Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1.O>C1(C)C=CC=CC=1.C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1
Reactant: Brc1ccc(C2CO2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc([C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R,R)-(−)-N,N′-Bis(3,5-di-tert-butyl-salicylidene-1,2-cyclohexane-diaminocobalt(II) (9.7 g, 0.016 mol) was dissolved in 100 mL of toluene in an open flask at 0° C. with magnetic stirring and acetic acid (9.2 mL, 0.16 mol) was added. The bath was removed and then the mixture was maintained at room temperature for 1 h with vigorous stirring. The mixture was concentrated in vacuo to a brown solid, and then the residue was put under high vacuum overnight. The brown residue was dissolved in 100 mL of THF, and to the resulting solution was added to 2-(4-bromophenyl)oxirane (400 g, 2 mol) dissolved in THF (300 mL). The reaction mixture was cooled to 0° C. and distilled water (19.8 g, 1.1 mol) was added slowly into the mixture. The resulting mixture was maintained at room temperature for 16 h with magnetic stirring, concentrated and the 1 L 5% EtOAc/Hexane was added to the residue. The resulting mixture was maintained at room temperature for 1 h with vigorous magnetic stirring. The insoluble solid material was filtered away (100% diol by HPLC). The filtrate was concentrated and dissolved in 1 L hexane. The resulting mixture was maintained at room temperature for 1 h with vigorous magnetic stirring. The insoluble solid was filtered off. The filtrate was concentrated, and put under high vacuum for 2 h to yield a brown oil (250 g, a mixture of desired product, trace amount of diol, and Co Salen catalyst).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)nnn2CC1CCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)nnn2CC1CCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(cyclobutylmethyl)-5-nitro-1H-benzotriazole (3-2, 1.2 g, 5.17 mmol, 1 equiv) and 10% palladium on carbon (0.6 g) in ethanol (50 mL) was stirred at 23° C. under a hydrogen balloon for 20 h. The catalyst was filtered onto a pad of diatomaceous earth and washed with ethanol (100 mL). The filtrate was concentrated to give 1-(cyclobutylmethyl)-1H-benzotriazol-5-amine (3-3) as a grey solid. 1H NMR (300 MHz, CDCl3) δ 7.32 (d, 1H, J=8.9 Hz), 7.20 (d, 1H, J=1.8 Hz), 6.92 (dd, 1H, J=8.5, 1.8 Hz), 4.56 (d, 2H, J=7.3 Hz), 3.80 (br s, 2H), 2.95 (p, 1H, J=7.3 Hz), 2.05 (m, 2H), 1.88 (m, 4H) ppm. LRMS m/z (M+H) 203.0 found, 203.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19].CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])[S:10][C:3]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of the chloride 2 (18.72 g, 110 mmol) in THF (200 mL) at −78° C. n-BuLi (51 mL, 127 mmol) was added and the reaction mixture was stirred for about 30 minutes. The tributylchlorostannane (25.4 mL, 93 mmol) was added and the mixture was stirred at −78° C. for another 60 minutes, quenched with water [at the same temperature] and allowed to warm up to room temperature. The warmed mixture was extracted with EtOAc, the extract was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluents EtOAc-hexane (15:85), then EtOAc-hexane (25:75) to afford title compound 98 (30.2 g, 77% yield) as a yellow oil. LRMS (M+1) 459.1 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([OH:17])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2].S(OCC)(O[CH2:23][CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:23][CH3:24])=[CH:10][C:9]=2[Br:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)cc(Br)c2o1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Yield: 65.6 %

Procedure:
Into a 100 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is added 700 mg (2.24 mg, 1.0 equiv.) of 8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23a). This material is dissolved in 50 mL of toluene, then 689 mg, 586 μL (4.47 mmol, 2.0 equiv.) of diethyl sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K2CO3 were added. The reaction was then heated to reflux for 24 hr. At the end of this time, monitoring by LC/MS reveals that the reaction is>than 95% complete. The reaction is then cooled, 100 mL of ethyl acetate is added and the organic layer is washed with 0.5N HCl solution, dried over Na2SO4, filtered and concentrated. The residues were subjected to flash chromatography, using 40% ethyl acetate in hexane as eluent. The purified fractions were concentrated to yield 500 mg (65%) of a colorless solid.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Cl:8])[C:3](Br)=[O:4].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][Cl:8])[C:3]([N:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CNc1ccccc1
Reactant: O=C(Br)C(Br)CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)C(Br)CCCl)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2-Bromo-4-chlorobutanoyl bromide (80.3 g, 300 mmol) was slowly added to a solution of N-methylaniline (34.5 g, 320 mmol) and triethylamine (33.5 g, 330 mmol) in toluene (340 mL). The reaction was exothermic, and the mixture was cooled to maintain the temperature at about 40° C. After the addition was complete, the resulting thick mixture was stirred for 30 minutes, 150 mL water was added, and the mixture was stirred further. The aqueous and organic phases were separated, and the organic phase was washed with 5% hydrochloric acid and with water. The toluene was evaporated completely under slight vacuum to yield 86.3 g 2-bromo-4-chloro-N-methyl-N-phenylbutanamide (98% yield, approximately 95-96% pure). The triethylamine may be recovered from the aqueous phase by addition of base and separation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CCN(CC)CC>CO.C(Cl)Cl.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NCC#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: NCC=Cc1ccc(Cl)cc1
Yield: 74.1 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-prop-2-ynylamine (14.0 g) in 200 mL each of MeOH and CH2Cl2 was added Et3N (1.2 mL) and Lindlar catalyst (1.4 g) and the resulting suspension was stirred under a H2 balloon. The reaction was followed by TLC (i.e., thin layer chromatography) using 6% methanol-dichloromethane as eluent and once completed, filtered through a CELITE pad, concentrated and purified by chromatography to provide 10.5 g of 3-(4-chloro-phenyl)-allylamine. MS: m/e 168.6 (MH+)
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:30](O)=[O:31].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:30]([NH:2][CH3:1])=[O:31]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
HATU (0.501 g, 1.319 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (0.2 g, 1.014 mmol), DIPEA (0.265 mL, 1.522 mmol) and 2M methylamine solution in THF (1.0 mL, 2.029 mmol) in THF (2.7 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 80/20 to 60/40 followed by a second chromatography eluting with cyclohexane/EtOAc 50/50 to 40/60 to afford the title compound as a white solid (166 mg, 78%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C@H:17]([NH2:19])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:20]/[CH:21]=[CH:22]/[CH2:23]Cl.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC(C)=O.O>[Cl:20][CH:21]=[CH:22][CH2:23][NH:19][C@@H:17]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:18]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: Cl/C=C/CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](NCC=CCl)c1cccc2ccccc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (72.5 g), Tetrabutyl ammonium bromide (30 g) and de-ionized water (75 mL) were added to (R)-1-(1-naphthyl)ethylamine (150 g) in toluene (750 mL) at room temperature. The reaction mixture was heated to 60° C. to 70° C. and added trans 1,3-dichloropropene (126.4 g). The reaction mass was refluxed for 3 hours at 90° C. to 95° C. The reaction mixture was cooled to 40° C., and washed with de-ionized water (2×450 mL). The organic layer was separated and concentrated under vacuum at 55° C. to 60° C. to give an oily residue. The residue was dissolved in acetone (750 mL), added de-ionized water (150 ml) and the pH of the reaction mixture was adjusted to 1-2 using aqueous hydrochloric acid (6 Normal; 150 mL). The solid was stirred at 30° C. to 40° C. for 30 min, cooled to 20° C. to 25° C. and stirred for 1 hour. The resulting solid was filtered and suspended in acetone (300 mL), the suspensions were filtered and washed with acetone (150 mL). The resulting solid was suspended in de-ionized water (300 mL), filtered and washed with de-ionized water (225 mL). The resulting wet solid was suspended in a mixture of toluene (750 mL), methanol (375 mL) and de-ionized water (375 mL). The pH of the mixture was adjusted to 11-11.5 using aqueous sodium hydroxide solution (20%; 150 mL) and stirred for 30 minutes. The layers were separated and organic layer was washed with de-ionized water (2×300 mL). The organic layer was concentrated under reduced pressure to give 3-chloro-N-[(1R)-1-(naphthalen-1-yl)ethyl]prop-2-en-1-amine as an oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:15][Cl:16])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:18]([O:17][CH:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8])[CH2:15][Cl:16])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(CCl)c1ccsc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(CCl)c1ccsc1S(N)(=O)=O
Reaction time: 12 h
Yield: 60.9 %

Procedure:
1.5 g (0.0044 mole) of N-t-butyl-3-(1-acetoxy-2-chloroethyl)-2-thiophenesulfonamide synthesized in Example 7 was dissolved in 5 ml of trifluoroacetic acid. The reaction solution was stirred at normal temperature for 12 hours and then concentrated under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed with aqueous sodium bicarbanate solution. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated. The residue was subjected to column chromatograpy on silica gel to obtain 760 mg (Yield: 72%) of the pure title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:34][N:35]([CH:37](OC)OC)[CH3:36].CN(C)C=O>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2](/[N:1]=[CH:34]/[N:35]([CH3:37])[CH3:36])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(/N=C/N(C)C)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (500 mg), N,N-dimethylformamidedimethylacetal (155 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and 3-(4-(4-chlorophenyl)-2-{(E)-[(dimethylamino)methylidene]amino}-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (510 mg, yield: 92%) from a fraction eluted with 5% methanol-ethyl acetate. Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 150–151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(Cl)(Cl)Cl.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:17][CH2:18][CH2:19][Cl:20])[C:6]2=[O:15]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: ClCCCBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncn(CCCCl)c(=O)c2cc1OC

Procedure:
1-(6,7-Dimethoxy-4-(3H)-quinazolinone-3-yl)-3-chloro-propane was prepared analogous to Example 1 (a) by reaction of 6,7-dimethoxy-4(3H)-quinazolinone with 1-bromo-3-chloro-propane in dimethyl-formamide. Rf -value (chloroform/methanol = 19/1) : 0.75.
Reaction SMILES: CC(OC([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]=[N:9]1)=O)(C)C.[ClH:16].CCOCC>O1CCCC1>[ClH:16].[NH:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1N=CC[C@H]1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC=NN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a 2000 ml round bottom flask was added (5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (34 g, 159 mmol) in tetrahydrofuran (THF) (600 mL), followed by HCl (397 mL, 1587 mmol) (4 M in dioxane). The mixture was stirred at room temperature for 18 hours, and then ether (600 mL) was added. After stirring for 5 min, the mixture was allowed to stand for 10 min and then the organic solvents were decanted. The solid was collected by filtration and dried under high vacuum to provide (5S)-4,5-dihydro-1H-pyrazole-5-carboxylic acid, hydrochloride (22.4 g, 149 mmol, 94% yield) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4): δ ppm 3.40-3.66 (m, 2H) 4.75-4.84 (m, 1H) 8.05-8.13 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:14][CH2:15][C:16](=O)[CH2:17]Cl>>[Cl:14][CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[O:7][CH:17]=1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(CCl)CCl
Product: FC(F)(F)c1cccc(-c2nc(CCl)co2)c1
Temperature: 130 °C
Yield: 67.3 %

Procedure:
3-(Trifluoromethyl)benzamide (0.300 g, 1.59 mmol) and 1,3-dichloro-2-propanone (0.201 g, 1.59 mmol) were heated to 130° C. for 0.5 h. Then another 0.201 g of 1,3-dichloro-2-propanone (1.59 mmol) was added and the mixture was heated again at 130° C. for 1 h. After being cooled down, the residue was purified by radial chromatography (0-30% EtOAc-hexanes gradient) to afford the title compound (0.280 g, 67% yield): 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.58 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][N:17]=1>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:12]2[C:13]3[C:20]([C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Reactant: Nc1cccc(CCO)c1
Product: O=C(c1ccccc1)c1c[nH]c2ncnc(Nc3cccc(CCO)c3)c12

Procedure:
(4-((3-(2-Hydroxyethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized using 2-(3-aminophenyl)ethanol and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone according to the general procedure A. A white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.25 (s, 1H), 8.42 (s, 1H), 7.90-7.81 (m, 4H), 7.65-7.55 (m, 4H), 7.26 (m, 1H), 6.90 (d, J=7.2 Hz, 1H), 4.63 (s, 1H), 3.61-3.60 (m, 2H), 2.74-2.70 (m, 2H); LCMS [M+H] 359.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2N=C(C(Cl)(Cl)Cl)O[N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#[N:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2noc(C(Cl)(Cl)Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1

Procedure:
[1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (500 mg, 1.25 mmol) and 30% aqueous trifluoro-acetic acid (5 ml) were stirred for 24 hours at room temperature. The mixture was evaporated and lyophilised. The product contains excess of trifluoro-acetic acid.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)(C(C)(C)C)(C)C.[Si:33]([O:40][C@@H:41]1[C@@H:46]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:45][CH2:44][N:43]([C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[CH2:42]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C12OC1CCN(C(OCC1C=CC=CC=1)=O)C2.CCO.O>C([O-])([O-])=O.[K+].[K+]>[OH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1.[Si:33]([O:40][C@@H:41]1[C@@H:46]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:45][CH2:44][N:43]([C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])[CH2:42]1)([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)O[C@H]1CCN(C(=O)OCc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](O)C1
Temperature: 25 °C

Procedure:
benzyl (3R,4R)-3,4-bis((tert-butyl(dimethyl)silyl)oxy)-1-piperidinecarboxylate and benzyl (3S,4S)-3,4-bis((tert-butyl(dimethyl)silyl)oxy)-1-piperidinecarboxylate (1/1). Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.00 g, 21.44 mmol, Bioorg. Med. Chem. Lett. 2007, 17, 1254) in 5% K2CO3 in 1/1 EtOH/H2O (214 mL) was heated at reflux for 3 h. After cooling to RT, the mixture was concentrated. EtOH (300 mL) was added to the liquid and removed in vacuo. The resulting solid was extracted with CHCl3 (2×250 mL). The combined CHCl3 fractions were dried over anh. Na2SO4, filtered and concentrated to give benzyl (3R,4R)-3,4-dihydroxy-1-piperidinecarboxylate and benzyl (3S,4S)-3,4-dihydroxy-1-piperidinecarboxylate (1/1) (5.98 g) as a light yellow syrup. MS (ESI, pos. ion) m/z: 252.1 [M+H]. A heterogenous mixture of benzyl (3R,4R)-3,4-dihydroxy-1-piperidinecarboxylate and benzyl (3S,4S)-3,4-dihydroxy-1-piperidinecarboxylate (1/1) (5.98 g, 23.80 mmol), tert-butyldimethylchlorosilane (10.76 g, 71.4 mmol) and imidazole (7.85 mL, 119 mmol) in DMF (24 mL) was stirred at RT overnight. H2O (300 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined organic layers were washed with H2O (300 mL) followed by brine (200 mL) and dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide benzyl (3R,4R)-3,4-bis((tert-butyl(dimethyl)silyl)oxy)-1-piperidinecarboxylate and benzyl (3S,4S)-3,4-bis((tert-butyl(dimethyl)silyl)oxy)-1-piperidinecarboxylate (1/1) (6.37 g, 13.28 mmol, 62% yield over two steps) as a clear, colorless oil. MS (ESI, pos. ion) m/z: 480.1 [M+H].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][N:4]=1.C[O-].[Na+].[Na].[N:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][C:32](OCC)=[O:33])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CO>[O:33]=[C:32]1[N:4]2[CH2:5][CH2:6][CH2:7][CH:8]([N:9]3[C:10](=[O:19])[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]3=[O:18])[C:3]2=[N:2][C:30]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:31]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCCC1N1C(=O)c2ccccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C1CCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a suspension of 9.166 g (32.77 mmol) of (+/−) 2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) in 50 mL of toluene was added sodium methanolate (freshly prepared from 0.754 g (32.77 mmol) of sodium in 10 mL of methanol and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, dissolved in 50 mL of toluene and 4.87 g (25.21 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate was added. The resulting solution was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/310.3 led to afford 3.2 g (34%) of the desired compound as a white powder.