Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.FC(F)(F)S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([N:33]([CH3:44])[CH:34]3[CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]3)=[N:31][N:32]=2)=[C:24]([O:45][CH3:46])[CH:23]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:46][O:45][C:24]1[CH:23]=[C:22]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[S:29][C:30]([N:33]([CH3:44])[CH:34]2[CH2:39][C:38]([CH3:40])([CH3:41])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)=[N:31][N:32]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.849 mmol) and 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl trifluoromethanesulfonate (332 mg, 0.653 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (38 mg, 0.033 mmol) followed by a solution of Na2CO3 (208 mg, 1.958 mmol) in water (1 mL). The resulting mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase was separated, dried over MgSO4, and filtered. To the filtrate was added SiliaMetS DMT (541 mg, 0.61 mmol/g, 0.33 mmols) and the resulting suspension stirred at room temperature for 18 hours. The SiliaMetS DMT was removed by vacuum filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to afford the crude product as a pale yellow solid. The crude material was recrystallized from MeOH (3 mL) to afford the title compound as a white solid (0.166 g, 57% yield). LC-MS: Rt 0.86 min; MS m/z 441.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.59, 1.52 Hz, 1H), 4.35 (tt, J=12.38, 3.28 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 2.97 (s, 3H), 1.61 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.26 (s, 1H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.60 min; MS m/z 440.4 [M+H]+ [Method B]. HR-MS: Rt 1.43 min; MS m/z 441.2419 [M+H]+ [Method C].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+]>CN(C)C=O.O>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(Bromomethyl)-1-methoxy-4-nitrobenzene (100.0 mg, 0.34 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (93.0 mg, 0.38 mmol) were combined in dimethylformamide (4 mL) and cooled to 0° C. The reaction was treated with sodium hydride (9.0 mg, 0.38 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 110 mg (71%). 1H-NMR (CDCl3, 500 MHz) δ 8.11 (dd, J=6.1, 3.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.34 (m, 4H), 7.21-7.24 (m, 1H), 6.80 (d, J=8.9 Hz, 1H), 4.37 (s, 2H), 3.85 (s, 3H), 3.74-3.75 (m, 2H), 3.48 (s, 2H), 3.02-3.07 (m, 2H), 2.21-2.24 (m, 2H), 1.87-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 479.16 (MNa)+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH:23]1([C@H:29]2[CH2:35][NH:34][C:33](=O)[C@H:32]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([C@H:29]2[CH2:35][NH:34][C:33](=[S:10])[C@H:32]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=S
Temperature: 90 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
Lawesson's reagent [2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (140 mg, 0.35 mmol) was added to a suspension of tert-butyl [(3R,6S)-6-cyclohexyl-2-oxoazepan-3-yl]carbamate (210 mg, 0.68 mmol) in toluene (8 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/ethyl acetate) gave the title compound (132 mg). MS 327.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Yield: 89.9 %

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 77.4 mmol) in ethanol (400 mL) was added sodium hydroxide (4.02 g, 100.6 mmol), water (11 mL) and the mixture was stirred at reflux condition for 6 h. Ethanol was distilled off and residue was diluted with water, extracted with ethylacetate (40 mL) adjusted aqueous layer to PH-3 with 1N HCl and extracted with ethyl acetate (3×250 mL), finally organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. The crude was washed with pet ether, filtered the solid and dried to afford desired product 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (20.6 g, 89.8%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N:29]1([CH:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([N:3]4[CH2:4][CH2:5][C:6]5([CH2:7][CH2:8][O:9][CH2:10][CH2:11]5)[C:2]4=[O:1])=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N(c2ccc(C3CCC(N4CCCC4)CC3)cc2)CCC12CCOCC2
Temperature: 80 °C

Procedure:
Cis-Methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and pyrrolidine (20 mg, 0.28 mmol, 4 equiv.) were dissolved in anhydrous CH3CN (2 mL). To this colorless solution was added powder K2CO3 at r.t. The suspension was heated in an oil bath maintained at 80° C. for 24 h. The suspension was concentrated to dryness. The residue was taken in water (2 mL) and DCM (2 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 mL×2). The combined DCM extracts were washed with sodium bicarbonate (2 mL), brine (2 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% of MeOH in DCM and 5% 7N NH3 of MeOH solution in DCM to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Clc1cccnc1N1CCNCC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
To a stirred solution of 1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.975 mL, 5.6 mmol) then 4-tert-butylbenzene-1-sulfonyl chloride (372.4 mg, 1.6 mmol). The mixture was stirred at room temperature for 1.5 hour. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine in 59.3% yield (374 mg) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:28]=5)=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5ccc(OC)c(C(F)(F)F)c5)o4)cc32)cc1
Yield: 34 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 34%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>COCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[N:4][CH:3]=[C:2]2[NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: FC(F)(F)c1ccc2nncc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CC(C)(C)OC(=O)CNc1cnnc2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8 mL vial, was placed a solution of 4-chloro-6-(trifluoromethyl)cinnoline (as prepared in the previous step, 260 mg, 1.12 mmol, 1.00 equiv) in 2-methoxyethyl ether (2 mL), tert-butyl 2-aminoacetate (187 mg, 1.12 mmol, 1.10 equiv) and triethylamine (339 mg, 3.36 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 4 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate, and the combined organic layers washed with 2×10 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[CH2:29]>>[N:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:17][CH2:16][CH:15]([NH:14][N:11]3[CH2:12][CH2:13][C@H:9]([NH:8][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH:28]=[CH2:29])=[CH:31][CH:32]=4)(=[O:38])=[O:37])[C:10]3=[O:27])[CH2:20][CH2:19]2)=[CH:26][CH:25]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Product: C=Cc1ccc(S(=O)(=O)N[C@H]2CCN(NC3CCN(c4ccncc4)CC3)C2=O)cc1
Yield: 78.2 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 4-vinylbenzenesulfonyl chloride (105 mg), the title compound (179 mg) was obtained as a colorless amorphous material.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with benzyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-(4-benzyloxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, which was used as the crude product in the reaction for BOC cleavage.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), tetrahydropyran-4-one (27 mg, 0.27 mmol) and AcOH (50 μL) in DCE (2 mL) was allowed to stir at r.t. for 20 min before the addition of sodium triacetoxyborohydride (104 mg, 0.49 mmol). The resulting mixture was allowed to stir for 18 h then partitioned between DCM and H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with MeCN and H2O and the resulting solid dried in vacuo affording 827 (92 mg, 82%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.65-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.40-4.10 (4 H, brd s), 3.91 (2 H, d, J=8.05 Hz), 3.80-3.79 (6 H, m), 3.71 (3 H, s), 3.41 (2 H, d, J=8.07 Hz), 3.28-3.26 (4 H, m), 3.02 (3 H, s), 2.37-2.28 (1 H, m), 1.67-1.63 (2 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.23-1.10 (2 H, m)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1.[CH3:18]OS(OC)(=O)=O.Cl>[OH-].[Na+]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]([OH:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH:11][CH3:18])=[CH:16][CH:17]=1
Reactant: COCOc1ccc(C(O)[C@H](N)C(=O)O)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN[C@H](C(=O)O)C(O)c1ccc(OCOC)cc1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 23.4 %

Procedure:
To a solution of O-methoxymethyl-β-hydroxytyrosine (21.0 g) in 1N-sodium hydroxide (250 ml) was added dimethylsulfate (16.5 g). After stirring for 20 min. at 90° C., the solution was acidified with diluted hydrochloric acid in ice bath. The acidic solution was washed with diethyl ether and adjusted to pH 6.0 with 1N-sodium hydroxide. After evaporation, the solid was collected by filtration to give O-methoxymethyl-N-methyl-β-hydroxytyrosine (5.2 g).
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:11][C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)[CH2:35][C:36]5[CH:43]=[CH:42][C:39]([CH3:40])=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CN(Cc2ccc(C)cc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 175.3 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and stirred at 100° C. for 30 minutes. This solution was added with a solution of 4-methylbenzyl bromide (71.6 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, and stirred for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane:EtOAc=8:1) to obtain the title compound (131 mg).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=O)[CH:28]2[CH:23]([CH2:24][CH:25]=[CH:26][CH2:27]2)[C:22](=[O:29])[O:21]1>>[CH2:1]([N:19]1[C:20](=[O:21])[CH:28]2[CH:23]([CH2:24][CH:25]=[CH:26][CH2:27]2)[C:22]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1OC(=O)C2CC=CCC12
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCN1C(=O)C2CC=CCC2C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Octadecylamine (5.31 g) was added to 4,7,3a,7a-tetrahydroisobenzofuran-1,3-dione (3.00 g). After being stirred for 2 hours at 110° C., the reaction mixture was purified by silica gel column chromatography (silica gel 80 g, chloroform), thereby yielding the entitled compound (7.85 g) as yellow crystals.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(CN)Cc1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 58 %

Procedure:
3-(3-Bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride (1.52 g, 5.45 mmol) was dissolved in anhydrous THF (50 mL). Et3N (1.5 mL, 10.76 mmol) was added slowly to produce a white slurry. Ethyl trifluoroacetate (2 mL, 16.8 mmol) was added and the mixture was stirred at room temp for 15.5 h. Additional ethyl trifluoroacetate (˜0.75 mL, 6.2 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added and the mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The product was taken up in EtOAc and the solution was washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (30) as a yellow oil. Yield (1.84 g, 58% yield for two steps): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.29 (t, J=1.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.05 (dt, J=7.6, 1.6 Hz, 1H), 6.16 (br s, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.53 (s, 2H), 0.93 (s, 6H).
Reaction SMILES: [N:1]#[C:2]Br.[N:4]#[C:5]Br.CC(C)=[O:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>CC(C)=O.O>[O-:9][C:2]#[N:1].[O-:11][C:5]#[N:4].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)([CH3:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: CC(C)=O
Reactant: N#CBr
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: N#C[O-]
Reaction time: 0.33 h

Procedure:
A quantity of 222.45 grams (2.10 moles) of cyanogen bromide was added to a reactor containing 350 milliliters of stirred acetone under a nitrogen atmosphere. The cyanogen bromide-acetone solution was cooled to -5° C., then 228.30 grams (1.00 mole) of Bisphenol A dissolved in 700 milliliters of chilled acetone was added to the reactor. The stirred solution was allowed to equilibrate at -5° C., then 203.39 grams (2.01 moles) of triethylamine was added to the reactor over a 25-minute (1500 s) period and so as to maintain the reaction temperature at -5° to 0° C. After completion of the triethylamine addition, the reaction temperature was maintained at -6° to 7° C. for an additional 45 minutes (2700 s), followed by addition of the reaction product to chilled water (1 gallon, 3.78 liters) with agitation. After 20 minutes (1200 s), the water and product mixture was added to a separatory funnel and the resulting slurry of crystals was filtered. The recovered crystalline product was dissolved in methylene chloride (400 milliliters), washed with 5 percent hydrochloric acid (500 milliliters), washed with water (1000 milliliters) and then dried over anhydrous sodium sulfate. The dry methylene chloride solution was filtered and solvent removed by rotary evaporation under vacuum. Bisphenol A dicyanate (245.3 grams) was recovered in 88.1 percent yield as a light tan colored crystalline solid. Infra-red spectrophotometric analysis confirmed the product structure.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[Br:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2Br)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro -2H-indol-2-one (2 g, 9.48 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)) in concentrated sulfuric acid (20 mL) at −5° C., with stirring. The mixture was stirred for an additional 1 h at −5° C., then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%).