Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[F-].[Cs+].[CH3:18]I.O>C1COCC1>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:18])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1oc2ccc(O)c(Br)c2c1N
Reactant: CI
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 12F (5.6 g, 0.020 mol) and CsF (9.5 g, 0.0625 mol) in THF (20 mL) was added MeI (2.9 g) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise into water. The solids were precipitated out dissolved in ethyl acetate and purified by column chromatography on silica gel to give 12G (2.4 g, 40.7% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:24]=[CH:23][C:22]=1[CH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([O:42][CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:22]2[CH:23]=[CH:24][C:25]([O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29])=[CH:26][C:21]=2[O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:40][CH2:39]1)(=[O:11])[CH2:9][CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCC1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 16 h

Procedure:
4-Dimethylaminopyridine (catalytic amount), triethylamine (68 μl) and propionyl chloride (42 μl) were added to a stirred solution of [4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol in anhydrous dichloromethane (3 ml) at room temperature under argon. After 16 hr, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:19 v/v) to give the title compound as a yellow oil and a mixture of diastereoisomers (114 mg, 92%); δH (CDCl3) −0.04 (6H, s), 0.02 (6H, s), 0.96 (9H, s), 1.00 (9H, s), 1.08-1.18 (3H, m), 1.20-2.10 (9H, m), 2.24-2.40 (2H, m), 2.76-2.92 (1H, m), 3.94 (0.6H, d), 4.18 (0.4H, d), 6.26 (1H, m), 6.40 (1H, dd), 6.94-6.98 (1H, m).
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH2:16])[CH3:15])[NH:8]1)=[O:6].[C:20]([O:24][C:25]([N:27]([CH3:35])[C@@H:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:19][C:2]([Cl:1])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH:16][C:29](=[O:30])[C@@H:28]([N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH3:35])[CH:32]([CH3:34])[CH3:33])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
A solution of 1d (1.08 g, 2.5 mmol) in dichloromethane (35 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (682 mg, 0.55 mL, 3.1 mmol) was added and the reaction mixture was stirred at 0° C. for 45 min. N,N-diisopropylethylamine (1.29 g, 1.73 mL, 10 mmol) was added and the solvent was evaporated to afford crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol), which was used in the next step. A solution of crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol) in acetonitrile (30 mL) was stirred at 0° C. under nitrogen. (S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (635 mg, 2.75 mmol, obtained from Sigma-Aldrich Inc.) and N,N-diisopropylethylamine (1.29 g, 1.7 mL, 10 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.33 g, 3.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to afford the title compound (756 mg, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.88 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 1.49-1.54 (m, 9H), 1.65-2.30 (m, 5H), 2.82 (s, 3H), 2.82-2.94 (m, 1H), 3.62-4.18 (m, 3H), 4.30-4.45 (m, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.29-5.39 (m, 1H), 6.62-6.77 (m, 1H). LCMS (m/z) 545.2/547.1 [M+H], Tr=3.02 min.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[OH:16])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[O:16]1[C:4]2[CH:5]=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:14]=[CH:15][C:3]=2[CH:1]=[C:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC(C)(C)C)cc2o1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 4-formyl-3-hydroxybenzoate (1.2 g, 5.40 mmol) and potassium carbonate (1726 mg, 12.4 mmol) in DMF (17 ml) was admixed dropwise with ethyl bromoacetate (0.56 ml, 5.0 mmol) and stirred at 80° C. for 6 h. Then ethyl bromoacetate (0.28 ml, 2.5 mmol) was added again and the mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction mixture was added to ice-water and extracted with ethyl acetate. The organic phases were dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([N:15]([CH3:39])[C:16]([N:18]([C@@H:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:22][C@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.C(N(CC)CC)C.[C:49]([Cl:52])(=[O:51])[CH3:50]>C(#N)C.C(OCC)(=O)C>[ClH:52].[C:49]([N:29]1[CH2:30][CH2:31][CH:26]([N:23]2[CH2:24][CH2:25][C@@H:20]([N:18]([CH3:19])[C:16]([N:15]([C:7]3[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:5]([C:4]([F:3])([F:40])[F:41])[CH:6]=3)[CH3:39])=[O:17])[C@H:21]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:22]2)[CH2:27][CH2:28]1)(=[O:51])[CH3:50]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)N(C)[C@@H]1CCN(C2CCNCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N1CCC(N2CC[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of the compound (0.18 g) obtained in Example 81 and triethylamine (0.13 mL) in acetonitrile (6.0 mL) was added acetyl chloride (0.032 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 60→100% ethyl acetate/hexane) and treated with 2N hydrogen chloride/2-propanol to give the title compound (0.15 g, 80%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>[Cu]I.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.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([C:42]#[C:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH3:39])[CH:36]=[N:35]3)[C@@H:31]([OH:40])[C@H:30]2[OH:41])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: C#CCCCC
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCCC#Cc1nc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ncn([C@@H]3C[C@H](n4cc(C)cn4)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BB1) (0.1 g, 0.17 mmol), 1-hexyne (0.42 g, 1.70 mmol), copper (I) iodide (0.008 g, 43 μmol), dichlorobis(triphenylphosphine)palladium(II) (0.031 g, 43 μmol), triphenylphosphine (0.023 g, 86 μmol), diethylamine (1 mL) and DMF (0.5 mL) are placed in a 0.5-2.5 mL microwave vial. The reaction mixture is heated to 120° C. using microwave radiation. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). MS (ES+) m/e 622 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:4]2[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][C:5]=2[OH:9])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(Cc2c(O)cccc2O)cc1
Temperature: 180 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.0 g, 23.4 mmol) and pyridine hydrochloride (21.6 g, 187 mmol) was heated and stirred at 180° C. for 15 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with diluted aqueous hydrochloric acid and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 2-(4-ethylbenzyl)resorcinol (5.2 g, 97%) as a light-brown oil.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)=[O:28])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:10][CH:11]=3)=[CH:25][N:24]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea (605, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0412, 17.9 mg, 24.8%). MS (ESI) [M+H+]+=362.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:27])=[O:28])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Pd]
Product: CCOC(=O)CCc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 91.6 %

Procedure:
Palladium (15.7 mg, 10% on activated carbon) was added to a suspension of 3-{1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl}-acrylic acid ethyl ester [100 mg, Reference Example 37] in industrial methylated spirit (25 mL). The resultant suspension was then stirred under an atmosphere of hydrogen for 16 hours. The reaction mixture was then filtered through a pad of celite and the filtrate evaporated in vacuo. The resultant solid was triturated with water, filtered and dried to give the title compound (92 mg) as a white solid, m.p. 280–282° C. MS: 502 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])[CH3:14]
Reactant: NCCc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In pyridine (33 ml) was dissolved 5.559 g of 3-nitrophenethylamine (Preparation Example 25), followed by dropwise addition of acetyl chloride (2.5 ml) under ice-cooling. After stirring at room temperature for 0.5 hour, the mixture was again ice-cooled. Water was added thereto, followed by extracting with ethyl acetate, The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (6.323 g, 91%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]1[CH2:14][O:13][S:10](=[O:12])(=[O:11])[CH2:9][CH2:8]1>C(O)(C)C>[N:1]1([CH2:14][CH2:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=S1(=O)CCCCO1
Solvent: CC(C)O
Product: O=S(=O)(O)CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
Morpholine (3.56 g) was dissolved in isopropanol (25 ml) and treated with 1,4-butane sultone (5.58 g) at 10° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 days. The white precipitate that had formed was filtered and dried to give the title compound (1.64 g). Mass spec MH+ (found) 224 MH+ (calc) 224.
Reaction SMILES: F[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][NH2:4].[N+:13]([C:16]1[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=1)[C:20](O)=[O:21])([O-:15])=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[F:43][P-](F)(F)(F)(F)F>>[NH2:25][C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[CH:23][C:19]=1[C:20]([NH:4][CH2:3][CH2:2][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[F:43])=[O:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(C(F)CN)cc1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Product: COc1ccc(CCNC(=O)c2ccc([N+](=O)[O-])cc2N)c(F)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2-Fluoro-4-methoxyphenylethylamine ((a): 1 equivalent), 4-nitroanthranilic acid ((b): 1 equivalent), HBTU (1.5 equivalents), and dry THF (0.5 M in (a)) were added to a dry round bottom flask. The mixture was allowed to stir for 10 hours at room temperature. The reaction was then dry loaded onto silica gel and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the product ((c): 2-amino-N-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-nitro-benzamide) as a pure solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:45]=1)=[CH:6][C:7]1[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C([Li])CCC.C(N)(C)(C)C.[C:56]([NH:60][Si:61](C1C2C(=CC3C(CCCCCCCCCCCCCC)(CCCCCCCCCCCCCC)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]>C(OCC)C>[C:56]([NH:60][Si:61]([CH:45]1[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH:3]=[C:2]1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3[Si](C)(C)NC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C([Si](C)(C)NC(C)(C)C)C(C)=C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
In a 250 mL round flask, 2-methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (4.9 g, 8.0 mmol) was dissolved in 100 mL of anhydrous diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (1.6M hexane solution, 5.5 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 100 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (2.9 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 250 mL round flask, and dissolved in 100 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (1.8 g, 24.1 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of n-hexane was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 5.5 g of a mixture of N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (ratio=˜1:1), (yield: 92.7%), as high viscous material.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][CH2:35][C:34]1=[O:41]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:34](=[O:41])[CH2:35][N:36]([CH2:11][C@H:9]([NH:10][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]2[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]2)[C:37]([CH3:40])([CH3:39])[CH2:38]1
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2cc(F)ccc2Cl)C(=O)CN1
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 89.1 %

Procedure:
A solution of 1.15 g of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (3.25 mmol) and 889 mg of 1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (62d) (3.9 mmol) in toluene (32 ml) was stirred at 110° C. for one hour. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=10/1) to obtain 1.77 g of the title compound (yield: 91%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(F)cc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5.8 g of 2,4-difluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a white powder having the following physical properties.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)c1ccco1
Yield: 70.5 %

Procedure:
Ethyl 2-(furan-2-yl)-2-oxoacetate (15.5 g, 92.1 mmol) in ethanol (500 mL) and water (25 mL) at 0° C. was treated with sodium borohydride (1.74 g, 46.05 mmol). The mixture was stirred for 15 minutes, at which point acetic acid (10 mL) was slowly added. After the cessation of gas evolution, water (100 mL) was carefully added, and the reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with brine. The crude product was dried and concentrated to give ethyl 2-(furan-2-yl)-2-hydroxyacetate as a pale brown viscous oil (11.05 g, 71%) which was used without further purification.