Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=N[O:36][C:37]([N:41]([CH3:43])[CH3:42])=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:37]([N:41]1[CH2:42][CH2:13][N:12]([C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH2:8][CH2:43]1)=[O:36])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 15.4 g (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 24.4 ml NEM and 15.6 g TOTU in 80 ml DMF 7.5 g piperazine-1-carboxylic acid ethyl ester were added at RT and stirred for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous LiCl (4 w/w) and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 23.0 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[N:17][C:16]=2[CH:33]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (200 mg, 0.42 mmol) dissolved in DCM and added Trifluoroacetic acid (0.75 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg). 5-(2-fluoro-4-(methylsulfonyl)phenyl)-2-(piperidin-4-yl)-benzo[d]oxazole 2,2,2-trifluoroacetate (190 mg, 0.39 mmol) was dissolved in DCM (20 ml) and added TEA (0.43 ml, 3.12 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (0.095 g, 0.78 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (120 mg) as a pale-yellow solid. M.P.: 96.5-101.2° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (s, 1H), 7.81 (dd, J 1.7, 8, 1H), 7.80-7.75 (m, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.94 (septet, J 6.2, 1H), 4.19 (d, J 10.9, 2H), 3.22-3.13 (m, 1H), 3.12 (s, 3H), 3.04 (t, J 10.9, 2H), 2.22-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.[CH3:10][C:11]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1.CC(OC(C)=O)=O>>[C:6]([C:19]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[C:16]=2[S:17][CH:18]=1)(=[O:7])[CH3:5]
Reactant: CCOCC
Reactant: Cc1cccc2ccsc12
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1csc2c(C)cccc12

Procedure:
420 mg of borontrifluoride-etherate are added to a mixture of 2 g of 7-methylbenzo[b]thiophene and 1.4 ml acetanhydride at 50° and the mixture warmed to 60° for 80 minutes. The resulting mixture is poured onto ice, extracted with ether and the organic phase washed, dried and concentrated on a rotary evaporator. The residue is chromatographed on silica gel (eluant: n-hexane) to obtain the title compound, contaminated with the 2-acetylisomer, as an oil for direct further reaction.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:13][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:4][CH2:3][C:2]([F:16])([F:15])[F:1])[CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)cc1OCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
2-(2,2,2-Trifluoro-ethoxy)-4-hydroxymethyl-benzonitrile (1.4 g, 6.1 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.15 mmol) followed by CBr4 (3 g, 9.15 mmol). The reaction mixture was stirred at room temp. for 2 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (20% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a mixture of 2-amino-4-(trifluoromethyl)benzoic acid (150 g, 0.73 mol) in MeOH (2.5 L) was added conc. HCl (0.5 L, 16.5 mol). The reaction mixture was allowed to stir at reflux. After 3 h, an additional portion of HCl (0.5 L, 16.5 mol) was added and the reaction was allowed to continue to stir at 80° C. for 60 h. The reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue, and the solution was basified with 10% aqueous NaOH solution. The resulting precipitate was filtered to give methyl 2-amino-4-(trifluoromethyl)benzoate (120 g, 75%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and cyclopropanamine (0.34 g, 92%); MS: 201.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:3]=1[CH:4]=O.[SH:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1>>[OH:1][C:2]1[C:3]([CH2:4][S:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Reactant: COc1cc(O)c(C=O)c(-c2nc(C)no2)c1C
Product: COc1cc(O)c(CSC[C@H](NC(C)=O)c2nc(C)no2)c(-c2nc(C)no2)c1C

Procedure:
2-Hydroxy-4-methoxy-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl) -ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 1(g) to yield (R)-N-[2-[6-hydroxy-4-methoxy-3-methyl-2-(3-methyl -1,2,4-oxadiazol-5-yl)benzylsulfanyl]-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Cl.[C:9]([Cl:12])(C)=O.CCOCC>CO>[NH2:1][C@@H:2]([C:5]([O:7][CH3:9])=[O:6])[CH2:3][SH:4].[ClH:12]
Reactant: CC(=O)Cl
Reactant: N[C@H](CS)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](N)CS
Yield: 80.7 %

Procedure:
To a cooled (0° C.) solution of H-D-Cys-OH.HCl (2.0 g, 0.013 mol) in 89.0 mL of MeOH was added 4.5 mL (0.063 mol) of AcCl. The resulting colorless solution was heated at reflux for 5 h, cooled, concentrated on a rotary evaporator, and then stripped down with Et2O until a white solid resulted. Additional Et2O (~100 mL) was added, the solid filtered, washed with Et2O, and excess solvent removed in vacuo to provide H-D-Cys-OMe.HCl as a white solid (1.80 g). The synthesized compound was identical (1H NMR) to commercially available H-Cys-OMe.HCl (Sigma).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:25](OC(Cl)(Cl)Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:5]1[C:6]([O:7][C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][C:2]([N:1]=[C:25]=[O:26])=[C:3]([F:23])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccccc1Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
Into a mixture of ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23], trichloromethyl chloroformate and toluene is added dropwise activated carbon, and the mixture is heated under reflux. The reaction solution is filtrated and the solvent is distilled off to obtain 4-chloro-2-fluoro-5-{2-(ethoxycarbonylmethoxy)phenoxy}phenyl isocyanate [Intermediate compound A12-23].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[C:9]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([Si:21]([Cl:20])([CH3:23])[CH3:22])[CH:7]=[C:6]([CH3:8])[CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution composed of tetrahydrofuran (31.5 ml), hexane (139 ml) and 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (45 g) synthesized in the above-described procedure (2) was added a 1.6 mol/liter hexane solution (115 ml) of n-butyllithium dropwise at −40° C. over 20 minutes. The resultant mixture was kept at −40° C. for 1 hour, and tetrahydrofuran (31.5 ml) was then added dropwise. To a solution composed of dichlorodimethylsilane (131 g) and hexane (306 ml) was added the above-described mixture dropwise at −40° C. The resultant mixture was allowed to warm to room temperature over 2 hours, and further stirred at room temperature for 12 hours. The solvent and excess dichlorodimethylsilane were removed under reduced pressure from the reaction mixture, hexane-soluble components were extracted from the residue with hexane, and the solvent was distilled off from the resultant hexane solution to obtain 41.9 g of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane as a pale yellow oil. Yield was 84%.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DBU (0.764 mL) was added to a mixture of benzyl bromide (0.61 mL), (S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (1 g) in anhydrous toluene (10 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give benzyl (S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (0.859 g)
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:11]([NH2:13])=O)[O:3]1.[CH3:20][C:21](N)([CH3:24])[CH2:22][NH2:23].C1(C)C=CC=CC=1>O>[OH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2](=[O:1])[N:23]2[CH2:22][C:21]([CH3:24])([CH3:20])[N:13]=[C:11]12
Reactant: CC(C)(N)CN
Reactant: NC(=O)C1(c2ccccc2)OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccccc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 3-oxo-1-phenyl-1,3-dihydro-2-benzofuran-1-carboxamide (10 g), 2-methyl-1,2-diaminopropane (15 mL), and toluene (100 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (57.3 g), m.p. 186-188° C.
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C[O:7][P:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:11])[O:9]C>>[CH3:3][Si:2]([O:7][P:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:11])[O:9][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: C[Si](C)(C)Br
Product: C[Si](C)(C)OP(=O)(Cc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
Bromotrimethylsilane (6.0 mL, 45.4 mmol) was added dropwise to (4-fluoro-benzyl)-phosphonic acid dimethyl ester (4.57 g, 20.95 mmol) and stirred in a reaction flask chilled to 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for an additional hour, then concentrated by rotary evaporation to remove volatiles yielding crude (4-fluoro-benzyl) phosphonic acid bis(trimethylsilyl) ester which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1F

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl (2-fluorophenyl)-5-(pent-1-enyl)pyridine (Example 137) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.78 (t, J=7.0 Hz, 3 H), 1.07-1.40 (m, 18 H), 2.29 (m, 2 H), 3.26 (m, 1 H), 3.46 (m, 1 H), 4.34 (m, 2 H), 7.20 (m, 3 H), 7.42 (m, 1 H). Rf=0.24 (10% ethyl acetate/n-hexane).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1>>[C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15]([NH:32][CH:33]2[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:40])([CH3:39])[CH2:38]2)=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Product: CC1(C)CC(NC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
Reacting ethyl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate analogously with 4-amino-2,2,6,6-tetramethylpiperidine produces 4-[4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valeramido]-2,2,6,6-tetramethylpiperidine having a melting point 133°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:36]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:35])[C@@H:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[NH2:36])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Product: COc1ccc([C@@H](N)[C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 1.0 g (2.1 mmol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 15 ml of EtoH, abs., 15 ml of ammonia.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][O:11][CH3:20])[CH:9]=1
Reactant: CCC1CCCCN1c1ccc(Br)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CCCCN1c1ccc(Br)cc1COC
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of sodium hydride (2.3 g, 93 mmol) in anhydrous DMF (130 mL) was added a solution of [5-bromo-2-(2-ethylpiperidin-1-yl)phenyl]methanol (15 g, 48.3 mmol) in DMF (20 mL) drop wise at 0° C. After 30 minutes, methyl iodide was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), then diluted with water (100 mL) and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (15.2 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 7.59 (1H, s), 7.35 (1H, d), 7.02 (1H, d), 4.49-4.59 (2H, m), 3.43 (3H, s), 2.88 (1H, d), 2.75 (1H, bs), 2.51 (1H, bs), 1.79-1.86 (2H, m), 1.62 (3H, d), 1.40 (2H, m), 0.88 (2H, m), 0.70 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.NC(N)=[S:13]>C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:5][SH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: Fc1c(Cl)cccc1CBr
Solvent: CCO
Product: Fc1c(Cl)cccc1CS
Yield: 89.8 %

Procedure:
3-Chloro-2-fluorobenzyl bromide (1.00 g) and thiourea (0.35 g) were heated together at reflux in ethanol (10 ml) for 1 hour. The solvent was removed in-vacuo and the residue was suspended in 10% aqueous sodium hydroxide (10 ml) and heated at reflux for 3 hours. The solution was then acidified with conc. HCl and extracted into ether. Concentration of the organic phase in-vacuo gave the subtitle compound as a pale yellow oil (0.71 g).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:15]([N:19]([CH3:28])[C:20](N1C=C[N+](C)=C1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[H-].[Na+]>C1COCC1.CN(C=O)C>[C:15]([N:19]([CH3:28])[C:20](=[O:21])[O:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C(=O)n1cc[n+](C)c1)C(C)(C)C
Reactant: OCCNc1ccc2ncc(Br)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OCCNc1ccc2ncc(Br)n2n1)C(C)(C)C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a solution of 2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethanol (0.35 g, 1.5 mmol) and 1-(tert-butyl(methyl)carbamoyl)-3-methyl-1H-imidazol-3-ium (0.30 g, 1.5 mmol) in THF/DMF (6.0 mL/3.0 mL) was added NaH (0.15 g, 60% in mineral oil, 2.5 mmol). The reaction was stirred for 24 h and then quenched with water, extracted with ether, concentrated and purified by ISCO column chromatography give 2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethyl tert-butyl(methyl)carbamate as product (0.17 g, 31% yield). LRMS (ESI) m/e 372.0 [(M+H)+, calcd for C14H21BrN5O2 371.2].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](OC)(OC)[CH3:12]>>[CH3:9][O:10][C:11](=[N:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: Nc1cccc(O)n1
Reactant: COC(C)(OC)OC
Product: COC(C)=Nc1cccc(O)n1

Procedure:
4.4 g (40 mmol) of 6-amino-2-hydroxypyridine are heated under reflux for 12 hurs in 30 ml of orthoacetic acid trimethyl ester The reaction mixture is then concentrated by evaporation Ether is added to the residue while stirring, the product crystallising out spontaneously. The product is filtered off with suction and dried under a high vacuum. N-(2-hydroxy-6-pyridyl)-acetimidic acid methyl ester having a melting point of 128°-129° is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]#[N:14])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:27])[NH2:14])=[N:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2c1CCC2
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 3.600 g (14.92 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile were dissolved in 37 ml of absolute methanol. 1.306 (24.17 mmol) of sodium methoxide were added and the mixture was stirred at RT for 4 h. 1.452 g (24.17 mmol) of acetic acid and 1.197 g (22.38 mmol) of ammonium chloride were added and the suspension was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was suspended in 100 ml of water and 25 ml of 1N hydrochloric acid. The mixture was extracted with dichloromethane. The aqueous phase was basified (pH=12) with 2N sodium hydroxide solution and extracted three times with a mixture of dichloromethane/methanol (v/v=8:2). The combined organic phases were dried with sodium sulphate and concentrated, toluene was added and the mixture was again concentrated to dryness. 1.94 g (50% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[CH2:24]([C:26]1[NH:27][CH:28]=[CH:29][N:30]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:24][CH3:25]
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: CCc1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1nccn1CCCCCCOc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2 gms. of the iodide prepared in Examples 2 or 3, 2 gms. of 2-ethylimidazole, 2.5 ml. DMF and 0.4 gm sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride and then 10% methanol to yield the title compound. MS:m/z 337 (M+) H1 -NMR-200 mHz, εH (CDCl3), 1.34 (3H,t,J 7.5 Hz), 1.3-1.65 (4H,m), 1.70-1.90 (4H,m) 2.66 (2H,q,J 7.5Hz), 3.75 (3H,s), 3.83 (2H,t,J 7Hz), 3.95 (2H,t,J 6Hz), 6.7-7.0 (5H,m).