Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:6][OH:7])([CH:4]=[CH2:5])[CH3:3].[CH3:8][C:9](O)([CH:11]=[CH2:12])[CH3:10].S(=O)(=O)(O)O.CCCCCC>O>[CH3:1][C:2]([O:6][O:7][C:9]([CH3:10])([CH:11]=[CH2:12])[CH3:8])([CH:4]=[CH2:5])[CH3:3]
Reactant: C=CC(C)(C)O
Reactant: C=CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Product: C=CC(C)(C)OOC(C)(C)C=C
Temperature: 30 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A mixture of 21.0 g of 2-methyl-3-buten-2-yl hydroperoxide and 17.2 g of 2-methyl-3-buten-2-ol was added, with stirring, to 80 g of a solution of 40% by weight-sulphuric acid in water over a period of 30 minutes and at a temperature of 20° C. Subsequently, the reaction mixture was stirred for 4 hours at 30° C. After the mixture had been cooled 50 ml of water and 50 ml of hexane were added. The organic phase was separated and washed with aqueous sodium hydroxide and, finally, with water. After the hexane had been distilled off under reduced pressure 22.5 g of colourless liquid were obtained. This liquid was then purified by fractional distillation, which resulted in 11.3 g of colourless liquid having a peroxide 2 content determined by G.L.C. of 75%.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl.C(O[C:11](=[NH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:11](=[NH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)NCCN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N-dimethyl-1,2-diaminoethane (8.8 g, 0.1 mmol) in absolute ethanol (40 ml) is added ethyl 3-ethoxy-3-iminopropionate hydrochloride (20.0 g, 0.1 mmol). After stirring at ambient temperature for 16 hours, evaporated solvent and dissolved residue in water, made basic with sodium carbonate and extracted product into methylene chloride. This solution is evaporated to dryness to give 17 g of crude viscous title A product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OCC1C=CC=CC=1.CCOCC.[BrH:30]>C(O)(=O)C>[BrH:30].[BrH:30].[CH3:14][NH:13][CH2:12][CH2:11][CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CN(CCCc1nc2ccccc2s1)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNCCCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.1 %

Procedure:
1.7 g (4.99 mmol) of benzyl [3-(2-benzthiazolyl)propyl]methylcarbamate are dissolved at 0° in 40% hydrogen bromide in acetic acid and stirred at room temperature for 20 hours. Thereupon, 60 ml of ether are added and, after 1.5 hours, the precipitate formed is filtered off. After washing the crystalline precipitate with ether and drying there are obtained 1.71 g (93.1%) of 2-[3-(methylamino)propyl]benzthiazole dihydrobromide, m.p. 196°-197°.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18]([O:21][C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24](O)=[O:25])(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([O:21][C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)=[O:25])(=[O:20])[CH3:19]
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
2.4 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are boiled for 1 hour with 2 g. acetyl-salicylic acid and 1.32 g. triethylamine in 100 cc. chloroform. After working up in the usual manner, there is obtained 3-(acetylsalicyloylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide in the form of colourless crystals which, after recrystallisation from ethyl acetate, melts at 160°C. Structurally, the compounds of this invention are: ##SPC4##Example R1R2 salt melting point (°C)______________________________________ 4 methyl phenoxy -- 138-139 5 phenyl methyl -- 119 6 phenyl ethyl -- 170 7 phenyl iso- -- 122 propyl 8 methyl -- 168-169 9 phenyl -- 13410 methyl -- 17011 methyl methoxy -- 16612 phenyl ethoxy -- 16313 methyl butoxy-2 -- 12514 phenyl phenoxy -- 17315 methyl --O--CH2 --CH2 -- -- 108-190 OCH316 phenyl --CH2 --O--C6H4 -- -- 196 Cl(r)17 phenyl --CH2 --C6H5 -- 12018 methyl --O--C6H11 -- 126-12819 phenyl --C6H4 --O--CO-- -- 160 CH 3 (o)______________________________________
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[CH3:30])[N:20]=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCl>[CH3:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:21]1[N:20]=[C:19]([NH:18][C:11]2[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN)c3)nn3ccnc23)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (50 mg, 1.52 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (38 mg, 0.188 mmol) and NaBH(OAc)3 (80 mg, 0.375 mmol) in dichloromethane (5 mL) was added HOAc (12 mg). The mixture was stirred at room temperature for 3 h. The solvent was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give tert-butyl 4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzylamino)piperidine-1-carboxylate (35 mg, 48%) as a yellow oil. LC/MS: 583.3 [M+H]+, tR=1.52 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].[H-].[Na+].Cl>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24](/[CH:25]=[CH:38]\[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:23][N:22]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COc1cc(COc2nc(-c3ccccc3)ncc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C\c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a mixture of 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carbaldehyde (1.00 g), tetraethyl methylenediphosphonate (0.58 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.090 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (2:3, v/v) to give diethyl (Z)-2-(4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidin-5-yl)ethenylphosphonate as crystals (0.095 g, yield 7%). Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 154-155° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.6 %

Procedure:
2 g (8.0 mmole) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethylcarbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dimethylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoyl-3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=CC(O)=CC=1)O.[C:28](#[N:31])[CH:29]=[CH2:30]>>[C:28]([CH2:29][CH2:30][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:31]
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: C=CC#N
Agent: Oc1ccc(O)cc1
Product: N#CCCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The solution of 22.2 g of 7,7-diphenyl-hexahydro-1,4-oxazepine and 0.2 g of hydroquinone in 50 ml of acrylonitrile is refluxed for 18 hours, cooled and evaporated. The residue is taken up in chloroform, the mixture filtered through a short column of silica gel, eluted with chloroform and the eluate evaporated. The residue is recrystallized from ethanol, to yield the 4-(2-cyanoethyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 106°-107°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][CH:34]([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (204 mg, 0.458 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (R)-(+1-amino-2-propanol (72.0 μmL, 0.914 mmol), WSCI.HCl (130 mg, 0.678 mmol) and 4-dimethylaminopyridine (115 mg, 0.941 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (191 mg, yield 83%) as a white solid.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:50]=[CH:49][C:14]([CH2:15][NH:16][C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:51]([O:58][CH2:59][C:60](Cl)=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH2:60][CH2:59][O:58][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:49][CH:50]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCOCc1ccccc1)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 94.7 %

Procedure:
Synthesized from [4-(2-azepan-1-ylethoxy)benzyl]{5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}amine (400 mg) and benzyloxyacetyl chloride (520 mg) according to an analogous synthetic method to Example 152, the title compound (450 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([O:25][C:26](=O)[C:27]#[C:28][CH2:29][F:30])C>C(Cl)(Cl)Cl>[F:30][CH2:29][C:28]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:26](=[O:25])[CH:27]=1
Reactant: CCOC(=O)C#CCF
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2Cn3c(CF)cc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and 4-fluoro-but-2-ynoic acid ethyl ester (see Example 105) employing the procedure described in Example 95. [α]D25 −28.00 (c 0.5, CHCl3).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH:18]=[CH2:19])[O:7][CH:6]1OC(=O)C)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[C:55]([NH:63][C:64]1[N:72]=[CH:71][N:70]=[C:69]2[C:65]=1[NH:66][CH:67]=[N:68]2)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(#N)C>[C:55]([NH:63][C:64]1[N:72]=[CH:71][N:70]=[C:69]2[C:65]=1[N:66]=[CH:67][N:68]2[CH:6]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:21][SiH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])([CH:18]=[CH2:19])[O:7]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(OC(C)=O)C(OC(C)=O)C1OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C(OC(C)=O)C1OCc1ccccc1
Yield: 68 %

Procedure:
A flask was charged with Acetic acid 3-acetoxy-4-benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-5-vinyl-tetrahydro-furan-2-yl ester, acetonitrile, the trimethylsilyl triflate (TMSOTf). To the reaction was added N6-benzoyl adenine. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled compound in 68% yield.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]([CH3:23])([O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[C:12]#[CH:13]>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([CH3:23])([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1)[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1I
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccccc1C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 48 h
Yield: 34 %

Procedure:
2.34 g of 2-iodoanisole were added at room temperature to a solution of 9 mg of palladium(II) chloride, 26 mg of triphenylphosphine and 19 mg of copper(I) iodide in 25 ml of diethylamine. This mixture was treated with 1.85 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and the resulting mixture was stirred for 48 hours. The mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 0.99 g of 4-[1,1-dimethyl-3-(2-methoxyphenyl)-2-propynyloxy]benzonitrile in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:10][C:11]1[C:12]([O:9][CH2:8][C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(CO)CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCCCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution of (1-methylcyclohexyl)methanol (4.98 g, 38.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (20.67 g, 83.10 mmol) in anhydrous dimethylsulfoxide (80 mL) was added cesium carbonate (25.14 g, 77.20 mmol). The mixture was heated to 70° C. and stirred for 16 hours. The mixture was then cooled to ambient temperature, filtered through a pad of diatomaceous earth and the solid was washed with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (6.26 g, 44%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.2 Hz, 1H), 3.70 (s, 2H), 1.57 (s, 9 H), 1.52-1.31 (m, 10H), 1.08 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[C:14]([O:16]CC)=O.[CH3:20]/[C:21](/[NH2:24])=[N:22]/[NH2:23].Cl>CCO>[CH3:20][C:21]1[NH:24][C:14](=[O:16])[C:13]([CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[N:23][N:22]=1
Reactant: CCOC(=O)C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: C/C(N)=N/N
Agent: Cl
Solvent: CCO
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropanoate [J. Org. Chem., (1985), 50 (1), 91] (4.29 g, 16.4 mmol), acetamidrazone hydrochloride (1.80 g, 16.4 mmol) in anhydrous EtOH (85.8 mL) was heated to 80° C. for 3 h then cooled to rt and stirred for an additional 16 h. The reaction mixture was filtered through a fitted funnel resulting in 3.28 g, (73% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 4.73 (s, 2H) and 7.74-8.12 (m, 4H); MS (ES+): m/z 271.08 [MH+].
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[CH:9]=1>CCOCC.[Cl-].[NH4+].[Cu](I)I>[CH3:3][C:4]1([CH3:1])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [Li]C
Reactant: COC(=O)C1CCC(=O)C=C1C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C1CCC(=O)CC1(C)C
Temperature: -20 °C
Reaction time: 5 h

Procedure:
Copper iodide (121.8 g, 639.54 mmol) was suspended in Et2O (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at −40° C. over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in Et2O (400 mL) was added at −40° C. over 2 minutes. The resulting solution was stirred 5 hours at −20° C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with EtOAc (3×2 L). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (1:20 EtOAc/petroleum ether). Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate was obtained as a yellow oil. MS ESI calcd. for C10H17O3 [M+H]+ 185. found 185. 1H NMR (600 MHz, CDCl3) δ 3.49 (s, 3H), 2.43-2.40 (m, 1H), 2.35-2.29 (m, 1H), 2.21-2.17 (m, 1H), 2.11-2.04 (m, 1H), 2.00-1.96 (m, 1H), 1.91-1.85 (m, 1H), 0.85 (s, 3H), 0.77 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:19][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2cccc(Cl)c2)nc1C#N
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1nc(C#N)c(C#N)nc1-c1cccc(Cl)c1
Yield: 78.4 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-chlorophenyl)pyrazine (1.0 g; 0.0036 mole), 0.24 g (0.004 mole) of n-propylamine and 40 ml of a 0.1N aqueous solution of sodium hydroxide were worked up in the same way as in Example 17, and recrystallized from methanol to afford 0.84 g (yield 78%) of 2,3-dicyano-5-n-propylamino-6-(m-chlorophenyl)pyrazine.