Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[NH:7][C:8]([C:11]2[CH:24]=[C:23]3[O:25][CH2:26][C:20]4[C:21]5[C:22]3=[C:13]([CH2:14][O:15][C:16]=5[CH:17]=[C:18]([C:27]3[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5C(OC(C)(C)C)=O)=[N:29][CH:28]=3)[CH:19]=4)[CH:12]=2)=[CH:9][N:10]=1.N1CCC[C@H]1C1NC(C2C=C3COC4C5=C(C=C(C6NC([C@@H]7CCCN7)=NC=6)C=4)COC(C=2)=C35)=CN=1.[CH3:80][O:81][C:82]([NH:84][C@@H:85]([CH:89]([CH3:91])[CH3:90])[C:86](O)=[O:87])=[O:83].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH3:90][CH:89]([CH3:91])[C@H:85]([NH:84][C:82](=[O:83])[O:81][CH3:80])[C:86](=[O:87])[N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:18]2[CH:19]=[C:20]3[CH2:26][O:25][C:23]4[C:22]5=[C:13]([CH:12]=[C:11]([C:8]6[NH:7][C:6]([C@@H:2]7[CH2:3][CH2:4][CH2:5][NH:1]7)=[N:10][CH:9]=6)[CH:24]=4)[CH2:14][O:15][C:16]([CH:17]=2)=[C:21]35)=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6CCCN6)[nH]5)cc(c2-4)OC3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1nc([C@@H]2CCCN2)[nH]c1-c1cc2c3c(c1)OCc1cc(-c4cnc([C@@H]5CCCN5)[nH]4)cc(c1-3)OC2
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6CCCN6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Temperature: 25 °C
Yield: 12 %

Procedure:
The mixture of (S)-tert-butyl 2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and 2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene obtained in the previous step was dissolved in dimethylformamide (6 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (194 mg, 1.11 mmol), HATU (309 mg, 0.81 mmol), and N-methylmorpholine (0.24 mL, 2.2 mmol). The reaction was stirred at room temperature for thirty minutes, and then quenched by the addition of formic acid (0.05 mL). The reaction was concentrated and the resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H2O+0.1% TFA) to yield methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (59 mg, 12%) as the tris-TFA salt. Also isolated from the reaction were (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (124 mg, 23%) and dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno-[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (50 mg, 8%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17]C1C=CC=CC=1>O1CCCC1>[C:1]1([N:7]=[C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc(C(=O)NC2CCCCC2)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(N)=Nc2ccccc2)c1
Yield: 82.9 %

Procedure:
65.1 g (0.3 mole) of N-cyclohexyl-m-toluamide were dissolved in 500 ml of dried tetrahydrofuran and a benzene solution of 45 g of COCl2 absorbed in 30 ml dried benzene, and 30 ml dried pyridine were added dropwise and under agitation and ice cooling to the above tetrahydrofuran solution. Upon completion of the dropwise addition, the reaction mixture was adjusted in its temperature to room temperature and brought into reaction for 2 hours. The sedimented pyridine hydrochloride were filtered off and the filtrate was condensed under vacuo, to provide an oily substance containing N-cyclohexyl-m-toluimido chloride. The oil was then subjected to extraction with 400 ml of dried petroleum ether and 32.8 ml (0.36 mole) of aniline were added dropwise for 30 minutes under agitation and ice cooling to the extract and the mixture was let to react at room temperature for 1.5 hours. The thus deposited oily substance was decanted off from the mother liquor and dissolved in 100 ml of ethanol, adjusted pH to about 2 by addition of 1N-hydrochloric acid and added with 1.2 lit. of water. Then, the aqueous solution was washed twice with 150 ml of ethyl acetate. The aqueous phase was treated with active carbon for discoloration and then condensed under vacuo. The sedimented products were filtered off, washed, dried and recrystallized from ethanol/diethyl ether. In this way, 81.7 g of N-cyclohexyl, N'-phenyl-m-toluamidine were obtained. m.p. 174° - 176° C. Yield: 82.9%.
Reaction SMILES: C([O:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=[O:25])C1C=CC=CC=1.[Li].C=CC=C.CO>O1CCCC1>[OH:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CC(=CCCC(C)=CCOCc1ccccc1)CCC=C(C)CCC=C(C)C(=O)O
Agent: C=CC=C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5 g of the 16-benzyloxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid obtained as described in the previous (a) section. This solution was added dropwise to the above-prepared lithium solution over a period of 30 min. The mixture was stirred for 30 min., and 1,3-butadiene was introduced into the mixture until the color of the mixture (blue) faded. To the resulting yellow colored solution was added methanol until the yellow faded. Subsequently, this was left standing to reach room temperature. The solid product thus obtained was collected on a filter, and then dissolved in water. The aqueous solution was made weakly-acidic by addition of 1 N hydrochloric acid under ice-cooling, and then extracted with hexane. The extract was washed successively with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The dried extract was concentrated, and the thus-obtained concentrate was purified over a silica gel column to give 3.3 g of 16-hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9]([CH3:18])([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)([CH3:18])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[CH:3][CH:4]=1)=[O:19]
Reactant: CN1CCNCC1
Reactant: CN1CCN(C(C)(C)C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C(=O)C(C)(C)N3CCN(C)CC3)cc2)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
13.2 g (0.05 mol) of 1-(4-fluorophenyl)-2-methyl-2-(4-methylpiperazino)-propan-1-one and 6.5 g (0.065 mol) of 1-methylpiperazine are dissolved in 20 ml of dimethyl sulfoxide, and the solution is heated to about 115° C. together with 6.9 g (0.05 mol) of potassium carbonate. After 15 hours of stirring at about 115° C. the suspension is cooled down and is poured at about 60° C. onto ice. The crystals are filtered off and are recrystallised twice from ethyl acetate. Melting point 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 55 °C
Yield: 33 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.029 g, 0.0677 mmol), 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.018 g, 0.0599 mmol) and Cs2CO3 (0.024 g, 0.0736 mmol) in DMF (3 mL) was heated at 55° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and quenched with aqueous 1 N HCl (0.3 mL) and then was diluted with water and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a gradient of 4:1 to hexanes:EtOAc to 2:1 EtOAc:hexanes to afford 0.011 g (32%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:37]1([O:32][C:31](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([N:12]5[CH2:13][CH2:14][CH:9]([C:3]6[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=6)[CH2:10][CH2:11]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(On1nnc2ccccc21)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.9 %

Procedure:
To a suspension of 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid dihydrochloride salt (0.62 g) and 1-hydroxybenzotriazole (0.2 g) in dichloromethane (12 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.22 g) and stirred for 22 hours at ambient temperature. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (0.41 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:17]=2Cl)[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].COC(=O)CC1C=CC(OC)=C(Br)C=1.COC1C=C(C2C=NC=C(C=2[NH:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[NH:57][CH:56]=[CH:55]3)C#N)C=CC=1OC.NC1C=C2C(=CC=1)NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:17]=2[NH:51][C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[NH:57][CH:56]=[CH:55]3)[C:15]#[N:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1Br
Reactant: COc1ccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)cc1OC
Agent: COC(=O)Cc1ccc(OC)c(Br)c1
Agent: Nc1ccc2[nH]ccc2c1
Product: COc1ccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)cc1Br

Procedure:
Following procedures analogous to those described in Example 1, 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was prepared from methyl(3-bromo-4-methoxyphenyl)acetate. Following procedures analogous to those described above for preparing compound 101 (Example 1), 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was treated with 5-aminoindole to produce 5-(3-bromo-4-methoxyphenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 188. MS: 419.2 (M+H); melting range: 148-150° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O:24][NH2:25])(=[O:23])=[O:22]>ClCCl>[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([OH:24])(=[O:23])=[O:22].[C:1]1([S:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[NH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Sc2ccsc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Product: N=S(c1ccccc1)c1ccsc1
Yield: 65 %

Procedure:
In a manner analogous to that described in Example 1, Stage 1, from phenyl-(3-thienyl)-sulphide and O-mesitylsulphonyl-hydroxylamine in dichloromethane, there is obtained phenyl-(3-thienyl)-sulphimide mesitylene-sulphonate in a yield of 65% in theory; after recrystallisation from isopropanol, the compound melts at 116° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=2.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>ClCCl.C(=O)(O)[O-].[Na+]>[OH2:20].[C:22]([NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=2)(=[O:26])[CH2:23][CH2:24][CH3:25].[C:22]([NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=2)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc2ncc(N)c(O)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2ccc(C)cc2c1O
Product: O

Procedure:
Triethylamine (11.46 mL) was added to a suspension of 3-amino-6-methylquinolin-4-ol hydrochloride in dichloromethane (400 mL). Butyryl chloride (4.46 mL) was added. The reaction mixture was heated on a steam bath for 30 minutes. The solution was diluted with sodium bicarbonate and then filtered. The filtrate was washed with bicarbonate and then concentrated under vacuum. The residue was recrystallized from isopropanol to provide 3-butyramido-6-methylquinolin-4-ol hemihydrate as a solid, m.p. 274-277° C. Analysis: Calculated for C14H16N2O2½H2O: %C, 66.39; %H, 6.76; %N, 11.06; Found: %C, 66.56; %H, 6.46; %N, 11.03.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>CC(O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (420 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 85.3%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5]([CH3:24])=[N:6][C:7]2[N:8]([C:11]([CH3:23])=[N:12][C:13]=2[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]=1O.CN(C)C1C=CC=CC=1.NC(CC)CC.O.P(Cl)(Cl)([Cl:43])=O>C(#N)C>[Cl:43][C:9]1[N:8]2[C:11]([CH3:23])=[N:12][C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[C:7]2[N:6]=[C:5]([CH3:24])[C:4]=1[CH2:3][CH2:2][Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCCl)c(C)nc23)c(C)c1
Agent: CCC(N)CC
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Cc1cc(C)c(-c2nc(C)n3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 3-(2-chloroethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidin-4-ol (200 mg, 0.58 mmol) and N,N-dimethylaniline (0.3 mL) in phosphorus oxychloride (3 mL) was heated under reflux for six hours. After overnight, 3-aminopentane (2 mL) was added to a solution of the residue in acetonitrile (5 mL), followed by stirring at 80° C. for three hours. Water was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatogrpahy (10-20% ethyl acetate/hexane), to give the title compound (139 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][N:22]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
A solution of N-t-butoxycarbonyl-4(R)-t-butyldimethylsilyloxy-2(S )-azidomethylpyrrolidine (9.06 g, 25.39 mmol) in EtOAc (120 ml) was purged with argon and 10% palladium on carbon (1.05 g) added. The flask was evacuated and stirred under an atmosphere of hydrogen (49 psi) for 16 hrs. The hydrogen was replaced by argon, the catalyst removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 2.5 to 5% saturated NH4OH in acetonitrile gradient elution), to afford the title compound as an oil.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]=2[CH:4]=[C:3]1[C:12]#[N:13].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]2=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: N#Cc1cc2c([nH]c1=O)CCOC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1cc2c(nc1Cl)CCOC2
Temperature: 25 °C
Yield: 66 %

Procedure:
step 2 2-Oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonitrile (2.50 g, 14.4 mmol) obtained in step 1 was dissolved in phosphoryl chloride (20 mL), and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, and slowly added to a saturated aqueous sodium hydrogen carbonate solution at 0° C., then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.85 g, 66%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]=4[C:26]=3[CH3:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3].ClC1C=CC=C(C(OO)=[O:38])C=1>>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:29])=[C:18]([CH3:28])[C:19]4[O:23][C:22]([CH3:24])([CH3:25])[CH2:21][C:20]=4[C:26]=3[CH3:27])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:38])=[O:3]
Reactant: Cc1c(C)c(N2CCN(c3ccc(S(C)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1c(C)c(N2CCN(c3ccc(S(C)(=O)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 31.3 %

Procedure:
By using 1-[4-(methylsulfinyl)phenyl]-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (200 mg, 0.50 mmol) synthesized in Example 91 and 70% m-chloroperbenzoic acid (272 mg, 1.1 mmol), the reaction was carried out in the same manner as Example 91 to synthesis the title compound 67 mg (yield 31%). Melting point was 256 to 260° C. (hexane-THF).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[C:10]([CH3:24])=[N:11][S:12][C:13]=1[NH:14][C:15](OC1C=CC=CC=1)=[O:16])=[O:8])[CH3:5].O>C(O)C>[CH2:1]([NH:3][C:15](=[O:16])[NH:14][C:13]1[S:12][N:11]=[C:10]([CH3:24])[C:9]=1[C:7]([O:6][CH2:4][CH3:5])=[O:8])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1snc(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 50% w/v solution of ethylamine in ethanol (30 ml.) was added to a solution of 4-ethoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole (prepared according to the method of Goerdeler and Horn, Chemische Berichte, 1963, 96, 1551; 30.6 g.) in warm ethanol (120 ml.). The mixture was then heated under reflux for 1 minute, and allowed to cool to ambient temperature and stand for 2 days. The mixture was then heated under reflux for 5 minutes, allowed to cool to ambient temperature and stand for 1 day and poured into cold water (1 liter). The precipitated solid was filtered off, dried and recrystallised from benzene (300 ml.) to give 3-ethyl-1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)urea (24.8 g.), m.p. 141° C.
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][CH:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CC(N)c2cccnc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To 0.19 g (0.74 mM) of methyl 4-[2-amino-2-(3-pyridyl)ethyl]benzoate in 10ml of dichloromethane in solution were added triethylamine (0.13 ml, 0.9 mM) and p-chlorobenzenesulfonyl chloride (0.19 g, 0.9 mM), and stirred overnight at room temperature. After completion of the reaction, water was poured into the reaction mixture, followed by extraction of dichloromethane. The organic phase was then washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate, to distill off the solvent. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to yield 0.11 g of methyl 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]benzoate. The spectrometric data thereof supports the structure of [26] as follows.