Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]1([C:12]#[C:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:21]1([N+:26]#[C-:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.[Na+].[Cl-]>CO.C(Cl)Cl>[CH:21]1([NH:26][C:27]2[N:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]3=[N:28][C:19]=2[C:17]2[S:18][C:14]([C:13]#[C:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: [C-]#[N+]C1CCCC1
Reactant: O=Cc1ccc(C#Cc2ccccc2)s1
Reactant: Nc1cnccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CO
Product: C(#Cc1ccc(-c2nc3cnccn3c2NC2CCCC2)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 47 %

Procedure:
10 μl (0.022 mmol) of 20% aq. perchloric acid, a solution of 31.8 mg (0.15 mmol) of 5-phenylethynyl-thiophene-2-carbaldehyde in a mixture of MeOH and DCM (0.5 ml, 1:1 vol/vol) and a solution of 11.1 mg (0.115 mmol) of cyclopentyl isocyanide in MeOH (0.5 ml) were added in succession to a solution of 9.5 mg (0.1 mmol) of 2-aminopyrazine in MeOH (1 ml). The reaction solution was stirred at RT for 36 h and then combined with sat. aq. NaCl solution (3 ml) and stirred at RT for a further 45 min. The phases were separated and the aq. phase was extracted with DCM (2×3 ml). The collected organic phases were dried over MgSO4, filtered and evaporated under a vacuum. The group was purified by means of preparative HPLC, wherein 18 mg (0.047 mmol, 47%) of cyclopentyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1[NH2:26].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[F:21][C:19]1[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]2[N:15]([N:14]=[C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:26]=2)[CH:20]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reactant: COC(=O)c1cc(N)[n+](N)cc1F
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 100 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
A mixture of 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate (1.719 g, 4.46 mmol) and benzoyl chloride (1.03 ml, 8.92 mmol) in pyridine (12 ml) is stirred for 20 hours at 100° C. The solvent is evaporated and the residue stirred for 2.5 hours with sat. aqueous ammoniumchloride solution while neutralizing to pH 6-7 with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording methyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (603 mg, 49.8%) as a light brown solid. Mp.: 162-8° C. MS: m/z=272.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:14][C:15]#[N:16].[I-].[CH3:18][S+](C)(C)=O.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C@@H:13]1[CH2:18][C@H:14]1[C:15]#[N:16]
Reactant: COc1ccc2ccccc2c1C=CC#N
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2ccccc2c1[C@@H]1C[C@H]1C#N

Procedure:
5 g (23.9 mmol) of the compound obtained in Step A dissolved in 50 ml of DMSO are added dropwise to the ylid formed starting from 7.9 g (1.5 eq) of trimethylsulphoxonium iodide and 1.15 g (1.2 eq) of NaH (60% suspension in oil) in 20 ml of DMSO. The title compound is obtained in the form of an oil and is purified by chromatography over silica gel (eluant: CH2Cl2/i-PrOH 98/2).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11](S)[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].[SH:19]C1C=CC=CC=1O.C1(S(O[C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=O)(=O)=O)C=CC=CC=1>C(#N)C>[C:3]([C:7]1[CH:12]=[C:11]([C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[S:19])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: Oc1ccccc1S
Reactant: COC(=O)[C@H](C)OS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=S)[C@H](C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 60% sodium hydride in mineral oil (7.0 g, 0.20 mol) and acetonitrile (200 mL) under a nitrogen atmosphere was added dropwise a solution of 2,6-di-t-butyl-4-mercaptophenol (A) (53.7 g, 0.23 mol, 90%) in acetonitrile (100 mL) over a 1 h period. The reaction mixture was stirred at 25° C. for an additional hour to ensure complete anion generation. To the mercaptophenol anion was added a solution of methyl (2S)-2-(phenylsulfonyloxy)propanate (50 g, 0.20 mol, 12) in acetonitrile (100 mL) dropwise over a 1 h period. Upon addition of methyl (2S)-2-(phenylsulfonyloxy)propanate a white precipitate was observed. The reaction mixture was allowed to stir at 25° C. overnight. The mixture was worked-up by filtration through a coarse sintered glass funnel containing was Celite®. The solvent was removed by rotary evaporation to afford a smelly yellow oil. Purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 10 cm diameter×30 cm length) using hexane and ethyl acetate (9:1) afforded 51.3 g (81%) of methyl (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoate (31) as a thick oil: 1H NMR (CDCl3) δ1.42-1.45 (m, 21 H), 3.60-3.68 (q, J=7.2 Hz, 1 H), 3.67 (s, 3 H), 5.33 (s, --OH, 1 H), 7.29 (s, 2 H); 13C NMR (CDCl3) δ173.3, 154.6, 136.6, 131.8, 122.0, 52.0, 46.0, 34.3, 30.2, 17.4; IR (neat) 3635 (s), 2958 (vs), 2875 (s), 1737 (vs), 1426 (vs), 1237 (vs), 1160 (vs), 855 (w), 774 (w) cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:31].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:31])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:29])[C:24]([F:28])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(F)c(F)c1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 3-ethyl-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.070 g; 5.056 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-3-ethyl-8-[2-(3,4,5-trifluoro-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.220 g; 54%). LC-MS: tR=1.06 min.; [M+H]+=444.00 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:14])([F:13])[C:11]#[N:12].P([O-])(OCC)(SCC)=[S:23].O.[ClH:32].O1CCOCC1>C(OCC)C>[ClH:32].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:13])([F:14])[C:11](=[S:23])[NH2:12]
Reactant: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOP([O-])(=S)SCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: NC(=S)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile were added 0.2 ml of diethyl dithiophosphate and 0.04 ml of water. The resulting mixture was subjected to reaction at 80°-90° C. for 5hours. The reaction mixture was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain an oily matter. To the oily matter was added 0.5 ml of a 2N hydrochloric acid-dioxane solution, and then diethyl ether was added. The resulting crystals were collected by filtration to obtain 110 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1yl)butanethioamide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[CH2:30][CH2:31]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 47 mg (0.29 mmol) of 1-Pyridin-4-yl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: OCCCCCCBr
Reactant: C1=COCCC1
Product: BrCCCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
197.8 g (1.09 mol) of 6-bromo-1-hexanol was put in a 500-ml reactor and was cooled to 5° C. or below. 102.1 g (1.21 mol) of dihydropyran was dropped thereto at a temperature of not higher than 10° C. After the dropping was finished, the mixture was returned to room temperature and stirred for one hour. Residue obtained as a result of the reaction was subjected to purification by silicagel column with use of hexane/diisopropyl ether (IPE)=5/1, whereby 263.4 g of 6-bromo-1-(tetrahydropyranyloxy)hexane was obtained. The yield of the same was 90.9%. The reaction of the step 1 is expressed by a formula (12) shown below: BrCH26OH→BrCH26OTHP  (12) Step 2: Synthesis of N-[6-(tetrahydropyranyloxy)hexyl]pyrrole
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=CC(C(N3CCC3)=O)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:29]([O:36][C:37](=[O:46])[C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][C:39]=1[F:45])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:41]2[CH:42]=[CH:43][C:38]([C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:46])=[C:39]([F:45])[CH:40]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)OCc3ccccc3)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid benzyl ester (65a) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). 1H NMR (400 MHz, CDCl3) δ 7.96 (t, J=8.46 Hz, 1 H) 7.44-7.49 (m, 2 H) 7.32-7.43 (m, 3 H) 7.28 (s, 1 H) 7.25 (s, 1 H) 6.76 (dd, J=8.72, 2.40 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1 H) 5.38 (s, 2H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C26H23FO6 m/z 450.00 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(CC(c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: ClCCl.[CH3:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]([C:33]23OCC(C)(C[O:38]2)C[O:34]3)[CH:9]1[CH3:42])=[O:7].FC(F)(F)C(O)=O>O>[F:31][C:29]1[CH:28]=[CH:27][C:26]([CH3:32])=[C:25]([CH:30]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[NH:5][CH3:4])[CH:9]([CH3:42])[CH:10]2[C:33]([OH:38])=[O:34])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C(=O)O)C1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a dichloromethane (7 ml) solution of 4-[4-(5-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (compound of formula XLIV, 376 mg, 0.67 mmol) at about 23° C. was added water (0.14 ml) and trifluoroacetic acid (0.14 ml). The reaction mixture was stirred for about 0.5 hour then was concentrated in vacuo. The residue was diluted with methanol (20 ml) and water (6 ml) and cesium carbonate (45 ml of a 10% solution in water) was added to the mixture. The reaction mixture was heated to about 40° C. for about 24 hours then was cooled to about 23° C., acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated in vacuo, to give 330 mg of a compound of formula XLVI.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([C:26]([CH:28]=[CH2:29])=[O:27])[CH3:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:25]=[CH:24]/[C:26](=[O:27])[CH2:28][CH3:29])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (160 mg, 0.36 mmol), ethylvinyl ketone (50 mg, 0.43 mmol) and Pd(OAc)2 (8 mg) in MeCN (2 mL) is added triethylamine (0.5 mL, 3.6 mmol) and the mixture is heated at 100° C. in a pressure vessel for 4 h. The mixture is filtered and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: OCCCN1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(OCCCN3CCCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A mixture of 20.2 g (0.1 mol) 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (commercially available), 18.6 g (0.13 mol) 1-piperidinepropanol (commercially available), 50.4 g (0.2 mol) 1,1′-(azodicarbonyl)dipiperidine and 58 ml (0.2 mol) tri-n-butyl-phosphine in 400 ml THF was stirred at room temperature for 16 h. The suspension was filtered off and the filtrate evaoprated to dryness. The residue was taken up in 200 ml DCM and 400 g Isolute® HM-N (Argonaut Technologies Inc., support material for accelerated solvent extraction) was added and evaporated to dryness. The residue was chromatographed over silica eluting with a gradient formed from DCM/MeOH(2N NH3) 99/1 to 9/1. After evaporation the residue was treated with heptan/diethyl ether and the precipitate filtered of and washed again with heptan/diethyl ether. After drying under reduced pressure at 50° C. 25 g (76%) of the title compound was obtained as white solid. MS (m/e): 328.3 (MH+, 100%)
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:19][O:20][NH2:21].N1C=CC=CC=1>CCO>[CH3:19][O:20][N:21]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxohexyl)-3-pyridinecarbonitrile (0.80 g, 0.0034 mol), methoxyamine hydrochloride (0.32 g, 0.0038 mol) and pyridine (2.0 ml) were heated and stirred at reflux overnight in EtOH (30.0 ml). The solution was allowed to cool to room temperature and the solvent was removed on the rotary evaporator. The pasty residue was triturated with H2O, filtered and recrystallized (EtOH-H2O) giving 0.5 g (56%) m.pt. 159°-165° C. One more recrystallization gave the analytical sample m.pt. 170°-171° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: CCN(CC)CCCN
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
0.20 g (0.00051 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 8.0 ml of 3-diethylamino-1propylamine. The mixture was stirred at room temperature for 18 hrs., the solvent was removed and the residue was chromatographed twice on silica gel, firstly with 20% methanol in dichloromethane and then with 10% methanol in dichloromethane. There was obtained 0.09 g (41%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N',N'-diethylpropane-1,3-diamine as a pale yellow, amorphous solid. MS (ISP): me/e=443, 441 (C18H26BrN4O2S+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4]CC.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(#N)C1C=CC=CC=1>>[C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[C:14][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCC
Reactant: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCC#Cc1ccccc1
Reaction time: 20 h
Yield: 95 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.90 mmol (95% yield) of 1-hexynylbenzene and and 0.08 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.OC1C2N=NNC=2C=CC=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:11]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc2c(cc1Cl)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1cc2c(cc1Cl)OCO2)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
To a mixture of 6-chloro-1,3-benzodioxole-5-carboxylic acid (0.49 g,2.44 mmol) and hydroxybenzotriazole (66 mg, 0.49 mmol) in acetonitrile (20 mL) were added morpholine (0.53 mL, 6.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol). The orange solution was stirred 72 h at room temperature, diluted with ethyl acetate and poured into water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as white solid (0.53 g, 80%), mp 155° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([CH2:19][C:20](O)=[O:21])#N.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([S:15][CH3:16])[N:10]=[CH:11][C:12]=3[CH:13]=[CH:19][C:20]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)O
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: CSc1ncc2ccc(=O)n(C3CCCC3)c2n1
Temperature: 25 °C

Procedure:
A mixture of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (9), (1 g, 4.2 mmol), 1.2 equivalent of cyanoacetic acid, and a catalytic amount of benzylamine was taken into acetic acid and refluxed for about 6 h. After completion of the reaction by TLC, the reaction mixture was cooled to room temperature and product precipitated from the reaction mixture. Additional product was precipitated from the reaction mixture via the addition of hexane. The resultant solid was collected, washed with saturated NaHCO3, water, and subsequently dried under vacuum. The resultant crude product (10) was recrystallized in 2-propanol.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCC([Br:14])=O.[NH+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH:22][N:23]1[C:27]2C=[CH:29][CH:30]=[CH:31][C:26]=2N=N1.C(N(CC)CC)C>>[CH2:19]([C:20]([NH2:15])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH+:23]1[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=1.[Br-:14]
Reactant: CCCCCCCCCCCC(=O)Br
Reactant: On1nnc2ccccc21
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(N)=O
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PAMAM generation 2.0 core (0.0479 mmol; 50 mg) was evaporated from a 0.5 ml solution in MeOH and then re-dissolved in 10 ml of water. 1-N-pyridinium 12-dodecanoic acid bromide (0.14 g; 0.384 mmol), N-hydroxybenzotriazole hydrate [HOBT] (52 mg; 0.384 mmol); triethylamine (53 μl 0.384 mmol) and 1-(3-diethylaminopropyl-3-ethyl) carbodiimide. HCl[EDC] (74 mg; 0.384 mmol), were added to the solution. This reaction mixture was stirred overnight at room temperature. The volume was reduced to a third under reduced pressure and the solution was chromatographed on a LH20 column using water as the eluent. Fractions containing the product were collected and pyridinium dodecylcarboxamide PAMAM 2.0 bromide isolated as a fluffy white solid by freeze drying. 1H nmr (D2O): δ 1.15, 1.45, 1.9, 2.15, 2.75, 2.8, 3.15, 3.35, 3.5, 4.55, 8.05, 8.5, 8,8.