([O:23][CH3:24])=[CH:21][C:16]4[NH:17][C:18](=[O:20])[S:19][C:15]=4[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: Fc1c[nH]c2ncnc(Cl)c12
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]cc(F)c12

Procedure:
50 mg (291 μmol) 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 582313-57-3) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 2.9 mg (3%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[C:17](=O)[CH3:18].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:28]2[C:29](=[O:30])[O:1][C:2]3[C:3]([C:17]=2[CH3:18])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=3)=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(=O)O)cn1
Reactant: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1O
Product: COc1ccc(-c2c(C)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)cn1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone and (6-methoxy-pyridin-3-yl)-acetic acid as the starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH:12]([NH2:15])[CH2:13][CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 90 °C
Yield: 89.3 %

Procedure:
100 g (0.4 mol) of N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (1) was placed in suspension in a solution containing 300 ml of 37% hydrochloric acid and 660 ml of water in a 2 l three-necked flask. The reaction medium was heated at 90° C. for 7 hours 45 minutes. After cooling, the medium was neutralized gently with 300 ml of aqueous 35% sodium hydroxide (pH=8 approximately). The resulting solid was subsequently filtered off and then washed with water until the washing waters were neutral. The product was then dried under vacuum over P2O5. 74 g (89%) of 1-(4-nitrophenyl)pyrrolidin-4-ylamine (2) was thus obtained in the form of a yellow solid.