Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ccccn2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.24 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)-2H-pyridazin-3-one and 3 g phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 0.25 g 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2-pyridyl)pyridazine (hereinafter, described as compound (1) of the present invention.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(CCC(=O)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12](CC2C=CC(Cl)=CC=2C2C=CC=C(F)C=2)[N:11]2[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.S(=O)(=O)(O)O>C(O)(=O)C>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[CH:12][N:11]2[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]=12
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccc(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CCn2cnc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(5-chloro-3′-fluoro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (383) (60 mg, 0.113 mmol) in acetic acid (1 mL), concentrated sulfuric acid (0.001 mL, 0.023 mmol) was added. The reaction mixture was stirred for 4 h, at room temperature (monitored by LC-MS). Volatiles were removed from the reaction and the residue was quenched with ice cold water (5 mL). Aqueous saturated NaHCO3 was added to adjust the pH to 8. The quenched mass was extracted with ethyl acetate (2×15 mL) and the combined organic part was dried, concentrated and purified by preparative HPLC to get 6-(5-chloro-3% fluoro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (384) (20.0 mg, 40.06%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34](OC)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (6.09 g, 54.4 mmol) in dry THF (100 mL) was added a 2M solution of isopropylmagnesium chloride (27.2 mL, 54.4 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13.5 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (200 mL). The product was extracted with EtOAc (2×80 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a solid residue which was purified by column chromatography on silica gel using 2-2.5% MeOH-DCM system as eluent to afford 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (2.85 g, 47% yield) as the racemate. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.56-0.72 (m, 2H), 0.82-0.94 (m, 2H), 1.70-1.82 (m, 1H), 2.00-2.20 (m, 4H), 2.21-2.38 (m, 2H), 2.70-2.77 (m, 2H), 2.78-2.82 (m, 2H), 3.58-3.78 (m, 1H), 3.79-3.81 (m, 1H), 4.70 (dd, 1H), 6.25 (s, 1H), 6.98 (dd, 1H), 7.95 (s, 1H), 8.18 (s, 1H). Separation by chiral HPLC provided enantiomers 2a and 2b.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:28]2[CH2:27][CH2:26][CH:25]([O:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Clc1ccc(CCOC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCC(OCCc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 71.4 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.076 g, 0.350 mmol) and 4-[2-(4-chlorophenyl)ethoxy]-piperidine (0.080 g, 0.334 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-{4-[2-(4-chlorophenyl)ethoxy]-piperidin-1-yl}-2-methyl-propan-2-ol (0.109 g, yield 71%) as a light yellow oil in the same manner as in Example 254.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N+:16]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1O)([O-:18])=[O:17].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to a solution of 2-nitro-4-tert-butyl phenol (4.00 g, 20.5 mmol) and pyridine (2.16 mL, 26.7 mmol) in CH2Cl2 (50 mL) at 0° C. The yellow solution was stirred 0.25 h at 0° C., poured onto saturated NaHCO3 and extracted with CH2Cl2. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. The residue was purified by filtration through a plug of silica-gel (methylene chloride) to provide trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (5.82 g, 87%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=3)[O:30][N:29]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(C(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
A mixture of 2,4-bis(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.18 mmol), Cs2CO3 (0.064 g, 0.20 mmoL), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.052 g, 0.20 mmoL) and CH3CN (4 mL) was stirred at 75° C. for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.056 g, 62%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=8.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H) 8.23 (s, 1H), 8.09-8.06 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 6.03 (s, 2H); MS m/z 527 (M+Na).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=O)[CH2:6][C:7]#[N:8].C(C1C=C(N)[O:17][N:16]=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:5]1[CH:6]=[C:7]([NH2:8])[O:17][N:16]=1)([CH3:11])[CH3:10]
Reactant: COCC(C)(C)C(=O)CC#N
Reactant: CC(C)c1cc(N)on1
Product: COCC(C)(C)c1cc(N)on1
Yield: 69 %

Procedure:
Prepared from 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as a orange oil (380 mg, 69%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.08 (s, 1H), 4.41 (brs, 2H), 3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[CH2:9][CH2:10][O:11][C:12]2[C:13]([OH:25])=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:4][CH:3]=1.CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:26])[CH2:9][CH2:10][O:11][C:12]2[C:13]([O:25][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccccn1
Reactant: COc1c(C)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(C)c(C)c(C(C)=O)c(OCCc2ccccn2)c1OCCC(C)c1ccc(F)cc1
Yield: 43 %

Procedure:
Example 4e (100 mg, 0.28 mmol) was reacted with 2-pyridin-2-ylethyl methanesulfonate (1.6 eq.) as described under General Procedure F to give the title compound (56 mg, 43%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=4.2 Hz, 1H), 7.57 (dt, J=7.7, 1.8 Hz, 1H), 7.19-7.09 (m, 4H), 6.96-6.91 (m, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.83 (t, J=6.6 Hz, 2H), 3.73 (s, 3H), 3.11 (6.6 Hz, 2H), 2.99-2.92 (m, 1H), 2.26 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.95-1.88 (m, 2H), 1.25 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([CH:18]([CH3:20])[CH3:19])([OH:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C:13]1([CH:18]([CH3:20])[CH3:19])[O:17][C:29](=[O:31])[N:10]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:15]=[CH2:16]
Reactant: C=CCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg, 2.366 mmol) and triethylamine (139 mg, 2.366 mmol) in CH2Cl2 (20 mL) was added triphosgene (348 mg, 1.18 mmol) at 0° C. under N2, and the mixture was stirred at rt overnight. The reaction mixture was quenched with water, and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (480 mg, 56% yield),
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:23][CH3:24].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OCCBr
Product: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-(2-bromoethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.25 g) and morpholine (4 ml) was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether to give 6-methoxy-4-(3'-methylanilino)-7-(2-morpholinoethoxy)quinazoline (0.198 g), m.p. 168°-170° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: O=C(CCCCCl)c1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(=O)CC2)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A mixture of 6-hydroxy-1-indanone (250 g, 1687 mmol) (634549, commercially available from Sigma-Aldrich, St. Louis, Mo., USA), t-butyldiphenylchlorosilane (487 g, 1772 mmol) and imidazole (138 g, 2025 mmol) in degassed DMF (900 mL) was heated at 60° C. for 16 hours. The mixture was then concentrated to remove most of DMF, diluted with ether (3000 mL), filtered, and concentrated to give the initial product H1.1 (674 g, 100% yield) which was used in the next step reaction without further purification. MS ESI (pos.) M/E: 409 (M+Na).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH2:6]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:22]=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>C(Cl)(Cl)Cl>[CH2:6]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[S:5][CH2:1][CH2:2][CH2:3][S:4]2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Reactant: SCCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOc1ccc(C2SCCCS2)cc1OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
1,3-propanedithiol (4.7 mL, 46.8 mmol) was added to a solution of 3,4-bis(dodecyloxy)benzaldehyde (20.0 g, 42.1 mmol) in 100 mL of chloroform. The reaction mixture was stirred at room temperature for 2 h. Concentrated hydrochloric acid (1.5 mL) was added to the mixture and the mixture was stirred at room temperature for additional 2 h. The mixture was washed with water and a saturated aqueous NaCl solution several times. The organic phase was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the product was further dried under vacuum at 47° C. overnight to give an off-white solid (22.7 g, 95%). mp 73-75° C. 1H NMR (200 MHz, CDCl3, δ): 6.91-7.00 (m, 2H), 6.78 (d, J=7.8 Hz, 1H), 5.08 (s, 1H), 3.96 (q, J=6.2 Hz, 4H), 2.80-3.12 (m, 4H), 1.89-2.21 (m, 2H), 1.78 (m, 4H), 1.42 (m, 4H), 1.24 (s, 32H), 0.86 (t, J=6.2 Hz, 6H). 13C{1H} NMR (50 MHz, CDCl3, δ): 149.12, 131.56, 120.02, 113.52, 113.14, 69.12, 51.19, 32.15, 31.86, 29.57, 29.36, 29.30, 29.20, 25.97, 25.04, 22.63, 14.05. IR (cm−1): 2916, 2847, 1586, 1517, 1466, 1269, 1137. HRMS-FAB (m/z): [M+H]+ calcd for C34H61O2S2, 565.4113; found, 565.4087. Anal. Calcd for C34H60O2S2: C, 72.28; H, 10.70. Found: C, 72.47; H, 10.78.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1N1CCCC1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(C1C=C(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2OCCCC=O)C=CC=1[N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1)(C)(C)C>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])([N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:20][CH:19]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:33]=3)[CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCC=O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2=CCC(OCCCC=O)(N3CCCC3)C(c3cccc(C(C)(C)C)c3)=C2)cc1
Yield: 78 %

Procedure:
In a manner similar to that of Example 30a, by reacting 900 mg of ethyl 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 18e with 0.3 mL of oxalyl chloride, 0.54 mL of DMSO and 0.25 mL of triethylamine, 700 mg of ethyl 3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=78%) in the form of a yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C:19]2([CH2:21][CH2:20]2)[C@@H:18]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:29])[C@@H:12]2[O:13]C(C)(C)[O:15][C@H:11]12)(C(C)(C)C)(C)C>C(O)(C(F)(F)F)=O.O>[OH:13][C@@H:12]1[C@H:11]([OH:15])[C@@H:10]([CH2:9][OH:8])[C:19]2([CH2:21][CH2:20]2)[C@H:18]1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]1=[O:29]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)C1(CC1)[C@H]2n1ccc(=O)[nH]c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccn([C@H]2[C@H](O)[C@H](O)[C@@H](CO)C23CC3)c(=O)[nH]1
Temperature: 50 °C
Yield: 79.3 %

Procedure:
Compound 16 (0.2 g, 0.47 mmol) was dissolved in 20 mL of CF3COOH/H2O (2:1, v/v) and heated to 50° C. for 3 hr. The solvent was removed under vacuum and the residue was co-evaporated with ethanol (10 mL×3) under vacuum. The residue was purified by column chromatography on a silica gel (7% MeOH/CH2Cl2) to give 17 (100 mg, 79%) as white foam. mp 114-116° C.; [α]24D 9.84° (c 0.26, MeOH); UV(MeOH) λmax 265 nm (ε 11713, pH 2), 265 nm (ε 11887, pH 7), 264 nm (ε 9153, pH 11); 1H NMR (500 MHz, CD3OD-d6) δ 7.50 (d, J=8.5 Hz, 1H), 5.68 (d, J=8.5 Hz, 1 H), 4.77-4.73 (m, 2 H), 4.62 (d, J=3 Hz, 1 H), 3.71 (dd, J=4.5 & 11.0 Hz, 1 H), 3.62 (dd, J=5 & 11.0 Hz, 1 H), 2.26 (m, 1 H), 0.87 (m, 2H), 0.81 (m, 1H), 0.33 (m, 1H); 13C NMR (125 MHz, CD3OD) δ 165.1, 152.2, 146.3, 109.9, 74.3, 72.4, 63.4, 51.1, 29.8, 28.7, 10.9; HR-MS Calcd. For (C12H16N2O5+H)+ 269.1059, found 269.1261.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:17][C:11]1[CH:10]=[C:9]2[C:14]([N:15]=[CH:16][C:7]([NH2:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2cnc3ccc(C)cc3n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ncc(N)nc2c1
Yield: 85.1 %

Procedure:
N-(2,4-Dimethoxybenzyl)-7-methylquinoxalin-2-amine (0.85 g, 2.75 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous NaHCO3 (200 mL) was added to the red residue, which then precipitated a pink solid. The mixture was extracted extensively with DCM. The organic layer was dried over sodium sulfate, concentrated, and dried under vacuum to afford 7-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (640 mg, 2.34 mmol, 85% yield).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:17][C:18](=[O:29])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[C:33]([F:39])[CH:32]=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[CH:19]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][C:33]=1[F:39])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a stirred solution of diisopropyl amine (1.3 mL, 9.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M solution in hexanes, 5.6 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then cooled to −78° C. A solution of 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 2 hours. A solution of 4-Bromo-1-bromomethyl-2-fluoro-benzene (1.3 g, 4.9 mmol) in THF (4 mL) was added dropwise. After completion, the dry-ice bath was removed and the reaction was warmed to 0° C. in an ice bath. After stirring at 0° C. for 30 minutes, the reaction was poured into saturated NH4Cl aqueous solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 20:1 to 5:1) to give 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.35 g, 77%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, J=8.0 Hz, 2H), 7.08 (t, J=8.0 Hz, 1H), 4.86 (m, 1H), 3.28 (m, 2H), 2.92 (m, 3H), 1.43 (s, 9H), 1.36 (s, 9H).