Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][C@H:10]([C:19]([O:21][CH3:22])=[O:20])[C@H:9]1[C:23]([O:25]CC1C=CC=CC=1)=[O:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:15]([O:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:23]([OH:25])=[O:24])[C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate (80.0 mg, 0.000182 mol) in 5 mL of MeOH was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filter off the catalyst, the filtration was concentrated to dry and used directly in next step (43 mg, 91.1%). MS (ESI): (M+H)+=260.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2cc(Cl)cc(Cl)n2n1
Agent: Cl
Product: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.00 g; 4.93 mmol; 1.00 eq.) and nicotinoyl chloride hydrochloride (1052.16 mg; 5.91 mmol; 1.20 eq.) as a yellowish solid (1.06 g, 70%). HPLC, Rt 1.61 min. (purity 92.4%). LC/MS, M+(ESI): 307.7, M−(ESI): 305.8.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)=[O:36]>O1CCOCC1.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>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH:35]=[O:36])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(=O)OC(C)(C)C)c2c1
Yield: 53 %

Procedure:
To a solution of methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate in 1,4-dioxane (0.15 M) was added Na2CO3 (6 eq, 2 M solution), (2-formylphenyl)boronic acid (1.5 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq) and the mixture heated at reflux for 45 min. The reaction mixture was allowed to cool and filtered. The filtrate was diluted with EtOAc and the organic phase washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography (1:9 EtOAc/PE) to afford the title compound as a yellow solid (53%); MS (ES+) m/z 476 (M+H)+
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>O1CCCC1.O1CCOCC1>[NH2:10][C:8](=[O:9])[C@@H:7]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=O)[C@@H](NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a solution of L-Phenylglycine amide (670 mg, 5.9 mmol) in tetrahydrofuran (10 mL) and 1,4-dioxane (4 mL) was added 1,3-propanesultone (674 mg, 5.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (743 mg, 50%). 1H NMR (D2O, 500 MHz) δ ppm 7.38 (m, 5H), 4.92, (s, 1H), 3.01 (m, 1H), 2.91 (m, 1H), 2.78 (t, 2H, J=7.3 Hz), 2.0 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.15, 130.95, 130.24, 129.94, 128.74, 63.40, 47.99, 44.92, 21.27. [α]D=−124° (c=0.0041 in water), ES-MS 271 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1.CCN(CC)CC>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)[N:7]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2 mmol) in THF (100 mL) was added a solution of ZnCl2 (1M in ether; 16.2 mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added in small portions, followed by the dropwise addition of Et3N (1.63 g; 16.2 mmol) in 10 mL of THF. The reaction was then stirred at RT overnight. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 2.2 g (50% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (s, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H), 8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min. LRMS (M+) 329.1, 331.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:11]1[N:19]=[CH:18][C:17]2[NH:16][C:15]3[N:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]5)=[CH:26][CH:25]=4)=[CH:23][C:14]=3[C:13]=2[CH:12]=1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:19]=[CH:18][C:17]3[NH:16][C:15]4[N:20]=[CH:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)=[CH:23][C:14]=4[C:13]=3[CH:12]=2)[CH:2]=1
Reactant: OB(O)c1ccccn1
Reactant: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(-c6cccnc6)cc5c4c3)cc2)CC1
Temperature: 140 °C
Yield: 11.2 %

Procedure:
To a mixture of pyridine-2-boronic acid (27 mg, 0.22 mmol), 6-bromo-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (55 mg, 0.11 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9 mg, 0.011 mmol) in acetonitrile (1 mL) and saturated aqueous sodium carbonate solution (1 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM and water and the phases were separated using a hydrophobic fit and the organic phase evaporated. The residue was purified HPLC (C18 column, 50-98% MeCN in water (containing 20 mM triethylamine) over 30 minutes and the fractions containing pure product combined and concentrated then freeze-dried to afford the title compound (6 mg, 11%). 1H NMR (CDCl3 plus CD3OD, 400 MHz): 9.22 (dd, J=2.3, 0.8 Hz, 1H), 9.05 (d, J=1.1 Hz, 1H), 8.86-8.83 (m, 2H), 8.59-8.56 (m, 2H), 8.48-8.44 (m, 1H), 7.73-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.50 (d, J=8.0Hz, 2H), 3.64 (s, 2H), 3.11-3.03 (m, 2H), 2.17-2.04 (m, 3H), 1.93-1.85 (m, 2H), 1.74-1.61 (m, 2H). LCMS (Method A): RT=5.43 min, M+H+=488.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13][CH2:14][CH3:15])C(O)=O)[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1OCC
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])cc(OCC)c1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 3,4,5-triethoxybenzoic acid (20.0 g, 78.7 mmol) in acetic acid (68 mL) was stirred at 15° C., and concentrated nitric acid (d 1.38)(34 mL, 750 mmol) was added. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 3,4,5-triethoxy-1-nitrobenzene as a colorless oil (12.9 g, yield: 64%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:24][CH2:23][C:22]([N:25]([CH3:27])[CH3:26])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
500 ml (10 eq.) Cbz chloride were added dropwise to 50 g (1 eq.) 1-benzyl-N,N-dimethyl-4-phenylpiperidin-4-amine over a period of 1 h and the reaction mixture obtained was stirred for 2 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction mixture was cooled to 0° C., made alkaline with saturated sodium hydrogen carbonate solution and extracted 3 times with 300 ml EtOAc. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 12 g (21%) of product were obtained in the form of an oil.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14])C(OCC)=O)=[O:5])C.S(=O)(=O)(O)O>C(O)(=O)C.O>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:6][C:4]([OH:5])=[O:3])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of ethyl 2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate (6.2 g, 19 mmol) and sulphuric acid (1.0 g) in acetic acid:water (4:1, 50 ml) was stirred at reflux for 4 hours, then concentrated in vacuo to small volume. Dilution with water (100 ml) gave a precipitate which was filtered and dried at 50° C. under vacuum. Purification by chromatography on silica gel eluting with methanol:methylene chloride (3:97) and filtration of the resulting solid from diethyl ether containing a small percentage of methanol gave, after drying under high vacuum, 4-(4-nitrophenyl)-4-oxobutyric acid (2.1 g). 1NMR (DMSO-d6, 300 MHz) δ: 2.62 (t, J=6 Hz, 2H, CH2), 3.33 (t, J=6 Hz, 2H, CH2), 8.22 (d, J=8.5 Hz, 2H, Ar), 8.36 (d, J=8.5 Hz, 2H, Ar), 12.22 (s, 1H, CO2H). Anal. Calculated for C10H9NO5 : C, 53.82; H, 4.06; N, 6.28. Found: C, 53.65; H, 4.02; N, 6.21.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:8]([CH3:27])[NH:7][C:6]1=[O:28])=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:29][N:2]([CH3:1])[C:3]([N:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:27])[NH:7][C:6]1=[O:28])=[O:4]
Reactant: CC1=C(C(=O)OC(C)(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Reaction time: 2.5 h
Yield: 65.2 %

Procedure:
A solution of 3-[(dimethylamino)carbonyl]-1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-oxo-5-pyrimidinecarboxylic acid, t-butyl ester (230 mg, 0.59 mmol) in chloroform (4.0 ml) was treated with trifluoroacetic acid (1.2 ml) at ambient temperature under argon. Aftr stirring for 2.5 hours, the reaction was evaporated, coevaporated with toluene and crystallized from ethanol/ether to give the title compound as colorless crystals (134 mg), melting point 193°-195° C. TLC (5% methanol/dichloromethane) single spot, Rf =0.21.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12](OC)=[O:13])(=[O:9])=[O:8].[CH3:24][CH:25]([CH3:27])[O-:26].[Na+].C(O)(=O)C>C(O)(C)C>[ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:26][CH:25]([CH3:27])[CH3:24])=[O:13])(=[O:9])=[O:8]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Reactant: CC(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Yield: 31 %

Procedure:
A solution of methyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoate hydrochloride (12.0 g, 32.6 mmol) in dry isopropanol (500 mL) containing sodium isopropoxide (39 mmol) was stirred at reflux under N2 for 18 hours. After adding glacial acetic acid (1 mL) and concentrating under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The residue was converted to the hydrochloride salt with ethanolic anhydrous hydrogen chloride and recrystallized from methanol - ethyl acetate to give 4.0 g (31%) of product, m.p. 187.0-190.0° dec. Anal Calc'd for C14H21N3O6S.HCl: C, 42.47; H, 5.60; N, 10.61
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[NH:1]([C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:15]([CH3:16])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cn1)[nH]c1ccccc12

Procedure:
2 g of 3-amino-β-carboline are suspended in 35 ml of pyridine and mixed with 4 ml of acetic anhydride. The aminocarboline dissolves during slight heating. After 20 minutes the solution is evaporated. The crystalline residue is washed with water and is recrystallized from ethyl acetate. Yield: 1.5 g of 3-acetamino-β-carboline with a 200°-203° C. melting point.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[C@H:4]([CH2:20][OH:21])[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:21][CH2:20][C@@H:4]1[CH2:3][C:2]([F:1])([F:22])[CH2:6][N:5]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([C:16]([F:18])([F:19])[F:17])[CH:8]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CO)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol (275 mg, 0.84 mmol) in anhydrous DCM was added triethylamine (171 mg, 235 μL, 1.7 mmol) followed by methane sulfonyl chloride (106 mg, 72 μL, 0.93 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with DCM and quenched with 3 mL saturated NaHCO3. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl methanesulfonate as a yellow solid (330 mg, 96%). LC/MS: m/z 405 (M+H)+ at 1.71 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](I)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[CH2:47][CH2:46][CH:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:44][CH2:43]3)[CH:39]=[N:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:36]3[CH:37]=[C:38]([N:42]4[CH2:43][CH2:44][CH:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:46][CH2:47]4)[CH:39]=[N:40][CH:41]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
A suspension of 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (155 mg, 0.315 mmol), tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (222 mg, 0.551 mmol) Pd(PPh3)4 (36.4 mg, 0.031 mmol, Strem) and Na2CO3, 2.0 M (0.315 mL, 0.630 mmol) in Toluene (2 mL) and EtOH (2 mL) was capped, degassed and backfilled with argon. The reaction was heated to 100° C. After 18 h, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0-4% MeOH/DCM), affording tert-butyl 1-(5-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (134 mg, 66%). MS (ESI, pos. ion) m/z: 642.4 (M+1).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:53]([NH:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1)=[O:54])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:47]1([CH:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:53]([NH:55][CH2:56][CH2:57][N:58]3[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:54])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@H:11]2[C@H:10]([OH:9])[C@H:14]([OH:15])[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of (2R,3R,4R,5S)-4-(benzoyloxy)-2-[6-[(2,2-diphenylethyl)amino]-2-({[2-(1-piperidinyl)-ethyl]amino}carbonyl)-9H-purin-9-yl]-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 7) (104 mg, 0.12 mmol) in methanol (3 ml) was treated with potassium carbonate (100 mg, 0.72 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (90:10 by volume) to afford the title compound as a white solid (44 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:30]=1[O:38][CH3:39])=[O:27]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36][CH3:37])=[CH:31][C:30]=2[O:38][CH3:39])[C:6]1=[O:16]
Reactant: COC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)c(OC)cc2OC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (1 g, 4.27 mmol), K2CO3 (910 mg, 6.404 mmol) and 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (Intermediate C) (1.42 g, 4.697 mmol) in dry DMF (6 ml) is left to stir at RT overnight. The reaction mixture is diluted with water resulting in a cream precipitate which is filtered, washed with water and dried under vacuum to give the title compound as a pale yellow solid [M+H]+ 462.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br>C1(C)C(C)=CC=CC=1>[N:17]1([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=[CH:13][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCCCCBr
Reactant: COc1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cccc(CCN2CCCC2)c1
Temperature: 25 °C

Procedure:
A stirred suspension of anhydrous sodium carbonate (0.923 g), 2-(3-methoxyphenyl)ethylamine (0.5 g) and 1,4-dibromobutane (0.43 ml) in dry xylene (5.5 ml) was heated under reflux for 16 hours. The reaction mixture was allowed to cool to room temperature and was filtered. The filtrate was extracted with 5N hydrochloric acid. The acidic extracts were washed with ether and then basified with 5N sodium hydroxide solution and extracted with ether. The ether extracts were washed with water, dried and the ether removed by evaporation to give 3-(2-pyrrolidin-1-ylethyl)anisole.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[N:23]([C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][CH:41]=1)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[C:24]=[O:25]>O1CCCC1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([NH:23][C:24](=[O:25])[NH:1][CH2:2][C:3]([N:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH:6]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])[CH:41]=[CH:40][CH:39]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Reactant: O=C=Nc1cccc(C(=O)OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Yield: 28.3 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 2, but starting from 1.93 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate and 3.61 g of benzyl 3-isocyanatobenzoate in 50 cm3 of tetrahydrofuran. After treatment, 1 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetyl)-5-phenylprolinate, melting at 75° C., is obtained.