Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 0.0807 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0118 g, 0.0807 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])[CH3:49]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:54]6[CH2:55][CH2:56][N:51]([C:48](=[O:50])[CH3:49])[CH2:52][CH2:53]6)=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CC(=O)N1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCN(C(C)=O)CC4)nc3)cn2)cc1
Yield: 52.6 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and N-acetylpiperazine (59 mg, 0.461 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of 1-{4-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-piperazin-1-yl}-ethanone as a yellow solid (120 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-109) as a yellow powder (46 mg, 57%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml) are dissolved in benzene (50 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (3.9 ml) in benzene (8 ml) with stirring under ice-cooling and the mixture is stirred at the temperature for 3 hours and then allowed to stand overnight. The reaction mixture is filtered to remove the precipitates and the filtrate is concentrated to give crystals of ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (10.6 g; 96.3%), melting point: 79°-83° C. The product is recrystallized from benzene-petroleum ether to give crystals having a melting point of 79°-81.5° C.
Reaction SMILES: CS(C)=O.CC1C=CC(S([CH2:15][N+:16]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=O)[CH3:31]>[Cl-].[Na+].O.CCCCCC.C(OCC)(=O)C.CO>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([CH3:31])[C:15]#[N:16]
Reactant: CC(=O)c1ccccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 192.3 %

Procedure:
To a dried flask under nitrogen was added dimethyl sulphoxide (100 ml) and tosmic (20.95 g, 107.3 mmol). The reaction mixture was cooled to 0° C. before potassium t-butoxide (33.35° g, 297.1 mmol) was added. After 5 min, methanol (3.7 ml) was added followed by 1-(2-pyridinyl)ethanone (10 g, 32.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured in brine:hexane:ethyl acetate (50:25:25). The organic extracts were dried (Na2SO4) and concentrated in vacuo to yield a crude oil. The oil was purified by flash chromatography eluting with ethyl acetate:hexane (3:7) to give the title compound as a brown solid (8.26 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24])[CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[OH-].[Na+].[Pd].C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24])[CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CN(CC(=O)O)CC(c1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C(CN(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1

Procedure:
43 mg, 0.10 mmol of 1-(p-Nitrophenyl)-ethylenediaminetetraacetic acid was dissolved in 50 ml of aqueous NaOH (such that the final pH was 9), and 29 mg of 10% Pd/charcoal catalyst was added. The mixture was stirred gently for 5 hr in an ice bath under 1 atm of hydrogen. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. In D2O, the aromatic region of the 60 MHz nmr spectrum of the 1-(p-Aminophenyl)-ethylenediaminetetraacetic acid product consisted of an aa'bb' pattern centered 7.0 ppm downfield from Me4Si. The differences in the nmr spectra of the products of Steps V and VI make it convenient to monitor the progress of the reduction by nmr. By this criterion, the reduction was quantitative. The product was stored in the dark at -15°.
Reaction SMILES: OC(C1C=CC=CC=1)(C)[CH2:3][CH2:4][N:5]([C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6](=[O:12])[O:7][C:8](C)(C)[CH3:9].[H-].[Na+]>C1COCC1>[CH3:9][C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][C:6](=[O:12])[N:5]([C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:4][CH2:3]1
Reactant: C[C@@H](c1ccccc1)N(CCC(C)(O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CCC(C)(c2ccccc2)OC1=O

Procedure:
A mixture of crude tert-butyl 3-hydroxy-3-phenylbutyl((S)-1-phenylethyl)carbamate, obtained as described above, 60% NaH in oil (0.320 g) and THF (5 mL) was heated to reflux for 21 h. The reaction was then quenched with H2O (1.5 mL) and diluted with CH2Cl2. The organic layer was dried over Na2SO4. After the solvents were evaporated, the residue was purified by reversed-phase HPLC to afford 6-methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 13 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 4 min, flow rate 25 mL/min) to afford 6-methyl-6-phenyl-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one as a mixture of diastereomers. LC-MS Method 1 tR=1.71, 1.75 min, m/z=296 (MW); 1H NMR (400 MHz, CD3OD) δ 7.36-7.18 (m), 7.06-7.02 (m), 6.89-6.85 (m), 5.54 (q, J=7.1 Hz), 5.47 (q, J=7.0 Hz), 3.00-2.95 (m), 2.73-2.69 (m), 2.40-2.34 (m), 2.26-2.19 (m), 2.13-2.05 (m), 2.00-1.92 (m), 1.53 (s), 1.52 (s), 1.45 (d, J=7.0 Hz), 1.23 (d, J=7.0 Hz). A fraction containing on the less polar diastereomer was also isolated (Isomer 1). LC-MS Method 1 tR=1.75 min, m/z=296 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.35-7.18 (m, 10H), 5.54 (q, J=7.0 Hz, 1H), 2.72-2.69 (m, 2H), 2.39-2.33 (m, 1H), 1.99-1.92 (m, 1H), 1.52 (s, 3H), 1.23 (d, J=7.0 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[S:6][C:3]=2[CH:4]=1
Reactant: c1cc2sccc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of thieno[3,2-b]thiophene (see Fuller et al., J. Chem. Soc. Perkin Trans. 1997, 1, 3465-70) (2.00 g, 14 mmol) is dissolved in anhydrous THF (100 ml) and cooled to −78° C. under nitrogen. A solution of n-butyllithium (12 ml of a 2.5M solution in hexanes, 30 mmol) is added dropwise over 5 min, and the resulting solution is allowed to warm to 20° C. over 30 min and stirred at that temperature for 3 h. The resulting suspension is cooled to −78° C. and trimethyltin chloride (5.9 g, 30 mmol) is added at once as a solid. The reaction is allowed to warm to RT over 4 h and stirred at that temperature for an additional 20 h. The reaction is quenched by the addition of saturated sodium hydrogen carbonate (100 ml). Ethyl acetate (50 ml) is added and the layers separated. The organic layer is washed with sodium carbonate (80 ml of a 2M aqueous solution) and brine (80 ml), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product is dry loaded onto a 20 g reverse phase silica column and eluted with acetonitrile. The first fraction is collected, concentrated and recrystallised from acetonitrile to afford the product as white flakes. M/Z cluster centred at 466 (M+). Found C, 30.9; H, 4.4. Calc. for C12H20S2Sn2C, 30.9; H, 4.3. 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 2H), 0.39 (s, 18H). 13C NMR (75 MHz, CDCl3) δ 147.5, 141.2, 126.1, −8.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.Cl[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17]N=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:10]1[C:8]2=[O:9]
Reactant: COC(=O)c1cnc(Cl)s1
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COC(=O)c1cn2c(=O)c3cc(OC)ccc3nc2s1

Procedure:
16.5 g of 5-methoxyanthranilamide and 18.64 g of methyl 2-chlorothiazole-5-carboxylate were stirred for 11/2 hours at 160° C. After working up in the conventional manner 24.7 g (85%) of the above compound was obtained; m.p. 187°-192° C.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[N:9][CH:10]=1>[N+]([O-])([O-])=O.[Ag+]>[F:21][C:4]([F:20])([F:3])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([OH:1])=[O:17])=[CH:14][CH:13]=2)=[N:9][CH:10]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To aq. NaOH (3.2 g, 80 mmol) was added silver nitrate (3.4 g, 40 mmol) and stirred for 10 min., then the mixture was cooled to 0° C. and the above aldehyde (4.62 g, 17 mmol) was added. The mixture was stirred overnight, then filtrate through celite. The filtrate was collected and acidified with conc. HCl. The solid was collected by filtration and dried under vacuum to give 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid. (3.5 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21]O)=[CH:9][N:8]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][Cl:37])=[CH:9][N:8]=1
Reactant: COc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The above 1-(3-methoxybenzyl)-4-hydroxymethyl-6,7-dimethoxyisoquinoline (339 mg, 1.0 mmol) was dissolved in 5 ml of methylene chloride. Then at −30° C., triethylamine (160 ul, 1.10 eq) and methanesulfonyl chloride (85 ul, 1.10 eq) was added. The mixture was stirred at −30° C. for 30 minutes and then at room temperature overnight. The mixture was extracted with methylene chloride and water. After evaporation of solvents, a solid was obtained to give 1-(3-methoxybenzyl)-4-chloromethyl-6,7-dimethoxyisoquinoline (361 mg, 100%). ES-MS calculated for C20H20O3NCl (m/e) 357.39, observed 358.5 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:19])[C@H:14]([C@@H:16]([CH3:18])[OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-threonine methyl ester, hydrochloride (16.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-threonine methyl ester (21.5 g).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:16][C:10]1([CH3:17])[C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC(C)(C)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)(C)C1=O

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-3,3,5-trimethyl-4-piperidone (1.5 g, 6.5 mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 3,3,5-trimethyl-4-piperidinone. Yield 0.8 g (88%), C8H15NO, m/z 142 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10](=[O:38])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:14][CH:13]2[CH3:37])=[C:4]([Cl:39])[CH:3]=1.C(O)(=O)C.[O-:44][C:45]#[N:46].[K+]>O>[NH2:46][C:45]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10](=[O:38])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:14][CH:13]2[CH3:37])=[C:4]([Cl:39])[CH:3]=1)=[O:44]
Reactant: N#C[O-]
Reactant: CC1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(Cl)cc(N)cc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(Cl)cc(NC(N)=O)cc1Cl
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a stirred solution of 4.5 parts of N-(4-amino-2,6dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-2-methyl-1-piperazineacetamide in 60 parts of acetic acid was added dropwise a solution of 1.02 parts of potassium cyanate in 17 parts of water. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with ammonium hydroxide solution and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.49 parts (51.9%) of N-[4-[(aminocarbonyl)amino]-2,6-dichlorophenyl]-4-[5,5-bis(4-fluorophenyl)pentyl]-2-methyl-1-piperazineacetamide; mp. 119.9° C. (compound 76).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:10]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24](SC)[N:23]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:31]>O1CCOCC1>[NH2:31][C:24]1[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([C:10]2[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:12][C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:8][CH:9]=2)[N:23]=1
Reactant: COc1ccc(Nc2nc(NC3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A glass microwave reaction vessel was charged with N2-cyclopentyl-N4-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (36 mg, 0.085 mmol), ammonia (0.5 mL, 23.11 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N2-cyclopentyl-N4-(6-methoxypyridin-3-yl)pyrimidine-2,4-diamine (28 mg, 0.071 mmol, 84% yield). 1H NMR (300 MHz, CDCl3) δ 11.99 (s, 1H); 9.21 (s, 1H); 8.29-8.56 (m, 1H); 8.19 (s, 1H); 6.76 (d, J=8.92 Hz, 1H); 5.26 (s, 3H); 4.25 (s, 1H); 3.95 (s, 3H); 2.49 (s, 3H); 2.04 (s, 2H); 1.34-1.87 (m, 6H). m/z (ESI, +ve ion) 394.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br-:13]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: [Br-]
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(C)Br)cc1
Yield: 90.7 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. A white solid product was obtained in a yield of 90.7%, mp: 69-70 └. 1H-NMR (CDCl3, 400 MHz) δ: 1.89 (3H, d, J=6.44 Hz, CHBrCH3), 3.88 (3H, s, OCH3), 5.27 (1H, q, J=6.44 Hz, CHBrCH3), 6.96 (2H, d, J=8.72 Hz, ArH), 8.02 (2H, d, J=8.72 Hz, ArH); ESI-MS m/e (%): 242.0 (M+2, 11), 241.0 (M, 11), 135.0 (100).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[Cl:17])[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[K].[CH3:21][SH:22].O>O1CCCC1>[Cl:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([S:22][CH3:21])=[C:3]([C:18]#[N:19])[CH:4]=[N:5]1
Reactant: CS
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1Br
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of 3.5 g (0.01 mol) of 5-bromo-1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-pyrazole is added dropwise at 20°-25° C. to a suspension of 0.011 mol of potassium methylmercaptide, prepared by passing 0.6 g (0.011 mol) of methyl mercaptan into a solution of 1.4 g (0.012 mol) of potassium t-butylate in 50 ml of tetrahydrofuran. The mixture is stirred overnight, poured into water, and extracted by shaking three times with 100 ml of methylene chloride in each case. After drying the combined phases over sodium sulphate, the solution is concentrated in vacuo. An oily residue remains which crystallizes after standing overnight. 3.1 g (98% of theory) of 1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-methylthio-pyrazole of melting point 59°-62° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:34]([CH3:35])[CH3:33])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and isopropylamine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (53 mg, 79%) which was obtained as an off white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:3]/[CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[K+].ClCC(O)CO.C[O-].[Na+]>CO.OCC(CO)O>[CH3:1][C:2]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CCCCCCCCC/C(C)=C\CCCC(=O)OC
Agent: C[O-]
Agent: OCC(O)CCl
Agent: [K+]
Solvent: CO
Solvent: OCC(O)CO
Product: CC1=CCCCC(=O)OCCCCCCCCC1
Yield: 77.9 %

Procedure:
87 g (0.3 mol) of methyl 5Z-6-methylpentadec-5-enoate and 19.5 g of 86 percent potassium hydroxide were dissolved in 200 ml of methanol. 66 g of 3-chloropropane-1,2-diol and 200 ml of glycerol as well as, 5 ml of 5.4M methanolic sodium methylate solution were added. After usual work up the product were distilled in a high vacuum over a Vigreux column. 59 g (78%) of 7-methyloxacyclo-hexadec-6-en-2-one were obtained having the following characteristics: Z/E=56/46;