Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCCl
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 14.7 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.0 g, 4.9 mmol), 2-(2-chloro-ethyl)-1-methyl-pyrrolidine (722 mg, 3.90 mmol), DMF (20 ml) and K2CO3 (2.71 g, 19.60 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. and purified by prep TLC, eluting with DCM:MeOH:NH3 (95:5:3), to provide the title compound (180 mg, 15%) as a yellow oil. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.12-4.03 (m, 4H), 3.89 (td, 2H), 3.08 (m, 1H), 2.35 (s, 3H), 2.29-1.94 (m, 8H), 1.85-1.65 (m, 2H), 1.62-1.50 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:15]C.[Mg].Br[CH2:30]CBr>O1CCCC1>[CH3:30][CH:14]1[CH2:15][C:4]2[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:2][C:3]=2[O:13]1
Reactant: CCC(Oc1ccc(OC(F)(F)F)cc1I)OS(=O)(=O)c1ccc(C)cc1
Reactant: BrCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1Cc2cc(OC(F)(F)F)ccc2O1
Temperature: 25 °C
Yield: 36 %

Procedure:
10 ml solution of (2-iodo-4-trifluoromethoxyphenyloxy)-1-p-toluenesulphonyloxypropane (Description 20; 16 g, 28 mmol) in tetrahydrofuran (50 ml) was added dropwise to a stirred mixture of magnesium turnings (5 g, 208 mmol) in tetrahydrofuran (20 ml). 1,2-Dibromoethane (0.1 ml) was added. The exotermic reaction started. The mixture was warm up to reflux and the rest of (2-iodo-4-trifluoromethoxyphenyloxy)-1-p-toluenesulphonyloxypropane solution was added dropwise. The reaction mixture was heated at reflux for 24 hours, then cooled to room temperature and quenched with 2M aqueous hydrochloric acid. The mixture was extracted with a 1:1 mixture iso-hexane:diethyl ether (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-15%) to give the title compound (2.8 g, 36%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24]C)[C:18]=3[C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=3[C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:16]2)[CH2:11][CH2:10]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2cn([C@H]3CC[C@H](O)CC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-(trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)benzenesulfonamide (10.0 mg) in acetonitrile (1 mL) were added sodium iodide (7.3 mg) and chloro(trimethyl)silane (0.025 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (5.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: COc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCOCC2)ccc1N
Yield: 87.6 %

Procedure:
A mixture of 4-[2-(3-methoxy-4-nitrophenoxy)ethyl]morpholine (1.2 g, 4.3 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 0.95 g of the product as a light grey oil, in 87% yield: 1H NMR (CDCl3) δ 2.57 (t, J=4.6 Hz, 4H), 2.77 (t, J=5.7 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.82 (s, 3H), 4.05 (t, J=5.7 Hz, 2H), 6.34 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4C(F)(F)F)noc3C)CC2)c1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a gel-like required compound (602 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12](Cl)=[O:13].Cl>O>[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(C)(C)OO
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C
Yield: 98.2 %

Procedure:
Before the start of the reaction, the loop reactor is filled with a solution of 25.7% by weight of tert-butyl hydroperoxide and 15.0% by weight of potassium hydroxide in water. Initially 20.2 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 18.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 16.2 kg/h of water and 19.2 kg/h of 3,5,5-trimethylhexanoyl chloride are then fed to the loop reactor. Cooling with cooling water keeps the internal temperature at 25° C. in the loop reactor and in the stirred cell reactor. The partial neutralization is effected with 27.6 kg/h of 4% by weight hydrochloric acid at a temperature of 15° C. The organic phase is extracted with 23.6 kg/h of a 20% by weight aqueous solution of potassium hydroxide. This affords 26.2 kg/h of aqueous extract comprising 9.6% by weight of tert-butyl hydroperoxide and 18.0% by weight of potassium hydroxide, which are feeded into the loop reactor. From the time at which aqueous extract is recycled into the loop reactor, the metered addition of the feedstocks is changed to 16.6 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 7.8 kg/h of a solution of 45% by weight of potassium hydroxide in water and 4.8 kg/h of water. After the extraction, the organic phase is washed with 33.8 kg/h of a solution of 3% by weight of sodium sulphite and 1% by weight of sulphuric acid, and dried by stripping at 34° C. and 47 mbar. 24.6 kg/h of tert-butyl peroxy-3,5,5-trimethylhexanoate with a purity of 99.9% are obtained (98.2% yield based on 3,5,5-trimethylhexanoyl chloride).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[CH2:6][C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:4]1[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][S:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 798.4 %

Procedure:
To a stirred solution of 2-mercaptoethanol (7.8 g.) and ethyl 2-(2-chloroacetyl)-2-methoxyiminoacetate (2.08 g.) in dry chloroform (200 ml.) was added a solution of triethylamine (11 g.) in dry chloroform (30 ml.) at 20° C., and stirred at the same temperature for 3 hours. The resultant solution was washed with 10% hydrochloric acid twice, a saturated aqueous solution of sodium hydroxide twice and water twice in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C., and the residue was dissolved in dry toluene (200 ml.). After adding p-toluenesulfonic acid (3 g.) to the solution, the solution was heated under reflux for 30 minutes while removing the produced water. The resultant solution was allowed to cool at room temperature and treated with activated charcoal, and then ethyl acetate (150 ml.) was added thereto. The solution was washed with a saturated aqueous solution of sodium bicarbonate and water twice in turn dried over magnesium sulfate, and then concentrated in vacuo at 40° C. to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (mixture of syn isomer and anti isomer, 18.5 g.), yellow oil.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH:18]([C:23](C(OCC)=O)=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-:40].[Na+].Cl>CO>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH:18]([C:23]([OH:24])=[O:40])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [OH-]
Reactant: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-DL-Nle-CO2Et (1.0 eq), as prepared in Example 5, in methanol at R.T. is added 1 N NaOH (1.1 eq). The mixture is stirred for 6 h. The reaction mixture is cooled to 0° C., acidified with 1 N HCl (pH=3) and extracted with EA. The organic extracts are washed with water, dried (MgSO4), filtered and concentrated to give a crude residue. Trituration with hexane and drying in vacuo gives the title compound, N-Cbz-L-Leu-L-Leu-DL-Nle-CO2H.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(CC(O)c2cccnc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)=Cc1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
Ethyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]-α-methylcinnamate (1.84 g) was dissolved in 60 ml of acetone, followed by dropwise addition of 2.27 g of 2.67M Jones Reagent, and stirred for 30 minutes. After addition of 2 ml of isopropanol, the resulting mixture was concentrated under reduced pressure, followed by addition of water for extraction with ethyl acetate. The organic phase was washed in saturated aqueous sodium and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with chloroform-methanol(98:2 v/v) was obtained 0.77 g of ethyl 4-[2-oxo-2-(3-pyridyl)ethyl]-α-methylcinnamate.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[C:12](=S)[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>C(O)CCC>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH:23][C:12]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:18][C:7]=2[NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[N:11]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1NC2=S
Reactant: COC(CN)OC
Solvent: CCCCO
Product: COC(CNC1=Nc2ccccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 4, 3-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[CH:16]=[N+:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:16]([C:15]1[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=1[O:13][CH3:12])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: c1coc(-n2cccc2)c1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccco1)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-furan-2-yl-1H-pyrrole and 1-(2-methoxy-benzylidene)-piperidinium chloride.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][O:9][C:8]1[C:3]2=[C:4]([O:27]C(C)C)[CH:5]=[C:6]([O:23]C(C)C)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:20])[CH3:21])[C@H:11]1[CH2:10][O:9][C:8]1[C:3]2=[C:4]([OH:27])[CH:5]=[C:6]([OH:23])[CH:7]=1
Reactant: CC(C)Oc1cc2c(c(OC(C)C)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC[C@]2(C)[C@H]3COc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1R,10R,11S,16S)-1,11,15,15-tetramethyl-3,5-bis(propan-2-yloxy)-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 49) (0.20 g, 0.48 mmol) in CH2Cl2 (10 mL), cooled to 0° C., a 1 M BBr3 solution in CH2Cl2 (1.8 mL, 1.8 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 5 h. The reaction was quenched with MeOH (10 mL) and concentrated. This quench/concentration step was repeated 5 times. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 50) (0.08 g, 50%) as a tan solid. 1H NMR (CDCl3): δ 5.85 (d, 1H), 5.75 (d, 1H), 4.62 (s, 1H), 4.42 (s, 1H), 4.25 (m, 1H), 3.97 (t, 1H), 3.00 (m, 1H), 1.75-1.40 (m, 7H), 1.38 (s, 3H), 1.23-1.00 (m, 2H), 0.98-0.80 (m, 5H), 0.78 (s, 3H), 0.73 (s, 3H). MS m/z 331 (C21H30O3+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C1COCC1>[Cl:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)=[O:37]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.21 g (0.6 mmol) [6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine and 94 μl (0.67 mmol) triethylamine in 5 ml dry THF is treated dropwise with a solution of chloro-acetyl chloride (51 μl, 0.64 mmol) in 0.5 ml of dry THF at RT. After stirring for 30 min small amounts of insoluble material is removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography using ethyl acetate/methanol 100:2 to 100:4 as eluent. The title compound is obtained as light brown solid; HPLC tR=9.36 min; MS-ES+: (M+H)+=420.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:39][Si](CC)(CC)CC)[CH2:16][NH:17][C@H:18]([CH3:38])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:11][C:10]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:39])[CH2:16][NH:17][C@H:18]([CH3:38])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:11][C:10]=1[NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC[C@H](O[Si](CC)(CC)CC)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC[C@H](O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)cc1

Procedure:
Ethyl 4′-{(R)-2-[(R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-triethylsilanyloxyethylamino]propyloxy}biphenyl-4-carboxylate was dissolved in tetrahydrofuran (5.70 mL), and a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.63 mL) was added dropwise to the solution at room temperature with stirring. After being stirred at that temperature for 13 hrs, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride/ethyl acetate=1/1 and methylene chloride/methanol=10/1) to afford the title compound (0.284 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[CH:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)cc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)cc(C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyridine (24-4, 620 mg, 2.69 mmol) in toluene (12 mL) was added at reflux a solution of ethyl diazoacetate (614 mg, 5.38 mmol) in toluene (2 mL) in three portions over 10 minutes. The reaction mixture was refluxed for 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to afford ethyl trans-2-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-2-yl)cyclopropanecarboxylate (24-5) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.17 (d, 1H, J=1.7 Hz), 7.09 (d, 1H, J=1.7 Hz), 4.17 (q, 2H, J=7.2 Hz), 2.63-2.57 (m, 1H), 2.59 (s, 3H), 2.52 (s, 3H), 2.41 (s, 3H), 2.33-2.27 (m, 1H), 1.70-1.57 (m, 2H), 1.28 (d, 3H, J=7.2 Hz). LRMS m/z (M+H) 301 found, 301 required.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 2.5 °C

Procedure:
In a 1.0 L 4-necked RB flask fitted with a mechanical stirrer and a reflux condenser and under a nitrogen blanket, 1-tert-butyl(2S,4R) 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (100 gm) and dichloromethane (1000 ml) were added at a temperature 25-35° C. while stirring. The reaction mixture was cooled to 0-5° C. and triethyl amine (18.2 g, 0.180M) was added. The reaction temperature was maintained for 15 min and then methane sulfonyl chloride (16.6 g, 0.145M) was added dropwise at 0-5° C. while stirring. The reaction mixture was maintained for 3-4 hr at 0-5° C. The reaction was monitored by TLC. After ascertaining the completion of the reaction, water (168 ml) was added while stirring and the layers were separated. One more dichloromethane (600 ml) extraction was given to aqueous layer. Two water washings were given to the MDC layer. The dichloromethane layer was dried over anhydrous sodium sulphate. The MDC layer (95%) was concentrated under vacuum below 45° C. After distillation n-hexane (600 ml) was added and the mixture stirred for 20 min at 0-5° C. The solid precipitate was filtered and the product was washed with hexane (200 ml). The product was dried at 40-45° C. under vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.CCOCC>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]=1[C:21]1[N:25]([CH3:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]=1
Reactant: Cn1c(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)nc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(-c2cc(N3CCNCC3)ccc2F)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-Fluoro-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.86 g, 1.71 mmol) in DCM (2.0 mL) 2.0 M HCl in Et2O (10 mL) was added and the resulting suspension was stirred at room temperature overnight. The precipitate was filtered off and tritured with Et2O (3×15 mL) to afford the title compound (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>>[C:24]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCCCCCC1
Product: CC(C)c1nc(CCOC2=CCCCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 89.7 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclodecene (841 mg, 5 mmol) in the same manner as the example 41 to give the compound 48 (432 mg, 89%). Mp 94-96° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 6.6 Hz, (CH3)2C), 3.13 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, m, (CH3)2CH), 3.52 (3 H, s, NCH3), 4.01 (2 H, t, J 6.2 Hz, OCH2), 4.38(1 H, t, J 8.4 Hz, =CH), 6.80 (2 H, d, J 1.6 Hz, arom-H), 7.10 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3436, 3035, 1660, 1567, 1558, 1471, 1408, 1376, 1237, 1104. Elementary analysis (for C25H34N2Ocl2S) Calcd. : C, 62.36% H, 7.12% N, 5.82% S, 6.66% Cl, 14.73% Found: C, 62.54% H, 7.18% N, 5.69% S, 6.60% Cl, 14.52%