Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.FC(F)(F)C(N)=O.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C:14](=[O:16])[NH:19][C:10](=[O:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2ccccc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a suspensiopn of 15 g (67 mmoles) of benzyliminodiacetic acid in 300 ml of CH2Cl2, 28 ml (201 mmoles) of triethylamine, 21.77 g (161 mmoles) of 1H-hydroxybenztriazole and 10.6 g (94 mmoles) of trifluoroacetamide are successively added and then 28.34 g (147.8 mmoles) of 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture is quenched with cold H2O and extracted with CH2Cl2. The combined extracts are washed with H2O brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-Hexane:AcOEt=2:1) to give 10 g of desired 4-benzyl-piperazine-2,6-dione in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: COC(=O)C(C)(C)CO
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)COC1CCCCO1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 117 %

Procedure:
To a solution of 66.3 mL (0.51 mol) of hydroxypivalic acid methyl ester in DCM (325 mL) are added 95.8 mL (1.04 mol) of 3,4-dihydro-2H-pyran. The reaction mixture is cooled to 0° C. and sulfuric acid on silica gel (2.04 g, 0.2 mL sulfuric acid/10 g silica gel) is added and the reaction mixture is stirred at room temperature for 25 minutes. After this time, the reaction mixture is filtered and concentrated under reduced pressure to yield 129 g of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester as a yellow oil, which is used in the next step without further purification. Yield: quantitative; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (6H, s), 1.13 (6H, s), 1.4-1.7 (6H, m), 3.3 (1H, m), 3.4 (1H, m), 3.6 (3H, s), 3.65 (1H, d), 3.7 (1H, m), 4.55 (1H, t).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([S:12][CH2:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:11])[CH3:10]>>[C:9]([S:12][CH2:13][CH:14]([CH3:18])[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:16])(=[O:11])[CH3:10]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(=O)SCC(C)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
Following the procedure of Example 16, L-valine is reacted with 3-acetylthio-2-methyl-propanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-valine.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[C:4](=[O:13])[O:3]1.[O:14]1CCOCC1>Cl>[Cl:11][C:8]1[C:7]([Cl:12])=[CH:6][C:5]([C:4]([OH:3])=[O:13])=[C:10]([CH:2]=[O:14])[CH:9]=1
Reactant: C1COCCO1
Reactant: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Agent: Cl
Product: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Yield: 73 %

Procedure:
A suspension of 3-bromo-5,6-dichloro-3H-isobenzofuran-1-one (2.0 g) in 5% aqueous HCl (10 mL) and 80% aqueous dioxane (25 mL) were heated to reflux for 2 hours. The solvent was removed and the resulting residue re-dissolved in ethyl acetate, dried (magnesium sulfate) and concentrated. The resultant yellow solid was recrystallized from DCM/hexane to give the sub-title compound as a white solid (1.13 g, 73%); 1H NMR (400 MHz, CDCl3) δ 6.66 (0.84H, s), 7.95 (0.16H, s), 8.05 (0.84H), 8.12 (0.16H, s), 8.14 (0.84H, s), 8.41 (0.84H,), 10.41 (0.16H, s), 11.07 (0.16 H, brs).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:27])[CH3:26])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 0 °C
Yield: 88 %

Procedure:
To a mixture of 200 mg (0.850 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 128 μl (0.917 m mol) of triethylamine and 17 ml of methylene chloride were added 128 μl (0.917 m mol) of acetyl chloride with stirring at 0° C., followed by stirring for 30 minutes. After the completion of the reaction, the precipitated crystals were filtered. The crystals were washed successively with methylene chloride and water and dried at 80° C. under reduced pressure to obtain 223 mg (yield: 88%) of the intended compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:29])([F:28])[C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:17]([F:29])([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)[C:14]1[N:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]#[N:31])[CH:7]=3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccnc(Cl)c3)nn12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)ccn1

Procedure:
A mixture of 6-{[6-(2-Chloro-pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-difluoro-methyl}-quinoline (see Example 100b) (50 mg, 0.122 mmol) in DMF (4 mL) and Zn(CN)2 (43 mg, 0.367 mmol) was degassed with house vacuum for ˜5 min, and tetrakis(triphenylphosphine)palladium (13.4 mg, 0.012 mmol) were then added. The mixture was microwaved at 190° C. for 20 min. Following the aqueous work up, solvent was removed by vacuo. The target compound, 21 mg (41%), was obtained by column purification. 1H NMR(CDCl3) δ 9.04 (dd, J=4.2, 1.6 Hz, 1H), 8.95 (d, J=5.12 Hz, 1H), 8.41 (d, J=9.8 Hz, 1H), 8.22-8.35 (m, 4H), 8.00-8.05 (m, 2H), 7.70 (d, J=9.8 Hz, 1H), 7.54 (dd, J=8.2, 3.8 Hz, 1H); MS (ES) m/z 400.3 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[F:8][C:9]([F:31])([C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][OH:11].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:8][C:9]([F:31])([C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][O:11][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1
Reactant: CC1(CBr)COC1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 87 %

Procedure:
In a manner similar to the that of Example B14, a mixture of 3-bromomethyl-3-methyloxetane (468 g, 2.84 mol), 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (1032 g, 2.58 mol), tetrabutylammonium bromide (41.5 g), potassium hydroxide (208 g, 3.23 mol), and water (1680 ml) was heated under reflux for 3 hours. GLC analysis revealed complete consumption of starting materials. The reaction mixture was diluted with water, worked-up in the usual manner, and distilled under reduced pressure to give 1,085 g of 15-FOX, representing an overall yield of 87%; bp 82° C./0.1 mm-Hg. The distilled material was >99% pure as indicated by GLC and was used in subsequent polymerization reactions.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]1(/[C:13](/[CH2:42][CH3:43])=[C:14](\[C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[C:35]([CH:40]=[O:41])[CH:34]=[CH:33]3)/[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:19]=[CH:18]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O.O>[C:7]1(/[C:13](/[CH2:42][CH3:43])=[C:14](\[C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[C:35]([C:40]([OH:2])=[O:41])[CH:34]=[CH:33]3)/[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:19]=[CH:18]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC/C(=C(/c1ccc2cc(C=O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reaction time: 3 h

Procedure:
Potassium permanganate (5 mL of 1.0 M aqueous solution) was added to a solution of (E)-6-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)-2-naphthaldehyde (240 mg, 0.49 mmol) and acetone:H2O (2:1, 15 mL) at room temperature. The reaction was stirred for 3 h, quenched with sat. Na2SO3, acidified to pH 5 with 1.0 M aqueous HCl soln, and then extracted with 2× EtOAc. The organic layers were combined, washed with water then brine, dried over Na2SO4, and concentrated. The crude material was used without further purification. LCMS: 419 [(M-THP+H)+H]+.
Reaction SMILES: [CH3:1][C:2](=[N:5][OH:6])[CH2:3][CH3:4].[N:7]([CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13])=[C:8]=[O:9]>>[CH2:3]([C:2](=[N:5][OH:6])[CH2:1][C:8](=[O:9])[NH:7][CH2:10][Si:11]([O:14][CH3:15])([O:16][CH3:17])[O:12][CH3:13])[CH3:4]
Reactant: CO[Si](CN=C=O)(OC)OC
Reactant: CCC(C)=NO
Product: CCC(CC(=O)NC[Si](OC)(OC)OC)=NO
Reaction time: 1 h

Procedure:
A stirred mixture conditioned at a temperature of 80° C. of 86.1 g of 2-butanone oxime and 120 mg of “Borchi catalyst” (catalyst VP 0244 from Borchers GmbH, Langenfeld) was admixed over the course of 60 min with 150 g of (isocyanatomethyl)trimethoxysilane. After the end of the addition the mixture was stirred at the temperature stated for a further 60 min and excess 2-butanone oxime was removed by distillation. This gave N-[(trimethoxysilyl)methyl]carbamoylmethyl ethyl ketone oxime in quantitative yield with a purity of >95% (analysis by 29Si and 1H NMR).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)c1cccnc1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
To a solution of 3-(4-hydroxy phenyl)2-[(pyridine-3-carbonyl)amino]propionic acid methyl ester (0.53 g, 1.76 mmol) in DMF (1 mL) was added N,N′-Di isopropyl ethyl amine (0.47 mL, 2.00 mmol) then reaction mixture cooled to (0° C.), t-butyl-dimethyl-silylchloride (0.26 g, 1.76 mmol), was added to reaction mass at (0° C.). The mixture was allowed to stir at room temperature (25° C.) over 5 h. The reaction mixture was quenched with ice, diluted with ethyl acetate (100 mL)), washed with water (3×50 mL) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain product as pale brown liquid (0.6 g, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:11]([CH:10]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Product: COc1cc([N+](=O)[O-])c(C=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To concentrated nitric acid (200 ml.) maintained at 0° C. is added 3-benzyloxy-4-methoxybenzaldehyde (48 g., 0.198 mole) over a 30 minute period with stirring. When addition is complete, the temperature is allowed to rise to 15° C. and stirring continued for another 30 minutes. The mixture is then added to ice-water and the yellow precipitate collected by filtration and dried. Yield = 52.8g. (94%); m.p. 131°-132° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1C[O:12][C:13](=O)[CH2:14][CH2:15][C:16]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)=[CH:38][CH:37]=1)([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:20][CH:19]=1)[CH3:17].[BH4-].[Na+].CO.O>C1COCC1>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:53]=[CH:52][C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:45]=3)=[CH:38][CH:37]=2)([CH3:17])[CH2:15][CH2:14][CH2:13][OH:12])=[CH:19][CH:20]=1
Reactant: CC(CCC(=O)OCc1ccc2ccccc2n1)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture in THF (50 mL) of 4.4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid 2-quinolylmethyl ester (2.1 g, 3 mmol), prepared as in Example 1, and sodium borohydride (380 mg, 10 mmol) was added dropwise methanol at 50°-55° C. and the mixture was stirred for 30 minutes. The mixture was cooled to room temperature, poured into water (50 mL) and acidified to pH 4. The resulting mixture was extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 3:1) to afford 1.46 g (88%) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol: 1H NMR (300 MHz, DMSO-d6) d 1.18 (m, 2H), 1.48 (s, 3H), 2.00 (m, 2H), 3.34 (m, 2H), 4.34 (t, 1H, J=6 Hz), 5.30 (s, 4H), 6.96 (d, 4H, J=9 Hz), 7.09 (d, 4H, J=9 Hz), 7.64 (m, 4H), 7.79 (m, 2H), 8.00 (t, 4H, J=8 Hz), 8.41 (d, 2H, J=8 Hz); MS (DCl--NH3) m/e 555 (M+H)+. Anal. Calc'd. for C37H34N2O3.0.5 H2O: C, 78.84; H, 6.44; N, 4.97. Found: C, 78.67; H, 5.95; N, 4.70.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:13])(C(C)(C)C)(C)C.[F-].C([N+](CC)(CC)CC)C>CC#N>[Cl:20][C:16]1[CH:15]=[C:14]([C@@:12]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)([O:11][CH2:10][CH2:9][OH:8])[CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO)c2cccc(Cl)c2)C1
Temperature: 45 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate, tetraethylammonium fluoride (7.600 g, 50.9 mmol) in CH3CN was heated at 45° C. for 1 h and then was allowed to stir at rt overnight. The reaction mixture was evaporated under reduced pressure, the residue was dissolved into water and extracted with Et2O (3×), dried over Na2SO4. After the solvent was removed in vacuo, the crude product was purified by reversed-phase HPLC to give 1.000 g (35% in two steps) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 406 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C[N+](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)([OH:12])[C:27]([F:29])([F:28])[F:26]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of 6-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (1.17 g) in tetrahydrofuran (60 ml) was added a solution of (trifluoromethyl)trimethylsilane (703 mg) in tetrahydrofuran (10 ml) at 0° C. Tetramethylammonium fluoride (30 mg) was added and the mixture was stirred at 0° C. for 30 min and at room temperature for 15 min. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.26 ml) was added and the mixture was stirred for 20 min. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>7:3) to give the title compound (1.1 g) as a colorless solid. MS (m/e, ISP neg. ion)=428.4 [M−H+].
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[S:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](OCC)(=O)[CH3:26]>C1COCC1>[CH2:1]([N:8]1[CH:26]=[CH:25][N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@H]1C(=O)N(Cc2ccccc2)C=CN1C(=O)OC(C)(C)C

Procedure:
A solution of N-benzyl 2(R)-tert-butoxycarbonylaminohexanamide (1.0 g, 2.29 mmol) in THF (10 mL) was vigorously stirred with 6N HCl(10 mL) for 24h. Ethyl acetate was added, and the layers separated. The organic phase was washed with water, then saturated sodium chloride solution. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as an oil (0.140 g). NMR (CDCl3, 300 MHz) δ 7.3 (5H, m), 6.31, 6.14 (1H, 2 ds, J=7, 7 Hz), 5.55, 5.42 (1H, 2 ds, J=7, 7 Hz), 4.68 (2H, AB q, J=15 Hz, D n=36 Hz), 4.78 (1H, m), 1.66 (2H, m), 1.47 (9H, d), 1.33 (4H, m), 0.89 (3H, brt, J=7 Hz).
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][OH:24])[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C)C=O>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:27])[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(C)(C)C)CC(CO)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 8-tert-butyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (720 mg, 2.10 mmol) in N,N-dimethylformamide (7.0 mL) was added sodium hydride (588 mg, 14.7 mmol) and the reaction stirred for 10 min. Methyl iodide (916 μL, 14.7 mmol) was added and the reaction mixture stirred for 20 min. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide tert-butyl 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (732 mg, 2.05 mmol, 98%). ESI-MS m/z calc. 356.3. Found 357.3 (M+1)+; Retention time: 0.97 minutes (3 min run).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>CN(C)C=O.ClC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (3.8 g, 32.1 mmol) was slowly added to a solution of 4-fluorobenzoic acid 1a (3.0 g, 21.4 mmol) and N,N-dimethylformamide (5 drops) in 15 mL of chlorobenzene under a stream of nitrogen gas. The mixture was stirred at 60° C. for 2 hr. The solvent was removed under reduced pressure to afford 4-fluorobenzoyl chloride 1b. Yield: 3.0 g (88%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=[O:7])[CH3:6]>>[CH2:1]([N:4]=[C:9]([CH2:8][C:5](=[O:7])[CH3:6])[CH3:10])[CH2:2][CH3:3]
Reactant: CC(=O)CC(C)=O
Reactant: CCCN
Product: CCCN=C(C)CC(C)=O

Procedure:
0.1 Mole (5.9 g.) n-propylamine is mixed with 0.1 mole (10 g.) acetylacetone. An exothermal reaction takes place in which a yellowish, liquid ketimine is obtained which, even after comparatively lengthy storage, does not give a precipitate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:11][CH2:12][OH:13].[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:16]#[C:15][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: Nc1ncnc2c1nc(Br)n2CCO
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(C#Cc1cccnc1)n2CCO
Temperature: 60 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a solution of 258 mg of 2-(6-amino-8-bromo-purin-9-yl)ethanol in a mixture of Et3N and DMF were added under an atmosphere of argon 35 mg of Pd(PPh)3Cl2, 19 mg CuI and 150 mg 3-ethynylpyridine. The mixture was stirred under argon at 60° C. for 3 hours and over night at room temperature. The precipitate was isolated, washed with water and hot ethanol and dried to give 150 mg (53%) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][OH:13])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].[Li+].[OH-]>C1COCC1.O>[OH:13][CH2:12][C:10]1[CH2:11][N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6](=[O:27])[CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[CH2:8][CH:9]=1
Reactant: COC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of {6-hydroxymethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 19, (0.16 g, 0.41 mmol) in THF/H2O (4 mL, 3:1) is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified to pH 7, concentrated in vacuo and purified by HPLC to afford 0.15 g of the desired product.