Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[N:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=1)[CH3:2].C([O-])(O)=O.[Na+]>CCO.[Pd]>[CH2:1]([CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Reaction time: 8 h

Procedure:
7-Ethyl-2,3-di-p-tolylpyrido[2,3-b]pyrazine (2 g, 5.89 mmol) in EtOH (5 ml) was treated with Pd/C (0.2 g) and placed under an atmosphere of hydrogen. After stirring overnight the mixture was treated with a catalytic quantity of NaHCO3 and stirring continued under hydrogen overnight. The mixture was passed through Celite® (filter material) and the solvent was removed under reduced pressure. Purification of the crude product by chromatography on silica eluting with 5% EtOAc in hexane afforded the titled compound;
Reaction SMILES: OC[C:3]1(CO)[NH:14][C:13]2[C:15]3[C:9]([CH:10]=[CH:11][CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4]1.C1C=CC=CC=1.[OH-].[Na+].BrCC(OC(C)(C)C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH:4]1[C:5]2=[C:15]3[C:9](=[CH:8][CH:7]=[CH:6]2)[CH:10]=[CH:11][CH:12]=[C:13]3[NH:14][CH2:3]1
Reactant: OCC1(CO)Nc2cccc3cccc(c23)N1
Agent: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccccc1
Product: c1cc2c3c(cccc3c1)NCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 127.3 %

Procedure:
A mixture of 2,2-bis(hydroxymethyl)-2,3-dihydro-1H-perimidine (4.14 g, 18.0 mmol), benzene (45 mL), 50% aqueous sodium hydroxide (37.5 mL), tetrabutylammonium hydrogen sulfate (1.0 g, 2.94 mmol), and t-butyl bromoacetate (5.85 mL, 39.6 mmol) was vigorously stirred at room temperature for 18 hours using a mechanical stirrer. The reaction mixture was diluted with water (150 mL) and then extracted twice with chloroform (150 mL each). The chloroform extracts were combined and washed with brine (100 mL). The chloroform layer was dried using anhydrous magnesium sulfate, filtered, and then concentrated to give a tan solid. The solid was recrystallized with methanol to yield 3.90 g of 1,3-dihydroperimidine derivative I as tan crystals; m.p. 152°-154° C.; 1H NMR (500 Mz; CDCl3): δ 1.46 (s, 18H); 3.70 (s, 4H); 4.01 (s, 5H); 5.20 (s, 2H); 6.51 (δ, 2H, J=7.3 Hz); 7.12 (δ, 2H, J=8.Hz); 7.21 (t, 2H, J=7.8 Hz); 13C{1H} NMR (125 Mz; CDCl3): δ 28.00, 67.09, 69.43, 72.53, 81.75, 105.88, 112.33, 116.87, 126.92, 134.34, 138.74, 169.56.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22][CH2:23]CCCCC(C)(C1C=CC=CC=1)CO.O1C=CCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:23][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CO)(CCCCCBr)c1ccccc1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(CCCCCBr)(COC1CCCCO1)c1ccccc1
Yield: 76 %

Procedure:
According to the method described for the synthesis of 207d, 206h (51.0 g, 179 mmol) was reacted with 3,4-dihydro-2H-pyran (18.80 g, 223 mmol) and p-toluenesulfonic acid hydrate (1.21 g, 6.36 mmol). Filtration through aluminum oxide (370 g) and concentration in vacuo afforded 207h (48.75 g, 76%) as a yellowish oil. 1H NMR (CDCl3): δ 7.35-7.17 (m, 10H), 4.53 (m, 1H), 4.49 (m, 1H), 3.82 (m, 2H), 3.79 (m, 1H), 3.68-3.60 (m, 2H), 3.45-3.35 (m, 2H), 3.32 (t, 4H, J=6.9), 1.82-1.18 (m, 28H), 1.35 (s, 6H). 13C NMR (CDCl3): δ 146.12, 128.11, 126.66, 125.89, 99.18, 99.04, 76.46, 62.02, 61.83, 42.17, 42.07, 38.91, 38.73, 34.12, 32.80, 30.70, 29.04, 25.66, 23.33, 22.97, 22.89, 19.49, 19.39. HRMS (LSIMS, nba): Calcd for C19H30BrO2 (MH+): 369.1429, found: 369.1430.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1cc(F)c(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(C#N)cc1F
Temperature: 60 °C

Procedure:
Methyl 2,4,5-trifluorobenzoate (DSL Chemicals, 950 mg, 5 mmol), sodium cyanide (306 mg, 6.25 mmol) and tetrabutylammonium bromide (2.01 g, 6.25 mmol) were dissolved in DMF (10 mL) and the resulting mixture was heated at 60° C. overnight. Additional amount of sodium cyanide (306 mg, 6.25 mmol) was added and the mixture was stirred at 60° C. for 24 additional hours. The reaction mixture was diluted with EtOAc and washed with brine several times. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography (silica, EtOAc/cHex) to give the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 7.77 (dd, J=8.4, 5.5 Hz, 1H), 7.42 (dd, J=8.9, 5.0 Hz, 1H), 3.96 (s, 3H). LC/MS (Method B): 463.2 (M−H)−, 465.2 (M+H)+. HPLC (Method A) Rt 3.63 min (Purity: 99.9%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC1C=C(Br)C=C(F)C=1)C1C=CC=CC=1.[Mg]>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:4]2([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]2[O:2][CH3:1])[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC1CCCC1=O
Reactant: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Agent: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COC1CCCC1(O)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
After repetition of the above reaction, a solution of 2-methoxycyclopentanone (12.5 g) in tetrahydrofuran (10 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxy-5-fluorobromobenzene (31 g), magnesium powder (2.65 g) and tetrahydrofuran (20 ml) to 40° C. for 2 hours] and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained, as a mixture of diastereoisomers, 1-(3-benzyloxy-5-fluorophenyl)-2-methoxycyclopentanol (21.7 g, 62%), as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([O:12][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of 2-[(tert-butoxycarbonyl)amino]pent-4-enoic acid (20.0 g), potassium carbonate (13.2 g) and N,N-dimethylformamide (100 mL) was stirred for 15 min. The mixture was cooled to 0° C., iodomethane (9.2 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the residue was washed with ethyl acetate. The filtrate was successively washed with 5% hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (21.0 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=O>>[CH:17]1[C:18]2=[C:9]3[C:10](=[CH:11][CH:12]=[C:13]2[CH:14]=[CH:15][CH:16]=1)[N:8]=[C:1]1[C:2]([CH:3]=[CH:4][CH:5]=[CH:6]1)=[N:7]3
Reactant: Nc1ccccc1N
Reactant: O=C1C=Cc2ccccc2C1=O
Product: c1ccc2c(c1)ccc1nc3ccccc3nc12

Procedure:
Benzo(A)phenazine was prepared with 1,2-phenylenediamine and 1,2-naphthoquinone, using standard condensation conditions.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.[CH3:17][C:18]([CH3:20])=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.C(I)C=C>O1CCCC1>[CH2:20]([CH:3]([C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1])[C:4]([OH:6])=[O:5])[CH:18]=[CH2:17]
Reactant: CC(C)=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: C=CCI
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: C=CCC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 64 %

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.50 g, 2.8 mmol, from Reference Example 22) in tetrahydrofuran (5 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 3.1 mL, 6.2 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU, 0.37 mL, 4.2 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Allyl iodide (0.15 mL, 1.3 mmol) is then added neat via syringe and the reaction mixture is allowed to stir overnight while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. Flash chromatography (silica gel, hexane/dichloromethane/ethyl acetate) is performed to give a clear blond oil (0.39 g, 64%). MS (ES−): (M−H)=217.0
Reaction SMILES: [C:1]12([C:11]3[O:15][C:14]([NH:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]5[C:26]=4[CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[N:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[C:1]12([C:11]3[O:15][C:14]([NH:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]5[C:26]=4[CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]5)=[N:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C1CCc2cccc(Nc3ncc(C45CC6CC(CC(C6)C4)C5)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(C45CC6CC(CC(C6)C4)C5)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 12C for the product of Example 1I. 1H NMR (DMSO-d6) δ 8.64 (s, 1H), 7.55 (d, 1H, J=7.7 Hz), 7.05 (t, 1H, J=7.6 Hz), 6.77 (d, 1H, J=7.1 Hz), 6.41 (s, 1H), 4.76 (d, 1H, J=4.1 Hz), 3.90 (m, 1H), 2.72-2.94 (m, 3H), 1.63-2.05 (m, 18H); MS (ESI+) m/z 365 (M+H)+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[P:15]([O-:32])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][C:39]([CH3:48])([CH3:47])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CC1C=CC(S(OCCCOCC2C=CC=CC=2)(=O)=O)=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][P:15]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][C:39]([CH3:48])([CH3:47])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)OCCCOCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)COCCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
DIAD (1.36 mL, 6.97 mmol) was added dropwise to a stirred solution of PPh3 (76 mg, 0.30 mmol), dibenzyl phosphite (1.94 g, 6.97 mmol) and tert-butyl 3-(3-hydroxypropoxy)-2,2-dimethylpropanoate (53) (1.08 g, 4.65 mmol) [prepared using the same procedure as Example F1 steps (ii)-(iii) using 3-(benzyloxy)propyl 4-methylbenzenesulfonate in step (ii)] in THF (100 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 16 h, and the volatiles were removed in vacuo. The crude product was purified by silica gel chromatography (120 g, 0-60% EtOAc in isohexane) to afford tert-butyl 3-(3-((bis(benzyloxy)phosphoryl)oxy)propoxy)-2,2-dimethylpropanoate (54) (1.76 g, 54%) as a clear colourless oil: m/z 515 (M+Na)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.40-7.35 (m, 10H), 5.07-4.96 (m, 4H), 4.04-3.92 (m, 2H), 3.39 (t, J=6.2 Hz, 2H), 3.28 (s, 2H), 1.77 (quin, J=6.2 Hz, 2H), 1.35 (s, 9H), 1.02 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N+:11]([O-])=O)=[CH:4][CH:3]=1.Cl>CC(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 9.4 %

Procedure:
Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A, 0.73 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.06 g of (trans)-2-(4-bromophenyl)cyclopropanamine [white solid. 10% yield].
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:52])[CH2:24][CH2:25][N:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42]CC5C=CC=CC=5)=[C:36]([O:50][CH3:51])[CH:35]=4)=[N:32][CH:33]=3)[CH3:27])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:53][CH3:54])C1C=CC=CC=1.[CH3:55][S:56]([OH:59])(=[O:58])=[O:57]>C(O)(=O)C.[Pd].CO>[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[OH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:52])[CH2:24][CH2:25][N:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[C:36]([O:50][CH3:51])[C:37]([OH:42])=[C:38]([O:40][CH3:41])[CH:39]=4)=[N:32][CH:33]=3)[CH3:27])=[CH:19][N:18]=2)=[CH:11][C:10]=1[O:53][CH3:54]
Reactant: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(OCc5ccccc5)c(OC)c4)nc3)cn2)cc(OC)c1OCc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of N,N′-bis[2-(4-benzyloxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine (64.0 mg, 0.090 mmol) in acetic acid (1.0 mL) was added 10% palladium on charcoal (43.0 mg). Under hydrogen, the mixture was stirred at 50° C. for 1 hour and 30 minutes. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. A solution of the residue in methanolchloroform (1:10) was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in methanol (2.0 mL) was added a 1.0 M aqueous methanesulfonic acid (0.20 mL, 0.20 mmol), and the reaction mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to afford the title compound as a yellow crystalline powder (melting point:≧300.0°) (20.0 mg, yield: 31% based on N,N′-bis[2-(4-benzyloxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][OH:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:23]=[CH:24][N:25]=[C:26]([CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[CH:27]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(CO)ncn3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 0.25 h

Procedure:
5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.1001, 0.232 mmol) is dissolved in THF (6 mL) and TEA (0.18 mL, 1.29 mmol) is added followed by methanesulphonyl chloride (0.028 mL, 0.361 mmol). The solution is stirred for 15 min before being partitioned between ethyl acetate and saturated aqueous sodium chloride. The layers are separated and the organic layer is washed further with water. The organic layer is then removed, dried, and concentrated to obtain the title compound. MS (ESI) m/z 510.0 (m+1).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: OC1CNC1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N2CC(O)C2)C1(C)C

Procedure:
The product from Example 173 and 3-hydroxyazetidine hydrochloride (Oakwood) were processed using the method described in Example 178 to afford the title compound. 1H NMR δ 0.49-0.50 (m, 3H), 0.90 (t, J=7.2 Hz, 3H), 1.22 (s, 6H), 1.24-1.46 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.90-2.03 (m, 1H), 2.62-2.67 (m, 2H), 2.71-2.86 (m, 2H), 3.50-3.61 (m, 1H), 4.23-4.45 (m, 1H), 4.41 (br s, 1H), 3.83-4.09 (m, 2H), 3.50-3.61 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 450 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5]([Br:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[CH2:14]([C:26]1[CH:27]=[C:28]([Sn](C)(C)C)[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>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.C1(C)C=CC=CC=1>[CH2:14]([C:26]1[CH:27]=[C:28]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([Br:11])=[C:4]([Cl:12])[C:3]=2[Cl:13])[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Reactant: Clc1c(Cl)c(Br)c2nsnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(Cl)c(Cl)c(Br)c3nsnc23)c1
Temperature: 105 °C
Reaction time: 48 h
Yield: 41.8 %

Procedure:
4,7-Dibromo-5,6-dichloro-benzo[1,2,5]thiadiazole (0.86 g, 2.37 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (2.26 g, 5.45 mmol), and Pd(PPh3)4 (54.8 mg) were placed in a 100 mL Schlenk flask. The system was subjected to three quick vacuum-nitrogen cycles and 40 mL anhydrous toluene was added. The mixture was heated at 105° C. for 2 days. After 2 days, 1.2 g more of (4-dodecyl-thiophen-2-yl)-trimethyl-stannane and 50 mg more of Pd(PPh3)4 were added, and the reaction mixture was stirred at 105° C. for another 2 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was purified by silica gel column with chloroform/hexane (v/v, 1/1) as the eluent. The final product (530 mg, yield 42%) was obtained as a yellow solid after being dried in vacuo. The compound was used directly in the next step without any further purification and characterization. 1H NMR (CDCl3, 500 MHz): δ 7.47 (d, 1H, J=1.0 Hz), 7.22 (d, 1H, J=1.0 Hz), 2.71 (t, 2H, J=8.0 Hz), 1.70 (m, 2H), 1.26 (m, 18H), 0.89 (t, 3H, 7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([OH:19])[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)s3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1ccc(Cl)s1

Procedure:
Following the same procedure as described in example 1F, [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (740 mg, 1.49 mmol) was treated with HCl in aqueous THF to yield the title compound of 18B as a yellow solid, 469.2 mg (0.97 mmol, 65% yield).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 50 °C
Yield: 115.1 %

Procedure:
Trimethylsilylacetylene (0.70 mL, 4.94 mmol) and triethylamine (2.80 mL, 19.74 mmol) were added to a stirred solution of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 2.468 mmol) in dry dichloromethane (12 mL), then the reaction mixture was degassed with argon for 30 minutes at room temperature. To the reaction mixture were added Pd(PPh3)2Cl2 (0.173 g, 0.25 mmol) and CuI (0.047 g, 0.25 mmol), then the reaction mixture was heated at 50° C. for 14 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and then concentrated in vacuo to yield a crude residue, which was dissolved in dichloromethane (20 mL) and washed with water (2×5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a black colored crude product, which was finally purified using silica gel (100-200 mesh) column chromatography (2:23 ethyl acetate-hexanes to 2:18 ethyl acetate in hexanes) to furnish 1.20 g (80%) of 4-(4-trimethylsilanylethynyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a brown solid. MS cald. for C20H30N2O4SSi [(M+NH4)+] 440, obsd. 440.0.