Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:10]([CH:24]=1)[CH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](O)=[O:17].[CH:31]1[CH:36]=[N:35][C:34]2N(O)N=N[C:33]=2[CH:32]=1.N1CCCCC1.C(O)C(N)(CO)CO>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:25][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:24][C:10]=1[CH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](=[O:17])[N:35]1[CH2:36][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)O
Reactant: On1nnc2cccnc21
Agent: NC(CO)(CO)CO
Solvent: C1CCNCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)N1CCCCC1
Reaction time: 0.83 h

Procedure:
To a solution of PS-EDC (0.558 g, 1.42 mmol/g, 0.792 mmol) in DMF (2 mL) is added 2-[2-(5-chloro-2-methoxycarbonylmethoxy-benzyl)-phenoxy]-propionic acid (Intermediate B) (150 mg, 0.396 mmol) in DMF (2 mL) and HOAT (80.8 mg, 0.594 mmol) in DMF (2 mL). The reaction mixture is agitated for 50 minutes and then treated with piperidine (39.2 μL, 0.396 mmol) and agitated at RT for 2 days. Polymer supported trisamine (0.475 g, 1.42 mmol/g, 1.98 mmol) is then added and the mixture is further agitated overnight. The reaction mixture is filtered to remove the resins and rinsed with methanol and DCM. The filtrate is reduced in vacuo and the crude solid is re-dissolved in DCM and washed with water. The organic portion is separated using a phase separator and concentrated in vacuo to yield a solid which is purified by chromatography on silica eluting with EtOAc/iso-hexane (30% increasing to 50% EtOAc) to yield the titled product as a pale yellow oil; MH+=446.
Reaction SMILES: C([C:5]1[O:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:8]=2[CH:9]=1)(C)(C)C.[S]>>[C:8]([C:10]1[C:8]2[CH:9]=[CH:5][O:6][C:7]=2[CH:13]=[CH:12][C:11]=1[OH:14])([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)c1cc2c(o1)CCC(=O)C2
Agent: [S]
Product: CC(C)(C)c1c(O)ccc2occc12
Temperature: 225 °C

Procedure:
A mixture of 4 tert butyl-4,5,6,7 tetrahydro-5-benzofuranone (1.00 g, 5.2 mmol) and sulfur (0.167 g, 1 equivalent) in a sealable tube is flushed with nitrogen, sealed and heated to 225° C. for 30 minutes. An additional portion of sulfur (0.030 g) is then added and the mixture heated an additional 15 minutes. After cooling the total reaction mixture is taken up in a small portion of methylene chloride and applied directly to a flash silica gel column. Elution with 5% ethyl acetate in hexane gives 4-tert-butyl5-benzofuranol.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Cl:13])[CH:6]=1.[OH-].[Na+].S(O)(O[CH2:21][CH2:22][NH2:23])(=O)=O.C1(C)C=CC=CC=1>CO.O>[Cl:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[S:11][CH3:12])[CH2:4][C@H:3]1[O:14][CH2:21][CH2:22][NH:23][CH2:2]1
Reactant: CSc1ccc(C[C@@H](O)CCl)cc1Cl
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
The solution of 0.4 g (1.6 mmol) (R)-1-chloro-3-(3-chloro-4-methylsulfanyl-phenyl)-propan-2-ol in 1.4 mL methanol was treated with a solution of 0.39 g (1.0 mmol) sodium hydroxide in 0.7 mL water and 0.92 g (6.5 mmol) 2-aminoethyl hydrogen sulfate. The reaction was warmed to 45° C. and stirred for 2.5 h. After the addition of 0.42 g (10.5 mmol) solid sodium hydroxide and 7 mL toluene the reaction temperature was raised to 65° C. After 4 h the reaction mixture was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and dichloromethane: methanol: ammonia (9:1:0.1 v/v) as eluant to give the compound as a light brown oil (38%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:40])[N:12]2[C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[F:31])[C:18]([O:32][CH2:33][C:34](OCC)=[O:35])=[CH:17][C:16]=2[Cl:39])=[C:8]([O:41][CH3:42])[N:7]=1)(=O)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:39][C:16]1[CH:17]=[C:18]([O:32][CH2:33][CH2:34][OH:35])[C:19]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[F:31])=[CH:20][C:15]=1[N:12]1[C:11](=[O:40])[NH:10][C:9]2[C:13]1=[N:14][C:6]([CH2:5][OH:4])=[N:7][C:8]=2[O:41][CH3:42]
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(COC(C)=O)nc32)cc1OCc1c(F)cccc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCCO
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a solution of 2-acetyloxymethyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2-fluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g) in tetrahydrofuran (3.3 mL) was added diisobutylaluminium hydride (0.99 mol/L toluene solution, 1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours, and then stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=6/1) to give the title compound (30 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: CN1CCC[C@H]1CO
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@@H]1CCCN1C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of [(2S)-1-methylpyrrolidin-2-yl]methanol (11.5 g, 0.10 mol), DMF (150 mL) and NaH (4.0 g, 60% in mineral oil, 0.1 mol) was agitated for 30 minutes under an atmosphere of nitrogen. A DMF (100 mL) solution of 1-chloro-2-methoxy-4-nitrobenzene (18.7 g, 0.10 mol) was added and the mixture agitated overnight at RT. The mixture was concentrated, diluted with ethyl acetate, extracted three times with water, dried, filtered, then concentrated to give the product as a tan oil (16.78 g, 63%). LCMS m/z 267 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d, 1H), 7.73 (s, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.88 (s, 3H), 2.80 (m, 1H), 2.60 (m, 1H), 2.36 (s, 3H), 2.20 (m, 1H). 1.90 (m, 1H), 1.67 (m, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:15][C:24]([NH:23][CH3:22])=[O:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Br
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.53 mmol) and methyl isocyanate (61 mg, 1.07 mmol) in toluene (1 mL) was heated under reflux for 24 h. The reaction mixture turned very cloudy with the forming of a white precipitate. The reaction mixture was allowed to cool to 25° C. and then treated with hexanes. The reaction mixture was placed in the freezer for 1 h then filtered. The white solid was washed with cold hexanes to afford 1-[2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (100 mg, 44%) as a white solid: mp 259-260° C.; FAB-HRMS m/e calcd for C17H23BrN2O4S (M+H)+431.0641, found 431.0646.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH2:13].[CH2:18]([O:20][CH2:21][C:22]1[N:23]([CH2:35][C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:19].[H-].[Na+]>O1CCCC1.O>[CH2:18]([O:20][CH2:21][C:22]1[N:23]([CH2:35][C:36]2([O:40][CH2:13][CH2:12][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:39][CH2:38][CH2:37]2)[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1)[CH3:19]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.74 mmol) followed by methyl vinyl sulfone (1.60 g, 14.8 mmol) were added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (2.30 g, 7.39 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room temperature for 1 hour and a small amount of sodium hydride (60% dispersion in mineral oil) was added. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 2.0 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclobutyl}methyl)-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:20][NH:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH3:22])[CH3:20])=[O:9]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cnc1N1CCN(CCO)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Br)cnc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
630 mg (1.90 mmol) of 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinic acid was suspended in 50 ml of dichloromethane. 6 ml of 2 M dimethylamine in THF and 850 mg (1.63 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate were added and the resulting mixture was stirred for 18 h at ambient temperature. The resulting mixture was diluted with dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane and the organic phases were combined, dried over sodium sulfate and evaporated to afford crude 5-bromo-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N,N-dimethyl-nicotinamide as a pale brown oil containing tris(pyrrolidinyl)phosphoramidate as a contaminant. MS: m/z 357 [MH+].
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: CN
Reactant: COc1ccnc(CSCCN=C(NC#N)SC)c1
Solvent: CCO
Product: CNC(=NCCSCc1cc(OC)ccn1)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 20 cc) was added to a stirred solution of N-cyano-N'-[2-((4-methoxy-2-pyridyl) methylthio)ethyl]-S-methylisothiourea (3.56 g) in ethanol (25 cc) at 35°, and the mixture was left to stand overnight. Nitrogen was bubbled through the solution and the crystals were filtered off to give the title product, (2.74 g) m.p. 121°-122°.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C@H:9]1[CH2:22][O:23]C(=O)C1C=CC=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>CO>[C:1]([N:8]1[C@H:9]([CH2:22][OH:23])[CH2:10][CH2:11][C@H:12]1[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](COCc2ccccc2)CC[C@H]1COC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@H]1COCc1ccccc1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-benzoyloxymethyl-5-(S)-benzyloxy methylpyrrolidine (1.23 g, 2.89 mmol) in MeOH (30 ml) was added NaOH (1.0 M in water, 3.47 ml, 3.47 mmol) at rt, and the resulting mixture was stirred for 4 h. The mixture was neutralized with aq. 1N-HCl and concentrated in vacuo, then extracted with CHCl3. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (3:1) as eluent to give N-Boc-5-(S)-hydroxymethyl-2-(S)-benzyloxymethyl pyrrolidine (847 mg, 91%) as a colorless oil. 1H-NMR (CDCl3) δ 1.41 (s, 9 H), 1.57 (br s, 1 H), 1.95–1.97 (m, 2 H), 2.05–2.18 (m, 1 H), 3.36 (t, J=8.4 Hz, 1 H), 3.56–3.62 (m, 2 H), 3.67–3.72 (m, 2 H), 3.95 (br s, 1 H), 4.03 (br s, 1 H), 4.51 (s, 1 H), 7.28–7.37 (m, 5H); MS (FAB) m/z, 322 (M++H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=[CH:3]1.[H-].[Na+].FS([C:18](C(O)=O)([F:20])[F:19])(=O)=O.O>CC#N>[F:19][CH:18]([F:20])[O:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cccc(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc(OC(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate (3.074 g; 20.07 mmol) in anh. MeCN (310 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.167 g; 54.19 mmol), and stirring at rt, under nitrogen, was continued for 30 min. FSO2CF2CO2H (6.077 g; 34.12 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 30 min. Water (25 ml) was slowly added, and MeCN was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (2×100 ml). The mixed organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 6-(difluoromethoxy)picolinate as a yellow solid. LC-MS (conditions D): tR=0.89 min.; no ionisation.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].O>C1COCC1.O>[Br:2][CH2:3][CH2:4][NH:5][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
Into a solution of 2-bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.06 g) in THF/water (20/5 ml) was added at 0° C. benzyl chloroformate (4.16 g), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g). A solution of benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinyl-carbamate formic acid salt (4.63 g) and triethylamine (8 ml) in acetonitrile (30 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane) to obtain benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])([O-])=O>CCOC(C)=O.[Pd]>[S:13]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7]1)([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c([N+](=O)[O-])cccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)cccc32)cc1

Procedure:
To 4-nitro-1-tosyl-1H-indole (20.2 g, 63.9 mmol) in EtOAc (639 mL) was added 10% Pd/C (6.80 g, 6.39 mmol) and the mixture was stirred under hydrogen. After 4 hours the reaction was filtered through Celite®, rinsing with EtOAc. The filtrate was concentrated and purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 287.1 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]([O:10]/[N:11]=[C:12](/[C:38]1[N:39]=[C:40]([NH:43]C(OC(C)(C)C)=O)[S:41][CH:42]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]([O:33]C(C)(C)C)=[O:32])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:51])=[O:5])([CH3:9])[CH3:8])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]=[N:27]2)=[O:14])[N:39]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(C(=O)OC(C)(C)C)nn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(C(=O)O)nn1)c1csc(N)n1)C(=O)O
Yield: 27 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (180 mg, 0.237 mmol), DCM (8 mL) and TFA (2 mL, 26 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (35 mg, 27%) as a white solid. LCMS: m/z=544.9 (M−1); 1H NMR (400 MHz, D2O): δ 8.43 (s, 1H), 6.99 (s, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.92-4.71 (m, 3H; partially obscured by solvent residual peak), 1.33 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1.[H-].[Na+].Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=3)=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)cc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(2-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (0.50 g) is dissolved in 1,2-dimethoxyethane (20 ml) and cooled to 0° C., to which is added sodium hydride (60%, 0.07 g) and the reaction mixture is stirred for 15 minutes. Then, a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.34 g) in 1,2-dimethoxyethane (10 ml) is added dropwise and stirred for 3 hours. On completion of the reaction, the reaction solution is warmed to room temperature and poured into water and extracted with ether. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.62 g of desired compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of N2-butyl-8-methoxy-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purine-2,6-diamine (45 mg) in dry methanol (3 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (0.7 ml) in one go. The reaction was left to stir at room temperature for 3 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (5 ml) and the solid filtered and dried in vacuo (60° C.) for 30 minutes. This afforded the title compound as a solid (25 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC)(=O)CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:37][CH3:38])[C:33]([O:35][CH3:36])=[O:34]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:37]([CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:33]([O:35][CH3:36])=[O:34])[CH3:38]
Reactant: CCC(CCCCBr)C(=O)OC
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCC(=O)OC
Solvent: CN(C)C=O
Product: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)OC
Temperature: 100 °C
Reaction time: 40 h

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (2.8 g) (prepared by analogy with the method described in Patent EP 108 592 from methyl butanoate), methyl 6-bromo-2-ethylhexanoate (5.4 g), silver carbonate (1.6 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 31 hours then at 120° C. for 40 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil)
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[N:5]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:4]1=[O:9])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCC1NC(=O)NC1=O
Product: CCC1NC(=O)N(Cc2ccc(OC)cc2)C1=O

Procedure:
Using 5-ethylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.54 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (3.08 g) was obtained.