Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[Cl:16].C([Li])(CC)C.C1CCCCC1.CN(CN1C2C(=CC(OC)=CC=2)C=C1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:6]1[NH:7][C:8]2[C:13]([CH:5]=1)=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2
Reactant: COC(=O)Cc1c(Cl)[nH]c2ccc(OC)cc12
Agent: COc1ccc2c(ccn2CN(C)C)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1ccc2[nH]c(Cl)cc2c1
Reaction time: 0.3 h
Yield: 29 %

Procedure:
2-Chloro-5-methoxy-1H-indole-3-acetic acid methyl ester. Cooling with a dry ice-ethanol bath, 20 mL (0.026 mol) of 1.3M sec-butyl lithium/cyclohexane was added to 5.1 g (0.025 mol) of 1-dimethylaminomethyl-5-methoxy-1H-indole in 100 mL of THF keeping the temperature below -50° C. The cooling bath was removed and the temperature allowed to reach 0° C. and the bath then replaced. At -60° C., 3.32 mL (0.026 mol) of benzenesulfonyl chloride in 10 mL of THF was added, stirred 0.3 hours, the bath removed, and the temperature allowed to reach 20° C. over 1 hour. To this mixture was added 100 mL of 1N HCl and 50 mL of EtOAc and the mixture stirred for 20 hours. After making basic with 5N NaOH, the EtOAc layer was separated, washed with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with toluene to give 1.37 g (29% yield) of crude 2-chloro-5-methoxy-1H-indole. To this material (7.55 mmol) in 30 mL of THF was added 4.7 mL (7.55 mmol) of 1.6M n-butyl lithium/hexane keeping the temperature below 10° C. with an ethanol-ice bath. After 0.25 h, 7.55 mL (7.55 mmol) of 1M ZnCl2 /ether was added, stirred 2 hours, concentrated at reduced pressure, and 40 mL of toluene added followed by 0.72 mL (7.55 mmol) of methyl 2-bromoacetate. The mixture was stirred for 16 hours, warmed at 76° C. for 4 h, cooled, and 50 mL of 1N HCl and 40 mL of EtOAc added. After 0.5 hour, the organic layer was separated, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a solvent gradient (toluene→20% EtOAc/toluene) to give 0.79 g (41% yield) of 2-chloro-5-methoxy-1H-indole-3-acetic acid methyl ester, as an oil.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][OH:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]([OH:19])=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccc(C(=O)C(C)(C)C)cc1CO
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 83.9 %

Procedure:
5-Pivaloyl-2-methoxy benzyl alcohol (1.19 g, 5.35 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.449 g, 8.025 mmol in water (5 ml) was added followed by KMnO4 (1.69 g, 10.7 mmol). The mixture was allowed to stir at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (1.06 g).
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].O>CC1CCCO1>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:4]1[CH2:5][CH2:6][N:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2](=[O:8])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Solvent: CC1CCCO1
Solvent: O
Product: O=C1C=C(Nc2ccc(Cl)cc2Cl)CCN1N1CCCCC1
Temperature: 25 °C
Yield: 77 %

Procedure:
1,1′-bipiperidine-2, 4-dione (1,000 g, 4,739 mmol) and 2,4-dichloroaniline (0.921 g, 5.687 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml) and the reaction mixture was boiled under reflux for 22 h whilst the water formed was removed using a Dean and Stark apparatus. Upon cooling to rt the product precipitated and was collected by filtration to yield a white solid (1.490 g, 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)[O:3]1
Reactant: ClCc1ccncc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OB(c2cnn(Cc3ccncc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 899.8 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg, 0.387 mmol), 4-Chloromethyl-pyridine (740 mg, 0.581 mmol) and cesium carbonate (3.77 g, 1.16 mmol) was dissolved in acetonitrile (15 mL) was stirred overnight at room temperature. Stirring continued for 5 hrs at 60° C. and the reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate-4% 2M NH3 in MeOH/CH2Cl2) provided the title compound (993 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 8.59-8.57 (m, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.07-7.05 (m, 2H), 5.35 (s, 2H), 1.33 (s, 12H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH2:20][C:21]1([C:24]#[N:25])[CH2:23][CH2:22]1)(=O)=O.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:20][C:21]3([C:24]#[N:25])[CH2:23][CH2:22]3)[CH:10]=2)[O:3]1
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC3(C#N)CC3)c2)OC1(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), (1-cyanocyclopropyl)methyl methanesulfonate (0.14 g, 0.77 mmol), and sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 2 h. After cooling, it was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.15 g of the crude product which was used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH2:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]([F:16])([F:17])[F:15])=[CH:9][CH:8]=1
Reactant: N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Add methanesulfonyl chloride (16.42 mL, 0.21 mol) drop-wise to a mixture of (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethanamine (49 g, 0.19 mol), 4-dimethylaminopyridine (1.18 g, 9.0 mmol), 2,6-lutidine (67 mL, 0.57 mol) in DCM (250 mL) at 0° C. Warm the mixture to ambient temperature and stir at that temperature for 20 hours. Dilute the reaction mixture with DCM (300 mL) and wash it sequentially with 2M HCl (2×200 mL), water (250 mL), then brine (250 mL). Collect the organic phase and dry over magnesium sulphate; filter; and concentrate under vacuum. Triturate the residue with hexane (200 mL) for 10 minutes, filter and dry the solid under vacuum to give the title compound as a pale brown solid (60 g, 93% yield, 98% ee). MS (m/z): 332 (M+1).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19].O>O1CCCC1>[F:1][CH:2]([F:5])[CH2:3][O:4][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19]
Reactant: OCC(F)F
Reactant: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
2,2-Difluoro ethanol (418 mg, 5.1 mmol) was dissolved in tetrahydrofuran (15 ml), sodium hydride (60%) (180 mg, 4.5 mmol) was added thereto under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine (600 mg, 3.20 mmol) in tetrahydrofuran (15 ml) was dropped, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with sodium bicarbonate solution, dried over magnesium sulfate. The residue obtained by evaporating the solvent was triturated with n-hexane to yield the title compound (685 mg, 3.1 mmol, 96%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:3]=1.CN(C)C=O>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Nc1nc(-c2ccncc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccncc2)nc1N

Procedure:
A mixture containing 43.2 g. of 2-amino-3-nitro-6-(4-pyridinyl)pyridine, 360 ml. of dimethylformamide, 220 ml. of ethanol and 1 g. of 10% palladium-on-charcoal was shaken in a Parr apparatus under catalytic hydrogenation conditions for about one hour. The reaction mixture was filtered and the filtrate concentrated in vacuo to a volume of about 150 ml. and cooled. The separated solid was collected and dried to produce 20 g. of 2,3-diamino-6-(4-pyridinyl)pyridine which can be used directly in the next step without further purification. In another run, a sample was recrystallized from ethanol using decolorizing charcoal to produce the product, 2,3-diamino-6-(4-pyridinyl)pyridine, melting at 252°-254° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[F:8][C:7]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][C:4]([OH:9])=[N:5][CH:6]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(O)ncc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoro-pyrimidin-2-ol* (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with diethyl ether (200 mL), and filtered. The solid product was washed with heptane to give the title compound (5.23 g, 92% yield) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (bs, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); HPLC-MS (ESI) m/z 185 (M+H)+, 183 (M−H)−. *4-amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:2]1.C(O)(=[O:18])C.CS(C)=O.Cl>O>[O:18]=[C:2]1[CH:3]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: CC(=O)O
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCC1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
A mixture of methyl 3-indolepropionate (5.00 g, 0.0246 mol), acetic acid (10 mL), dimethylsulfoxide (26 mL, 0.369 mol, 15 eq.) and concentrated hydrogen chloride (37%) (22 mL, 0.738 mol, 30 eq.) was stirred at ambient temperature for 2.5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (30% ethyl acetate in hexanes) to afford the title compound as an oil (5.28 g, 98%); 1H NMR (DMSO-d6); δ2.03-2.10 (m, 2H); 2.32-2.39 (m, 2H); 3.46 (t, J=6.4 Hz, 1H); 3.54 (s, 3H); 6.81 (d, J=7.6 Hz, 1H); 6.93-6.97 (m, 1H); 7.15-7.17 (m, 1H); 7.24 (d, J=7.6 Hz, 1H);
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:35]([O:41]CC)(=O)[CH2:36][C:37]([CH3:39])=O>C(O)(=O)C>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[C:35](=[O:41])[CH2:36][C:37]([CH3:39])=[N:12]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
Di-tert-butyl 1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 4b (2.70 g, 7.18 mmol) was dissolved in 100 mL of acetic acid followed by addition of 20 mL of trifluoroacetic acid. After the mixture was reacted at room temperature for 2 hours, ethyl acetoacetate (0.98 g, 7.54 mmol) was added. Then the mixture was heated to 100° C. and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The reaction mixture was neutralized by saturated sodium bicarbonate solution, and then was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 4c (1.0 g, yield 47.7%) as a light brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40]([CH:43]=O)=[CH:41][N:42]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.[Zn]>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40]([CH:43]=[C:21]([F:23])[F:22])=[CH:41][N:42]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: FC(F)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)s2)CC1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C=C(F)F)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 6.73 mmol triphenylphosphine in 13 ml N,N-dimethylformamide was added 6.73 mmol dibromodifluoromethane and the mixture was stirred at room temperature for 1 h. 3.36 mmol 4-(5-formyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was added and the mixture was then cooled to 0° C. 6.73 mmol zinc dust was added in small portions and stirring continued for 10 min at 0° C. The mixture was then allowed to warm to room temperature and stirring continued for a further 2 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 19%). MS (m/e): 332.3 (M+H+, 10%), 276.0 ([M+2H−tBu]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[OH-].[Na+].C([CH:14]1[O:16][CH2:15]1)Cl.C[Si](O[Si](C)(C)C)(C)C>O>[CH2:1]([O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6])[CH:15]1[O:16][CH2:14]1
Reactant: COC(=O)C(C)(C)CO
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: CC(C)(CO)C(=O)OCC1CO1
Reaction time: 3 h

Procedure:
132 parts by wt. (1 mole) hydroxypivalic methyl ester, 48 parts by wt. (1.2 mole) sodium hydroxide solution and 250 ml water were heated for 1 hour at 100° C. in a 0.5-liter three-neck flask equipped with stirrer, thermometer and reflux cooler. The temperature was reduced to 50° C. To the mixture were added 276 parts by wt. (3 mole) epichlorohydrin (ECH) and 50 parts by wt. Dowex (Fluka AG, 1×8). The water was removed azeotropically at a temperature of 50° C. and at reduced pressure (200 mbar), the ECH being supplied back to the reaction mixture. The total reaction time was 3 hours. The salt formed was filtered off and washed twice with 20 ml ECH The excess ECH was removed by means of rotary film evaporation. Thus 167 parts by wt. hydroxypivalic glycidyl ester were obtained in the form of a light yellow liquid with an epoxide content of 5.5 meq/g and a hydroxy content of 307 mg KOH/g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: NCCSCc1ccco1
Product: COc1ccc(C(=O)NCCSCc2ccco2)cc1C
Yield: 58 %

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and 2-(furan-2-ylmethylthio)ethanamine. Yield 58%. 1H NMR (500 MHz, CDCl3) 2.23 (s, 3H), 2.76 (t, 2H, J=6.37 Hz), 3.59 (q, 2H, J=12.2 Hz), 3.76 (s, 2H), 3.86 (s, 3H), 6.22 (dd, 1H, J=3.49 Hz, J=2.67 Hz), 6.30 (dd, 1H, J=3.04 Hz, J=1.78 Hz), 6.46 (m, 1H, broad), 6.83 (d, 1H, J=8.51 Hz), 7.34 (dd, 1H, J=1.97 Hz, J=1 Hz), 7.56 (d, 1H, J=1.72 Hz), 7.61 (dd, 1H, J=8.53 Hz, J=2.25 Hz). MS (M+H, 306).
Reaction SMILES: C[O:2][CH:3]([O:28]C)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[O-][Mn](=O)(=O)=O.[K+].O>C(O)(=O)C>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[C:3]([OH:28])=[O:2])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (23.0 g, 0.053 mole) in acetic acid is treated with 54 ml of 2.5N H2 SO4 and heated at 70° C. for 12 hours. A portion of the reaction solution is concentrated, diluted with acetone and treated portionwise, at 25°-38° C., with an aqueous solution of KMnO4 (23.7 g, 0.15 mole). Addition is continued until a persistent pink color is obtained at 27° C. The reaction mixture is filtered to remove MnO2 and the filtrate is concentrated in vacuo to give a residue. Addition of water to the thus-obtained residue precipitates the title compound as a pale yellow solid, 16.6 g. A sample is recrystallized twice from 75% aqueous ethanol to afford a crystalline solid, mp 174°-175.5° C., identified by elemental and NMR analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2[nH]1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a solution of 5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (1.50 g, 4.12 mmol) in dimethylformamide (15 mL) was added 60% sodium hydride (0.25 g, 6.18 mmol). The reaction mixture was stirred at ambient temperature under argon for 2.5 h. 4-Bromobutyronitrile (0.92 g, 6.14 mmol) was then added and the reaction mixture stirred for another 14 h at ambient temperature. The reaction was diluted with ethyl acetate and washed three times with water. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded an off-white solid (1.60 g, 95%). MS(ES) m/e 431.0 [M +H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[OH:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C>[CH:37]1([CH2:36][O:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol, (Example 191), (50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2.0 mL) was added (bromomethyl)cyclohexane (20 μL, 0.14 mmol, Aldrich). The reaction mixture was stirred at 60° C. for 23 h. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography (gradient: 0% to 3.0% MeOH/CH2Cl2) to provide the title compound as a white amorphous solid. MS (ESI, pos. ion) nt/z: 480 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[CH2:31][O:22][C:15]1[CH:14]=[C:13]2[C:18]([N:19]=[CH:20][CH:21]=[C:12]2[C@H:11]([OH:23])[C@@H:10]2[N:5]3[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]3)[CH2:9]2)=[CH:17][CH:16]=1)#[N:36]
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Reactant: N#Cc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCc3cccc(C#N)c3)cc12
Yield: 79.1 %

Procedure:
To a solution of 0.6 g (1.91 mmol) of 6-hydroxycinchonine in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 8 ml of anhydrous dimethylformamide is added 0.516 g (2.87 mmol) of anhydrous potassium carbonate followed by 0.329 g (1.91 mmol) of 3-(bromomethyl)benzonitrile (Lancaster) and 4 mg of 18-crown-6. The reaction mixture is heated to reflux for 18 h, cooled and filtered. The filtrate is concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer is washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried with anhydrous magnesium sulphate to yield 0.647 g (1.51 mmol, 79%) of (9S)-6'-(3-cyanobenzyloxy) cinchonane-9-ol as pale off-white solids.