Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[C:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: CC(C(=O)NC(C)(C)C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC(C)(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.78 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(tert-butylaminocarbonyl)ethyl]piperazine and 0.31 g of triethylamine in 15 ml of chloroform, and the resulting solution is stirred at room temperature for 1 hour.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:2][C:1]#[N:3]
Reactant: BrCc1ccccc1Br
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCc1ccccc1Br
Temperature: -78 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of acetonitrile (49 g, 1.20 mol, 9.96 equiv) in tetrahydrofuran (150 mL). This was followed by the addition of BuLi (72 mL, 1.50 equiv) dropwise with stirring at −78° C. Stirred at −78° C. for 1 h. To this was added a solution of 1-bromo-2-(bromomethyl)benzene (30 g, 120.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stiffing at −78° C. The resulting solution was stirred for 1 h at −78° C. The reaction was quenched by the addition of 100 mL of water at −78° C. The resulting aqueous solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The crude product was purified by distillation under reduced pressure (2 mm Hg) and the fraction was collected at 98-107° C. This resulted in 13.21 g (52%) of 3-(2-bromophenyl)propanenitrile as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][OH:20])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][O:20][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: CCOC(=O)Cl
Product: CCOC(=O)ONC(=O)Cc1ccc2c(C(=O)OCC)c(N)c(C(=O)OCC)c-2cc1
Yield: 47 %

Procedure:
In an analogous manner to that described in Example 12, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate and ethyl chloroformate the title compound is obtained in 47% yield as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(=O)C(C)(C)C)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:25][CH:22]([CH3:24])[CH3:23])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)OC(=O)C(C)(C)C)=C1SC=CS1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A mixture of isopropyl 2-(1,3-dithiol-2-ylidene)-2-(pivaloyloxycarbonyl)acetate (13.2g), isopropylamine (2.6 g) and methylene chloride (60 ml) was stirred at room temperature for 5 hrs. The reaction mixture was washed with aqueous sodium hydroxide solution and water. After removal of solvent the residue was distilled to give the titled compound (9.43 g, 66%) as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][NH:84][CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]>CN(C=O)C>[CH2:76]([O:78][C:79]([N:81]1[CH2:86][CH2:85][N:84]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:35])[NH:31][CH2:32][CH2:33][F:34])=[O:24])[N:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH2:83][C@H:82]1[CH3:87])=[O:80])[CH3:77]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCCF)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 24 h

Procedure:
To a solution of 81 mg (S)-2-({5-[2-((S)-2-(2-Fluoroethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 22 μl DIPEA, 52 mg HATU and 24 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 24 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 300 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]2[O:19][C:18]([CH:20]3[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][N:21]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:17][N:16]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:11]1[CH2:14][CH:13]([C:15]2[O:19][C:18]([CH:20]3[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][N:21]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:17][N:16]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1c1nnc(C2CN(C(=O)OCc3ccccc3)C2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1c1nnc(C2CNC2)o1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 2-(5-{1-[(benzyloxy)carbonyl]azetidin-3-yl}-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (200 mg, 0.39 mmol) in ethanol (10 ml) was added 10% palladium on carbon (20.0 mg). The reaction was charged with 1 atm hydrogen gas and allowed to stir for 1 h. The reaction was filtered through celite, and the filtrate was concentrated to yield tert-butyl 2-(5-azetidin-3-yl-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (100%). LCMS (M+H)=385.2.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC#CCOc1cc(NCC(F)(F)F)ncn1
Temperature: 60 °C
Reaction time: 9 h
Yield: 24.4 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 220 mg of potassium carbonate, and 495 mg of 2,2,2-trifluoroethylamine, followed by stirring at a bath temperature of 60° C. for 9 hours. Then, 495 mg of 2,2,2-trifluoroethylamine was further added, and the mixture was stirred at 80° C. for 8 hours. Then, 495 mg of 2,2,2-trifluoroethylamine and 2 ml of dimethylsulfoxide were further added, and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 60 mg of 4-(2-butynyloxy)-6-(2,2,2-trifluoroethylamino)pyrimidine (the present compound (114)).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.CO>[OH:10][CH:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Temperature: 0 °C

Procedure:
0.57 g (0.015 mole) of sodium borohydride is added all at once at 0°, with stirring, to the solution of 5.6 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide [see Example 1a)] in 250 ml of tetrahydrofuran and 25 ml of methanol, and the whole is subsequently stirred for a further hour at room temperature. There is then slowly added dropwise, with ice-water cooling, 1N hydrochloric acid solution until the pH-value of the reaction mixture has reached 4. The mixture obtained is concentrated in vacuo to dryness. Water is added to the residue, and extraction is performed twice with ethyl acetate. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. There is obtained amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide, which can be used directly in the next stage. On the silica gel plate, the compound has an Rf value of 0.61 in the system ethyl acetate/methanol (95:5).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Cl)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-chlorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as stating materials, the title compound was prepared.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: NCCO
Reactant: CCOC(=O)c1cccnc1
Product: O=C(NCCO)c1cccnc1
Reaction time: 48 h
Yield: 85.1 %

Procedure:
A solution of 49.2 g (0.32525 mol) ethyl nicotinate and 72 g (1.17 mol) ethanolamine was heated at 70° C. for 60 hours. The excess ethanolamine was removed under reduced pressure and the resulting viscous cream oil was stirred with ether for 48 hours. The resulting white solid was removed by filtration, affording 46 g (85.1%) of the title compound melting at 75°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH2:31][OH:32].[O-]CC.[Na+]>C(O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH2:31][OH:32]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NCCO)c3cc2Br)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=N)(=O)c1cccc(COc2cc3ncnc(NCCO)c3cc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
According to GWP 6, (RS)-S-[3-({[6-bromo-4-(2-hydroxyethylamino)quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (67 mg, 0.13 mmol) is reacted with sodium ethoxide (29 mg, 0.46 mmol) in ethanol (3 mL). After cooling to room temperature, the reaction mixture is admixed with brine and stirred for 30 minutes and the resulting precipitate is filtered off with suction to leave the desired product in 81% yield (47 mg).
Reaction SMILES: [O:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4](O)[CH2:3][CH2:2]1.S(Cl)([Cl:14])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:14][CH:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:1][CH2:2][CH2:3]1
Reactant: OC1CCOc2ncccc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClC1CCOc2ncccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (21 mmol) in 80 mL DCM was added 2.3 mL thionyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at reflux for 30 min. After cooling to RT, sat. aq. NaHCO3 solution was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to obtain the desired product as orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]([NH:33][CH2:32][C:31]4[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:21][C:22]=3[CH3:23])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Solvent: O
Product: CCc1cnc(N2CCN(C(=O)c3cnc(NCc4ccc(OC)cc4)cc3C)CC2)c(C)c1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1OC.[C:11](O)(=O)[CH2:12][C:13](O)=[O:14].P(Cl)(Cl)(Cl)=O>>[NH:8]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][C:13]1=[O:14]
Reactant: COc1cccc(N)c1Br
Reactant: O=C(O)CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1ccc2ccccc2[nH]1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To 2-bromo-3-aminoanisole 2B4 (378 mg, 1.87 mmol, 1 eq) and malonic acid (194 mg, 1.87 mmol) was added phosphorous oxychloride (175 μL, 1.87 mmol). The reaction was placed in a pre-heated bath (95° C.) and stirred for 30 minutes. The mixture was cooled, and diluted with ice water and stirred ca. 2 h to afford a grey solid. This was filtered and washed with water until free of acid and then taken up into 1N NaOH. Insoluble material was removed by filtration and the resulting aqueous solution was treated with EtOH (8 mL) before adjusting the pH to 5-6 with 1N HCl (aq). The desired product was filtered and dried to afford quinolone 3J1 (0.12 g, 24%) as a yellow solid. MS: 270.0 (M+H)+ and 291.9 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([Se:21][C:22]#[C:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH:8]=1.O.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[C:16]2[C:15]([CH3:17])([CH3:18])[CH2:14][CH2:13][C:12]([CH3:19])([CH3:20])[C:11]=2[CH:10]=[C:9]([Se:21][C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3cccc(F)c3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2c(OCc3cccc(F)c3)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
650 mg (1.2 mmol) of methyl 4-[4-(3-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate are dissolved in 20 mL of THF. 10 mL of water are added, followed by addition of 240 mg (6 mmol) of sodium hydroxide. The medium is stirred for 4 hours at 80° C. and then acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 1/1 heptane/ethyl acetate) and then recrystallized in a heptane/ethyl acetate mixture. A pure yellow crystalline solid is obtained (m=577 mg; yield=90%; m.p.=206° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and N-phenylpiperazine (4.8 cc) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-[3-(4-phenyl-l-piperazinyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (5.7 g) is obtained, m.p. 126° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:18][C:11]3[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].[CH:25]1(N)CC1>>[CH:1]1([N:3]2[C:7]([C:8]3[S:18][C:11]4[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=4[CH:9]=3)=[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=[CH:4]2)[CH2:25][CH2:2]1
Reactant: NC1CC1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using cyclopropylamine in place of ethylamine. Solid (25 mg, 14%) (contains 30% of 1-cyclopropyl-4,5-phenyl-1H-imidazole);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:48][C:49]1[CH:54]=[CH:53][C:52](O)=[CH:51][C:50]=1[CH:56]1[O:61][CH2:60][CH2:59][CH2:58][O:57]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:52]2[CH:53]=[CH:54][C:49]([Br:48])=[C:50]([CH:56]3[O:57][CH2:58][CH2:59][CH2:60][O:61]3)[CH:51]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Reactant: Oc1ccc(Br)c(C2OCCCO2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1600 mg, 7.21 mmol) in toluene (72 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2728 mg, 10.81 mmol) at 0° C., followed by the additions of tributylphosphine (2.69 mL, 10.81 mmol) and 4-bromo-3-[1,3]dioxan-2-yl-phenol (2240 mg, 8.65 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (1000 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Brc1ccc2nccn2c1
Solvent: CC(=O)O
Product: Brc1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-bromo-imidazo[1,2-a]pyridine (1 eq, 96 mmol, 19 g) in acetic acid (200 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 96 mmol, 4.9 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered to afford the title compound as a beige solid; [M+H]+=275/277/278