Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([NH:28][C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12])[C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NCc1ccccc1)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N(Cc2ccccc2)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.95 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 258-2 (3.39 mmol, crude form) as starting materials, respectively 966 mg (Isomer A, colorless amorphous) and 501 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1.Cl.[NH2:26][OH:27].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[N:26][OH:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N(C)C)no1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(c1cccc(C(=NO)c2ccccc2)c1)c1nc(N(C)C)no1
Temperature: 0 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To 3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.0 g, 3.11 mmol) in ethanol (10 ml) were added hydroxylamine hydrochloride (0.25 g, 3.45 mmol) in water (2 ml) and sodium hydroxide (0.40 g, 9.5 mmol) in water (2 ml). After reflux with stirring for 24 h, the mixture was poured upon ice water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated NaCl aq. dried with anhydrous magnesium salfate, and evaporated under redused pressure to a residue, which was chromatographed to afford 3-dimethylamino-5-(1-(3-(α-hydroxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.873 g, 84% yield) as oily substance: NMR(CDCl3)δ 1.66(d)+1.77(d) (3H), 2.98(s, 6H), 4.20(m, 1H), 7.22-7.55(m, 9H) ppm; IR(neat) 3700-3100, 1600, 1405 cm-1.
Reaction SMILES: [C:1]([CH:4]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:8][C:7]=1[CH2:29][CH2:30][CH3:31])([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:53]([S:56]([NH2:59])(=[O:58])=[O:57])([CH3:55])[CH3:54].N12CCCN=C1CCCCC2>C1COCC1>[CH:53]([S:56]([NH:59][C:1]([CH:4]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:8][C:7]=1[CH2:29][CH2:30][CH3:31])=[O:3])(=[O:58])=[O:57])([CH3:55])[CH3:54]
Reactant: CC(C)S(N)(=O)=O
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)NS(=O)(=O)C(C)C)c1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A 15 mL capacity high pressure vessel equipped with a magnetic stir bar was charged with a solution of 0.230 g (0.42 mmol) of the product of Example 13 in 4.0 mL of anhydrous THF and 0.172 g (1.06 mmol) of 1,1'-carbonyldiimidazole was added. The vessel was sealed and the contents were stirred and heated at 80° C. for 4 hours. The reaction was then cooled to room temperature, opened and a solution of 0.130 g (1.06 mmol) of isopropylsulfonamide and 158 μL (1.06 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 4 mL THF was added. The reaction vessel was resealed and then stirred and heated at 80° C. overnight. The reaction vessel was then cooled, opened and the contents were partitioned between water and EtOAc. The organic layer was separated washed with 10% aqueous NaHSO4, brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted first with 250 mL of CHCl3 /MeOH/NH4OH (95:5:0.5), next with 200 mL of CHCl3 /MeOH/NH4OH (92:8:0.5), and finally with 200 mL of CHCl3 /MeOH/NH4OH (90:10:0.5). Evaporation of the purified fractions and drying in vacuo afforded 0.074 g (27%) of the title compound.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCOCC1.O>[C:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
4-piperidone monohydrate hydrochloride (250 g, 1.62 mole) was dissolved in dioxane (1.5 L) and water (0.5 L). 217 g of NaHCO3 was added at 0° C. followed by slow addition of (BOC)2O (459 g, 2.1 mole). Reaction mixture was stirred for overnight. Solution was concentrated; residue was taken in water and extracted with ethyl acetate, washed with water and dried over anhydrous Na2SO4. Solvent was evaporated and product obtained was washed with hexane to get N-boc 4-piperidone (280 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)C>[C].[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the obtained 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoic acid were added ethyl acetate 1.0 mL, methanol 1.0 mL and 10% palladium-carbon 2.0 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(4-(trifluoromethoxy)phenyl)ethyl)benzoic acid 3.4 mg of a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1
Reactant: C1=COCCC1
Reactant: CC(=O)N1CC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 mL of methylene chloride was dissolved 1.00 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p-toluenesulfonic acid monohydrate were added to the solution, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added 10 mL of water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform˜chloroform:methanol=25:1) to obtain 1.79 g of 1-[3-(tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@H:17]([OH:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:5])C.C(=O)(O)[O-].[K+].O>CO>[OH:28][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[C:23](=[O:27])[CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C:7](=[O:29])[CH2:6][C:4]([O:3][CH3:1])=[O:5])[CH2:16]1
Reactant: CCOC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 19.1 %

Procedure:
A solution of 21-ethoxycarbonyl-3α-hydroxy-5α-pregnane-11,20-dione 850 mg) in dry methyl alcohol (40 ml) was treated with potassium bicarbonate (1.02 g) and the mixture was refluxed, under nitrogen, for 1 hr., then poured into water. The product was extracted with ethyl acetate, and the extract washed with water, dried, and evaporated. The residue (506 mg) was purified by preparative t.l.c. and crystallisation from methyl acetate/petrol gave title compound (157 mg) m.p. 150°-152°, [α]D + 111.2°, λmax. 248.5 nm (ε 4,185).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[C:35]([CH3:45])=[CH:34][C:32]=1[NH2:33])([CH3:29])[CH3:28].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:27]([O:30][C:31]1[CH:37]=[C:36]([CH:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[C:35]([CH3:45])=[CH:34][C:32]=1[NH:33][C:16]1[N:15]=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=1)([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(S(C)(=O)=O)nc2ccnn12
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)n3nccc3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(2-(isopropylsulfonyl)phenyl)-2-(methysulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (1 mmol). The suspension was stirred at 150° C. for 3 hours. After cooling at RT and work-up, the residue was purified using a preparative HPLC to afford N2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine. 1H NMR (MeOD, 400 MHz) δ 8.51-8.54 (d, 1H), 7.94-8.04 (m, 2H), 7.35-7.47 (m, 3H), 6.90 (s, 1H), 6.34-6.35 (d, 1H), 4.54-4.60 (m. 1H), 3.82-3.85 (m, 2H), 3.23-3.30 (m, 1H), 2.91-3.01 (m, 6H), 2.25-2.33 (m, 5H), 2.03-2.06 (m, 2H), 1.33-1.35 (d, 6H), 1.26-1.28 (d, 6H); MS (ES+); 578.28 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.FC(F)(F)C(O)=O>C(OCC)(=O)C.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:9]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: O=C(CN1CCOCC1)NNC(=O)c1cc(Br)cc2[nH]ncc12
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCOCC1)NNC(=O)c1cc(Br)cc2c1cnn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
6-Bromo-N′-(4-morpholinylacetyl)-1H-indazole-4-carbohydrazide (0.232 g, 0.607 mmol) in ethyl acetate (3 ml) was treated with 3,4-dihydro-2H-pyran (0.111 ml, 1.214 mmol) then heated to 50° C. under nitrogen. Trifluoroacetic acid (4 drops) was added and heating continued for 1.5 h at 50° C. A further portion of 3,4-dihydro-2H-pyran (0.111 ml, 1.214 mmol) and trifluoroacetic acid (0.047 ml, 0.607 mmol) were added and heating continued for a further 1.5 h. The solution was left to stand at room temperature for 18 h. The clear solution was diluted with ethyl acetate (5 ml), washed with saturated aqueous sodium bicarbonate (2×10 ml), filtered through a phase separator cartridge then blown to dryness and left under vacuum. The crude product was dissolved in dichloromethane (2 ml) and purified on a silica (5 g) cartridge which was eluted with a gradient of methanol and chloroform and the appropriate fractions evaporated to give the title compound as a beige gummy solid (0.199 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][C:36]=2[C:37]#[N:38])=[CH:30][C:29]=1[C:46]([F:49])([F:48])[F:47]>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][I:20])=[CH:39][C:36]=2[C:37]#[N:38])=[CH:30][C:29]=1[C:46]([F:49])([F:48])[F:47]
Reactant: II
Reactant: N#Cc1cc(CCO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CCI)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To a solution of Ph3P (1036 mg, 3.95 mmol) and iodine (1003 mg, 3.95 mmol) in DCM (5 mL), which was stirred at room temperature for 10 min, was added imidazole (448 mg, 6.58 mmol). After stirring for another 10 min, 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(2-hydroxyethyl)benzonitrile (900 mg, 2.63 mmol) was added. The mixture was stirred at room temperature for 1 h, and quenched by water, extracted with DCM. Purification via flash chromatography then afforded the title compound (1.0 g, 2.214 mmol, 84% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.C([Li])CCC.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>>[CH:1]([C:4]1[CH:5]=[C:6]([O:12][CH3:13])[C:7]([O:10][CH3:11])=[CH:8][C:9]=1[C:30]([N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[O:31])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1OC
Reactant: CCN(CC)C(=O)Cl
Agent: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1cc(OC)c(OC)cc1C(C)C

Procedure:
Thirty-one grams of 4-isopropyl-1,2-dimethoxybenzene was treated with N-bromosuccinimide followed by butyllithium and diethyl carbamyl chloride as in preparation 6B to yield 15.2 g of 2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide as a viscous oil. The benzamide was treated according to preparation 18B with butyllithium and sulfur dioxide followed by sulfuryl chloride then ammonia to provide 4.5 g of the sulfonamide, mp 181°-182° C. from ether. This was cyclized in acetic acid as in preparation 18B to obtain 2.86 g of 6,7-dimethoxy-4-isopropylsaccharin, mp 210°-212° C. from ethyl acetate-hexane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][CH2:15][CH3:16])[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CCN
Solvent: CC(C)=O
Product: CCNc1nc(NC(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.5 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile in 100 ml of acetone was cooled to between 0° and -5°; a solution of 2.1 grams of aqueous 70% ethylamine in 25 ml of acetone was added dropwise. Upon complete addition, the reaction mixture was warmed to room temperature and stirred for 18 hours. The acetone was removed under reduced pressure, and the residue was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4-chloro-6-ethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 144°-146°.
Reaction SMILES: C=C[C@H](O)C#[C:5][C:6]#[C:7][CH2:8][C@H:9](O)[C@@H:10]([OH:18])[CH2:11][CH2:12]CCCCC.C(Cl)(Cl)Cl>O>[CH2:12]=[CH:11][CH:10]([OH:18])[C:9]#[C:8][C:7]#[C:6][CH3:5]
Reactant: C=C[C@H](O)C#CC#CC[C@H](O)[C@@H](O)CCCCCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(O)C#CC#CC

Procedure:
(S)-8-(4S,5S)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)octa-1-en-4,6-diyn-3-ol, ent-panaxytriol acetonide was prepared from (3S,9S,10S)-heptadeca-1-en-4,6-diyne-3,9,10-triol, ent-panaxytriol, by the method described in Yun, H.; Chou, T. C.; Dong, H.; Tian, Y.; Li, Y-M.; Danishefsky, S. J. J. Org Chem. 2005, 70, 10375, yielding the product with: [α]19.3D-70.5 (c=0.13, CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.94 (ddd, 17.1 Hz, 10.2 Hz, 5.4 Hz, 1H), 5.47 (d, 17.1, 1H), 5.26 (d, 10.2 Hz, 1H), 4.92 (d, 5.1 Hz, 1H), 4.36 (t, 6 Hz, 1H), 3.77 (m, 2H), 2.60 (m, 2H), 1.7-1.2 (m, 12H), 1.40 (s, 6H), 0.88 (t, 6.9 Hz, 3H). LRMS (APCI+) found 319.0, [M]+, 333.04, [M+H2O]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].ClCCl.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of 1-methoxy-2-propanol in dichloromethane (2.3 g, 25.5 mmol) (25 ml) and pyridine (5 ml) was cooled to between −5 and 0° C. 4-Methylbenzenesulfonyl chloride (5.35 g, 28.1 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. The mixture was then stirred at room temperature for 18 hours. Ice was added and the mixture was stirred for 1 hour. The organic phase was separated, washed with 10% aqueous sulfuric acid (4×) and water (1×), and then dried (MgSO4) and filtered. The filtrate was purified by column chromatography on silica gel eluting with dichloromethane. The solution obtained was dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound as a colorless oil, 4.3 g, 69% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:1][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:3][CH:4]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cncc(-c2nccs2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccnc2)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37.1 %

Procedure:
To a stirred solution of 3-thiazol-2-yl-pyridine (J. Med. Chem. 2005, 48, 224) (927 mg, 5.71 mmol) in dry THF (30 mL) cooled at −78° C. under an inert atmosphere was added n-BuLi (2.5M in hexanes) (2.75 mL, 6.87 mmol) dropwise. After stirring at −78° C. for 45 mins, tributyltin chloride (1.86 mL, 6.87 mmol) was added. The mixture was allowed to warm to 0° C. over 90 mins, then treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate 100/0 to 82/18 to afford 3-(5-tributylstannanyl-thiazol-2-yl)-pyridine as a colourless oil (955 mg, 37%). 1H NMR (DMSO-d6, 300 MHz) δ=9.11 (m, 1H), 8.62 (dd, J=4.77-1.52 Hz, 1H), 8.28 (m, 1H), 7.90 (s, 1H), 7.50 (dd, J=8.0-4.8 Hz, 1H), 1.52 (m, 6H), 1.28 (m, 6H), 1.13 (m, 6H), 0.84 (t, J=7.2 Hz, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12]C)=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:8]([CH:14]([CH3:16])[CH3:15])[O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[C:8]([CH:14]([CH3:15])[CH3:16])[O:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(N)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 7-amino-3-(4-chlorophenyl)-2-isopropyl-8-methoxy-chromen-4-one (0.178 g, 0.52 mmol) in methylene chloride (5 ml) under an argon atmosphere is cooled to −78° C. and treated with boron tribromide (1M solution in methylene chloride, 3.2 ml, 3.2 mmol, 6.2 eq.). The reaction mixture is stirred at −78° C. for 1 h and at room temperature for 45 min, whereupon HPLC analysis indicates that the reaction is complete. The reaction mixture is treated with water (32 ml) and stirred at ambient temperature overnight. The mixture is washed with methylene chloride, and the organic layer is washed with 5% sodium thiosulfate solution, followed by brine. The organic phase is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo to afford a brown oil. The oil is purified by flash chromatography (hexane/ethyl acetate=9:1 through 1% methanol in ethyl acetate to methylene chloride/methanol=9:1) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>C(Cl)Cl>[O:1]([CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([Cl:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C(=O)OCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenoxyethanol (536 mg, 3.9 mmol) in DCM (total volume: 0.5 mL) was added to a solution of oxalyl chloride (0.5 mL, 5.8 mmol) in DCM (total volume 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was dissolved in DCM (3.9 mL) to yield a 1.0M solution in DCM.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:26].N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[ClH:26].[CH2:52]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:2][CH2:3]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Agent: Cl
Product: O=c1c(N2CCN(Cc3ccccc3)CC2)nccn1CCOc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 starting from 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.35 g, 1.0 mmol; from the free base of Example 3) and benzyl bromide (0.19 g, 1.1 mmol) Yield: 0.17 g (35%); HPLC purity: 99%; mp 214-214.5° C. HRMS calc for C23H23F3N4O2 (M)+ 444.1773, found 444.1789.