Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[CH2:10])=[CH:5][C:4]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:12]=2)=[CH2:10])=[CH:5][C:4]=1[CH3:18]
Reactant: COc1cccc(CBr)c1
Reactant: C=C(c1cccc(O)c1)c1ccc(OC)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(c1cccc(OCc2cccc(OC)c2)c1)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(4-methoxy-3-methyl-phenyl)-vinyl]-phenol (400 mg, 1.67 mmol, 1.0 eq) in 3 mL of dry N,N-dimethylformamide, anhydrous cesium carbonate was added (1.08 g, 3.33 mmol, 2.0 eq.) and the mixture was stirred for 20 min at room temperature. After this time, 3-methoxybenzylbromide (167 mg, 0.832 mmol, 1.2 eq.) was added and the resulting mixture was further stirred for 16 hours at 50° C. The reaction mixture was examined LC-MS which showed>90% conversion to the desired product. The reaction mixture was cooled to room temperature, 10 mL of water was added and the mixture was extracted with DCM. The organic fraction was dried over sodium sulfate and the crude product was purified by flash chromatography eluting with cyclohexane/ethylacetate (100:0 to 90:10). 408 mg of clean product was obtained as colorless liquid (yield: 95%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cu](C#N)[C:19]#[N:20].CN(C)C=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:19]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1)#[N:20]
Reactant: O=C1c2ccccc2CCc2ccc(Br)cc21
Reactant: N#C[Cu]C#N
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CC2
Reaction time: 6 h

Procedure:
7.2 g. of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, together with 2.7 g. of copper cyanide and 10 ml. of dimethylformamide, are heated to boiling under reflux conditions for 6 hours. The resulting hot solution is poured into a solution containing 10 g. of iron trichloride in 15 ml. of water and 3 ml. of concentrated hydrochloric acid, stirred at 70° C. for 20 minutes and extracted with toluene. The toluene extract is washed first with 3N hydrochloric acid and then with 3N caustic soda, dried over sodium sulfate and evaporated. The 3-cyano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one which is obtained, is purified by adsorption on the 10-fold amount of Kieselgel (eluting agent: toluene); melting point 104°-106° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCCCCC.[CH3:23][CH2:24][O:25][C:26]([CH3:28])=[O:27]>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]=[CH:28][C:26]([O:25][CH2:24][CH3:23])=[O:27])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stirred and nitrogen inlet was charged with NaH (60%, 10.0 g, 0.25 mol) and anhydrous THF (200 mL). To the stirred mixture was slowly added triethylphosphonoacetate (53.8 g, 0.24 mol) over 20 minutes. A solution of crude 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (40 g, 0.20 mol) in THF (75 mL) was added dropwise. The solution turned orange and the stirring was continued for 1 h until no aldehyde remained by TLC analysis [1:1 hexane/EtOAc, Rf(aldehyde)=0.6; Rf(14)=0.8]. The solution was diluted with EtOAc and brine and the layers were separated. The EtOAc layer was washed with 1M HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14 (67 g) as a yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ6.92-6.76 (m, 1H), 5.82 (d, 1H), 4.56-4.32 (m, 1H), 4.25-4.12 (m, 2H), 3.48-3.27 (m, 2H), 2.20-1.98 (m, 1H), 1.91-1.72 (m, 2H), 1.43 (s, 9H), 1.25 (t, 3H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To 3-iodo-4-methylaniline (500.0 mg, 2.145 mmol) was added dichloromethane (DCM) (10 mL) followed by N,N-diisopropylethylamine (DIPEA) (520 μL, 3.0 mmol) and 3-(trifluoromethyl)-benzoyl chloride (0.36 mL, 2.4 mmol). The reaction was stirred at 25° C. for 16 hours and was transferred to a separatory funnel and partitioned between water and dichloromethane (DCM). The organic phase was sequentially washed with 0.1N HCl, saturated aqueous NaHCO3, water, then saturated aqueous NaCl. The washed organic phase was then dried over MgSO4 and filtered and concentrated to leave the crude product. The crude product was triturated with hexanes to leave the product as an off-white solid, (797 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 8.04 (d, 1H), 7.84 (bs, 1H), 7.81 (d, 1H), 7.63 (m, 1H), 7.58 (dd, 1H), 7.22 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=274 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[O:19]=[C:20]1[N:24]([CH2:25][CH2:26]OS(C)(=O)=O)[CH2:23][CH2:22][O:21]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][O:21][C:20]2=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCCN1CCOC1=O
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 39 %

Procedure:
To a mixture of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (1.00 g, 7.63 mmol) and Hunigs base (2.92 mL, 16.8 mmol) in dichloromethane (19 mL) at 0° C. was added mesyl chloride (0.650 mL, 8.40 mmol) slowly via syringe. The mixture was stir cold for three hours, diluted with 10 mL of water and 25 mL of dichloromethane. The layers were separated and the organic layer was washed with aqueous NaHCO3 (3×30 mL) followed by water (1×15 mL). The organic layer was then dried (Na2SO4), filtered, and concentrate under reduced pressure to provide 650 mg of methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester as a light brown oil. In a separate flask 6-nitroindazole (318 mg, 1.95 mmol) was treated with potassium carbonate (538 mg 3.9 mmol) in DMF (10 mL) for 30 minutes, afer which methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester (490 mg 2.34 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (210 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) ppm 3.49 (m, 2H), 3.62 (t, J=5.76, 2H), 4.13 (m, 2H), 4.76 (t, J=5.76, 2H), 7.97–8.03 (m, 2H), 8.33 (m, 1H), 8.83 (m, 1H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:36])([F:37])[F:38])=[N:33][N:34]=5)[N:31]=4)[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Product: CS(=O)(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 24 %

Procedure:
Obtained in 24% yield by an analogous method to Example 26, starting from 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 4.1, preparation of starting materials) and methanesulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1([CH2:13][OH:14])[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Br:1][C:2]1([CH:13]=[O:14])[C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)[C@H]1[C@H](C(=O)OC)C1(Br)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H]1[C@H](C(=O)OC)C1(Br)C=O
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a stirred solution of (1R,2R)-3-bromo-1,2-dicarbomethoxy-3-hydroxymethyl-cyclopropane (2.8 g, 10.5 mmol) in dichloromethane (120 ml) was added pyridinium chlorochromate (3.35 g, 15.7 mmol) and stirring continued over a period of 16 hours. Diethyl ether (120 ml) was added to the reaction mixture, which was then filtered with the aid of a Whatman glass microfibre filter and evaporated. Column chromatography of the crude product (diethyl ether/hexane 1:1) yielded (1R,2R)-3-bromo-1,2-dicarbomethoxy-3-formyl-cyclopropane (1.93 g, 69%) as a white solid. mp 52° C.; [α]20D=+108° (c=0.25 in MeOH): 1H NMR (CDCl3): d 3.16 (d, J=6.5 Hz, 1H), 3.27 (d, J=6.5 Hz, 1H), 3.76 (s, 3H), 3.83 (s. 3H), 9.26 (s, 1H). MS (EI) m/z 265, 267 [M+H+ ], 233, 235 (24) [M+ --OMe], 204, 206 (24), 176, 178 (44), 153 (100), 125 (95), 59 (69).
Reaction SMILES: [OH2:1].[CH3:2][S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[OH:11]O.Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:11])=[O:1]
Reactant: CSc1ccc(N)cc1
Reactant: OO
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N)cc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
67 mg of Na2WO4, 8 drops of acetic acid and 19 mL of H2O were placed in a flask and the mixture was heated to 65° C. 19 mL (153 mmol) of 4-methylthioaniline was added followed by 34.5 mL (337 mmol) of H2O2 dropwise. The mixture was stirred at 65° C. for 1.5 h and, after cooling, 800 mL of 1N HCl and 500 mL of CHCl3 was added. The layers were separated and the aqueous phase was washed with more CHCl3. The aqueous phase was basified with 25% NaOH and extracted with CHCl3. The organic phase was washed with brine and dried over MgSO4. The solvent was removed, yielding the product as a white solid (19.80 g, 75%).
Reaction SMILES: [N+:1]([O-])(O)=O.[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.CCO.O.[Fe]>[Br:15][C:9]1[C:10]([CH3:14])=[C:11]([CH:12]=[CH:13][C:8]=1[CH:5]([CH3:7])[CH3:6])[NH2:1]
Reactant: Cc1cccc(C(C)C)c1Br
Reactant: O=[N+]([O-])O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(N)ccc(C(C)C)c1Br
Temperature: 90 °C

Procedure:
Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in HOAc (60 mL). The mixture is heated 1 hour at 90° C. and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3×60 mL). The combined extracts are washed with 1 N NaOH (3×40 mL) and then water (40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in HOAc (75 mL)/EtOH (75 mL). To this is added Fe powder (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H2O (10 mL) is added dropwise at 0° C. to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H2O (15 mL), and the mixture is stirred for 1 hour at 0° C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl3 (70 mL) at room temperature. The mixture is stirred for 1 hour and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H-indazole. 1H NMR (CDCl3) 8.03 (br, s, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:14]#[N:15]>CN(C=O)C.CCOCC>[F:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:14]#[N:15]
Reactant: OC1CCCCC1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(OC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (1.92 g, 48.0 mmol) is slowly added to a stirred solution of cyclohexanol (4.01 g, 40.0 mmol) in DMF (30 ml) at 0-5° C. under nitrogen. After 2.5 hours, 3,5-difluorobenzonitrile (5.56 g, 40.0 mmol) is slowly added over 5 min. The mixture is allowed to warm to room temperature and stirred for an additional 12 hours. The mixture is diluted with ether (150 ml), washed with water, brine (30 ml), dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate:hexanes (1:10) to provide 3-fluoro-5-cyclohexyloxybenzonitrile as a yellow oil. MS: 220 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.Cl.NC(N)=N.Cl[C:34]1[C:43]2C(=CC=C(S(NC3(C(OCC)=O)CCC3)(=O)=O)C=2)C(Cl)=CN=1.O>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:21]([O:23][CH2:34][CH3:43])=[O:22])[CH2:20][CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCC1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCC3)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCC1
Temperature: 60 °C
Yield: 68 %

Procedure:
1-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclobutanecarboxylic acid hydrochloride ##STR47## NaH (37 mg, 80% dispersion by wt in mineral oil, 1.24 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (189 mg, 1.98 mmol) in DMSO (6 mL) and the mixture was heated at 60° C. under N2 for 30 min. Ethyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino)-cyclobutanecarboxylate (200 mg, 0.50 mmol) was added in one portion and the mixture heated at 80° C. for 10 h. The cooled mixture was poured into water, extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 0:100) as eluant to give ethyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino)cyclobutanecarboxylate (150 mg, 0.34 mmol) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CCN(CC)CC.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C.COC(C)(C)C.CCOC(C)=O>[C:20]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCC(=O)OCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a well-stirred solution of solketal (21, 62.6 ml, 500 mmol), Et3N (83.6 ml, 600 mmol) and DMAP (5 g, 40.9 mmol) in tert-butyl methyl ether (11) at 0° C., n-butyryl chloride (52.4 mL, 500 mmol) was added dropwise over a 75 minute period. The mixture was stirred for an additional hour at 0° C. and then at room temperature for an additional 5 hours. The mixture was diluted with AcOEt (11), washed with water (11), dried (MgSO4), filtered and evaporated to afford 22 (104.6 g, 500 mmol, 100%) as an oil. The material was used in the next step without any further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.ClCCl.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(OCC)(=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:3][CH2:4]1
Reactant: CN1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 0.570 g (0.00477 mole) of 4-amino-1-methylpiperidine, 1.5 mL of ethyldiisopropylamine and 20 mL of dichloromethane at 0 degrees, was added 1.000 g (0.00451 mole) of 4-nitrobenzenesulfonyl chloride. The mixture was stirred for 1 hour and then diluted with 100 mL of ethyl acetate and washed successively twice with 20 mL of saturated sodium bicarbonate solution, twice with 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.23 g of N-(1-methyl-piperidin-4-yl)-4-nitro-benzenesulfonamide as a yellow solid. The material was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as light-yellow gum (7.8 mg, 43%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][C:3]=1[C:13]#[N:14].O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:13]#[N:14])[CH:4]=2)[N:9]=1
Reactant: Cc1cc2[nH]c(=O)ccc2cc1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc2nc(Cl)ccc2cc1C#N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 7-Methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile (10 g, 54 mmol) and POCl3 (30 mL) was stirred at 110° C. for 2 h and then at 20° C. overnight. The mixture was carefully poured into a mixture of water and ice (400 mL) while being stirred vigorously. The product was collected by filtration and dried by co-evaporation with MeCN/Toluene to furnish the title product. LC/MS (IE, m/z): [M+1]+=203.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[NH2:31]>O1CCOCC1.O>[CH3:13][S:12][C:8]1[N:7]=[C:6]([C:5]2[N:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([O:23][CH3:22])=[O:32])[C:26]3=[N:31][CH:4]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CCO/C=C/c1ccnc(SC)n1
Reactant: COC(=O)c1cccnc1N
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccn2c(-c3ccnc(SC)n3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
137.2 mg of the 4-[(E)-2-ethoxyvinyl]-2-(methylthio)pyrimidine [25-2] was dissolved in a mixture solvent of 5 mL of 1,4-dioxane and 2 mL of water, and 124.1 mg of N-bromosuccinimide was added thereto. After stirring at room temperature for 1 hour, 106 mg of the 2-aminonicotinic acid methylester [25-1] was added, and stirred at 85° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography, to obtain 106.1 mg of methyl 3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyridine-8-carboxylate [25-3].
Reaction SMILES: O=[O+][O-].[F:4][C:5]1[C:10]2[CH:11]=C(C)[O:13][C:9]=2[C:8]([CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.FC1C2CC(C)[O:27]C=2C(CCC)=CC=1.CSC>>[F:4][C:5]1[C:10]([CH:11]=[O:27])=[C:9]([OH:13])[C:8]([CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1
Reactant: CCCc1ccc(F)c2c1OC(C)C2
Reactant: CCCc1ccc(F)c2cc(C)oc12
Agent: O=[O+][O-]
Solvent: CSC
Product: CCCc1ccc(F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Ozone was conducted at -78° C. into a solution of 6.6 g (34 mmol) of a 4:1 mixture of 4-fluoro-2-methyl-7-propyl-benzofuran and 4-fluoro-2-methyl-7-propyl-2,3-dihydro-benzofuran until the color became blue. Subsequently, argon was conducted through the solution which was then treated at -78° C. with 13 ml of dimethyl sulfide. After warming to room temperature the solution was concentrated in a vacuum and the residue was dissolved in 50 ml of ethanol. After the addition of 50 ml of 3% sodium hydrogen carbonate solution the mixture was stirred at 70° C. for 30 minutes. Subsequently, the mixture was poured on to 200 ml of ice-water, made acid with 10% HCl and extracted three times with 150 ml of diethyl ether each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 2:3). There were obtained 5.0 g (100%) of 6-fluoro-2-hydroxy-3-propyl-benzaldehyde as a pale yellow oil, which was used immediately in the next reaction.