Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3].CO.[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[N:28]([CH3:38])[C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (69 mg, 0.15 mmol) obtained in Example 5 and methanol (30 μL, 0.75 mmol) were dissolved in THF (1 mL), polymer-supported triphenylphosphine (150 mg, 0.45 mmol) and di-tert-butyl azodicarboxylate (104 mg, 0.45 mmol) were added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3 to 0/10) to give the title compound (compound 6) (65 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7](O)[CH2:8][CH3:9])[O:4][N:3]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:12][CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH2:8][CH3:9]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1cc(C)no1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(Br)c1cc(C)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-methylisoxazol-5-yl)propan-1-ol (0.589 g, 4.17 mmol) in 15 mL of THF was added CBr4 (1.730 g, 5.22 mmol) and triphenylphosphine (1.423 g, 5.42 mmol). The reaction mixture was stirred at room temperature for 3 h. The solid was filtered off, and washed with THF. The filtrate was concentrated and residue was purified by chromatography on silica gel, eluting with 5 to 30% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=204.2 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[C:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(O)CC1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 4-hydroxypiperidine (25.0 g, 0.247 mol) in methylene chloride (2000 mL) was cooled to 0° C. under nitrogen with overhead stirring. Triethylamine (86.1 mL, 0.618 mol, 2.5 eq) was added followed by benzyl chloroformate (35.3 mL, 0.247 mol, 1.0 eq). The reaction was warmed to room temperature over 1 h and maintained at this temperature for 5 h. A significant amount of amine hydrochloride precipitates in the course of the procedure. The organic phase was washed with 3N HCl (3×250 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to yield 47.0 g (81%) of the title compound as an oil. The product did not require any addition purification prior to the Swern oxidation. TLC analysis (Rf 0.17, 50% ethyl acetate in hexane). MS (CI, CH4) m/z 236 (M+1,42), 218 (4), 192 (10), 181 (9), 174 (15), 91 (100)
Reaction SMILES: [F:1][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:12].[Se](=O)=[O:14]>O1CCOCC1>[F:1][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]=[O:14]
Reactant: Cc1nc2ccccc2n1CF
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1CF
Yield: 82.8 %

Procedure:
Using the procedure of Example 10B and starting with 2.87 g of 1-fluoromethyl-2-methylbenzimidazole and 1.94 g of selenium dioxide in 50 ml of dioxane, 2.58 g of the desired product was isolated.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[OH:21].I[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: COCOc1ccc(O)c(OCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(OCOC)cc1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Potassium carbonate (322 mg, 2.33 mmol) was added to 3b (50 mg, 0.233 mmol) in N,N-dimethylformamide (2.33 mL) at room temperature. After 10 minutes, iodopropane (226 μL, 2.33 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×10 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, 5:1 Hexane:EtOAc) to afford 4b as a yellow oil (36.4 mg, 61%): 1H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H), 6.84 (d, J=2.9 Hz, 1H), 6.68 (dd, J=11.7, 2.8 Hz, 1H), 5.19 (s, 2H), 5.12 (s, 2H), 3.93 (t, J=6.6 Hz, 2H), 3.53 (s, 3H), 3.49 (s, 3H), 1.86-1.78 (m, 2H), 1.06 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 150.6, 146.5, 143.8, 113.7, 108.5, 106.6, 94.7, 94.2, 70.3, 55.2, 54.9, 21.6, 9.5; IR (film) νmax 2961, 2826, 1595, 1506, 1400, 1261, 1154, 1013, 1076, 924, 800 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C13H20O5, 257.1389. found, 257.1410; [M Na]+ calcd for C13H20O5, 279.1208. found, 279.1165.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][SH:79]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1ccccn1
Reactant: SCc1ccccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1nc(C(F)(F)F)c(SCc2ccccc2Cl)s1)c1ccccn1
Temperature: 100 °C

Procedure:
In a 5 mL microwave vial was charged with N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)picolinamide (0.06 g, 0.2 mmol), diisopropylethylamine (59 μL, 0.34 mmol), Pd2(dba)3 (0.0048 g, 0.0085 mmol), Xantphos (0.0099 g, 0.017 mmol), 1,4-dioxane (0.6 mL) and 2-chlorophenylmethanethiol (22 μL, 0.17 mmol). The reaction mixture was purged with argon for 5 min; the vial was capped and heated at 100° C. for 15 h. the reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered, washing with ethyl acetate (10 mL) and the filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 30% to give the product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:11]1[CH2:12][CH:7]([C:6]2[CH:5]=[C:4]([Cl:15])[S:3][C:2]=2[Cl:1])[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2cc(Cl)sc2Cl)C1
Yield: 96.3 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (42.0 g) and ammonium acetate (36.9 g) in ethanol (840 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The crystals were filtered, washed with toluene and dried to give 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (40.3 g). To a solution of 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (37.0 g) in ethanol (700 ml) and toluene (1400 ml) were added 3-oxobutylaldehydedimethylacetal (46.6 g) and powdery potassium hydroxide (7.7 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (1.6 g) 30 minutes later; powdery potassium hydroxide (1.6 g) and 3-oxobutylaldehydedimethylacetal (3.7 g) 1 hour later; and powdery potassium hydroxide (1.6 g) 1.5 hours later; and then the mixture was stirred at the same temperature for 2 hours. After the mixture was cooled, the solvent was evaporated under reduced pressure and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the thus obtained oil containing crystals were subjected to silica gel column (EtOAc/hexane) to remove starting materials. The thus obtained crystals were recrystallized from ethyl acetate-hexane to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (32.6 g).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:16]
Reactant: FC(F)(F)c1nc2c(Cl)nccc2[nH]1
Reactant: NN
Solvent: CCO
Product: NNc1nccc2[nH]c(C(F)(F)F)nc12

Procedure:
A mixture of 132 mg (0.6 mmol) of 4-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine, 0.0787 mL (2.4 mmol) of anhydrous hydrazine, and 3 mL of ethanol was stirred at reflux for 2 days. The cooled, filtered solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to yield the title compound. LC-MS 218 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:35][NH:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:42]3[CH2:43][CH2:44][CH:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:40][CH2:41]3)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(C(=O)CCn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with N-methylpiperidine-4-carboxamide via General Procedure F followed by Boc deprotection via General Procedure E to give 10.9 mg 111 as white solid following reverse phase purification. MS (Q1) 495.3 (M)+
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)([CH3:3])[CH3:2].[I:14]Cl>CO>[I:14][C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[CH3:11]
Reactant: CSc1nc(C)cc(NC(C)C)n1
Reactant: ClI
Solvent: CO
Product: CSc1nc(C)c(I)c(NC(C)C)n1
Reaction time: 3 h

Procedure:
To a crude solution of N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (44.6 g, 224 mmol), prepared using analogous procedures as described in Example 1, in 400 mL of methanol was added ICl (40.0 g, 246 mmol) in small portions at room temperature. The reaction mixture was then stirred at for 3 h monitoring by LC/MS. After evaporation of solvent by rotary evaporator, the residue was triturated with acetone to yield 5-iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine. NMR (400 MHz, CDCl3) δ 6.37 (br m, 1H), 4.47 (m, 1H), 2.78 (s, 3H), 2.67 (s, 3H), 1.41 (d, J=6.4, 6H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]2([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.[CH3:20][O-].[Na+]>CO.O>[CH3:20][O:11][CH2:12][C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC(=O)N2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a round bottom flask containing (4-methyl-2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (300 mg, 1.05 mmol) was added under a nitrogen atmosphere 3 ml of sodium methoxide in methanol solution (25% wt). The resulting thick suspension was stirred at ambient temperature for 24 hours, and then heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water, and the pH was adjusted to neutral. The mixture was concentrated, and the resulting solids were extracted with DCM and EtOAc. The combined organic layer was concentrated to afford 4-(methoxymethyl)-4-methyloxazolidin-2-one (129 mg, 85%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>N1C=CC=CC=1>[CH2:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)[CH3:18]
Reactant: CCc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
Compound 109 (250 mg, 0.88 mmol) was suspended in pyridine (1.3 mL). Decanoyl chloride (134 mg, 0.70 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4.5 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (372 mg, 0.85 mmol, 97%) as a solid, mp 121-122° C.; 1H NMR (500 MHz, DMSO) δ 0.82 (3, t, J=7.0 Hz), 1.17-1.30 (14, m), 1.57 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 2.80 (2, q, J=7.0 Hz), 7.72 (2, d, J=8.5 Hz), 7.76 (2, d, J=8.5 Hz), 10.21 (1, s), 13.89 (1, s); 13C NMR (125 MHz, DMSO) δ 12.2, 13.9, 22.1, 23.6, 24.9, 28.6, 28.7, 28.8, 28.9, 31.2, 36.5, 118.5, 126.8, 135.5, 142.7, 159.7, 167.2, 171.8; MS (LCQ, ESI+) Calculated for C20H31N4O3S2 439.2, found 439.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C20H31N4O3S2 439.1838, found 439.1843 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:18])[N:6]2[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:31][C:32]([N:34]([CH2:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>O>[Cl:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:31][C:32]([N:34]([CH2:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])[C:5](=[O:18])[N:6]2[CH3:17]
Reactant: CCN(C(=O)CCl)c1ccccc1
Reactant: Cn1c(=O)[nH]c2c(Cl)nc(-c3ccccc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of 6-chloro-7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one (1.6 g), potassium carbonate (1.0 g) and dimethylformamide (15 ml) is added 2-chloro-N-ethyl-N-phenylacetamide (1.4 g) at room temperature, and the mixture is stirred at the same temperature for two hours. To the reaction mixture is added water, and the precipitates are collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Product: Cc1ccc(S(=O)(=O)Nc2c(C(=O)c3ccccc3)[nH]c3cc(Cl)ccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-carboxylate (Example 1, step 2) and p-toluenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:26][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2nc3cc(Cl)ccc3c(Oc3ccc(Cl)cc3)c2c1
Temperature: 80 °C

Procedure:
A reaction mixture consisting of 1.39 g (5.0 mmol) of 6,9-dichloro-2-methoxyacridine and 3.0 g (23 mmol) of p-chlorophenol was heated at 80° C. for 4 h. The hot reaction mixture was poured into hot 5% aqueous NaOH. The combined solution was stirred until a fine yellow crystalline precipitate appeared. The crystals were filtered, washed to neutrality with water and dried at 70° C. in vacuo. Recrystallization from pyridine afforded 6-chloro-9-(p-chlorophenoxy)-2-methoxyacridine as yellow microcrystals, yield 1.06 g (57%), mp 151.5°-153° C.; λ max (CH3OH) 400, 381, 351, 333, 318 (sh) and 262 nm; 1H-NMR (CDCl3, (CH3)4Si) δ 3.76 (s, 3) 6.7-6.9 (m, 2) 7.1-7.6 (m, 5) and 7.8-8.2 (m, 3).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[C:27]([O:30][C@@H:31]1[C@@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@@H:66]([CH2:77][O:78][C:79](=[O:81])[CH3:80])[O:65][C@H:32]1[O:33][C:34]1[C:38]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][C:52]4([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:51]3)=[CH:42][C:41]=2[CH3:61])=[C:37]([CH:62]([CH3:64])[CH3:63])[NH:36][N:35]=1)(=[O:29])[CH3:28].[CH3:82][C:83]([O:86][C:87]([NH:89][CH2:90][C:91](O)=[O:92])=[O:88])([CH3:85])[CH3:84].C(N(C(C)C)CC)(C)C>ClCCl>[C:83]([O:86][C:87](=[O:88])[NH:89][CH2:90][C:91]([N:58]1[CH2:57][CH2:56][C:52]2([CH2:51][N:50]([CH2:49][CH2:48]/[CH:47]=[CH:46]/[C:43]3[CH:44]=[CH:45][C:40]([CH2:39][C:38]4[C:34]([O:33][C@@H:32]5[O:65][C@H:66]([CH2:77][O:78][C:79](=[O:81])[CH3:80])[C@@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:31]5[O:30][C:27](=[O:29])[CH3:28])=[N:35][NH:36][C:37]=4[CH:62]([CH3:64])[CH3:63])=[C:41]([CH3:61])[CH:42]=3)[CH2:55][CH2:54][CH2:53]2)[CH2:60][CH2:59]1)=[O:92])([CH3:85])([CH3:82])[CH3:84]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCNCC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CNC(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (HATU, 543 mg, 1.43 mmol) to a solution of 4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (1.0 g, 1.19 mmol), N-alpha-T-Boc-glycine (317 mg, 1.79 mmol), and diisopropylethylamine (769 mg, 5.95 mmol) in dichloromethane (10 mL). Stir the mixture at room temperature for 2.0 hours. Remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/dichloromethane from 30-85% over 20 min, 40 g column) to provide the title compound (1.0 g, 1.08 mmol). MS (m/z): 924.4 (M+1), 922.4 (M−1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C@H:9]1[CH2:13][NH:12][C@@H:11]2[C@@H:14]([OH:17])[CH2:15][O:16][C@H:10]12.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O.O1CCOCC1>[OH:17][C@@H:14]1[C@H:11]2[N:12]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:13][C@H:9]([O:8][CH3:7])[C@H:10]2[O:16][CH2:15]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CO[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of sodium carbonate (239 mg, 2.26 mmol) in water (10 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (7 mL). A solution of 9-fluorenylmethoxycarbonyl chloride (319 mg, 1.23 mmol) in 1,4-dioxane (3 mL) was added then the mixture stirred for 40 minutes then water (30 mL) was added and the product extracted into dichloromethane (1×40 mL then 2×30 mL). The organic layer was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 7:93 to 45:55 gave bicyclic alcohol (6b) (270 mg, 66%) as a white solid. TLC (Rf=0.34, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=15.990 min., HPLC-MS 382.1 [M+H]+, 404.1 [M+Na]+, 785.3 [2M+Na]+; [□]D18.5−35.4° (c=2.758, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.02 (0.6H, d, J=3.55 Hz, OH major), 2.59 (0.40H, d, J=3.19 Hz, OH minor), 3.10 (0.6H, dd, 3.89 Hz, FmocNCH2 major), 3.26 (1.8H, s, OCH3 major), 3.30 (0.4H, dd, 4.19 Hz, FmocNCH2 minor), 3.35 (1.2H, s, OCH3 minor), 3.49 (0.6H, m, OCH2CHOH major), 3.52 (0.6H, dd, 1.81 Hz, OCH2CHOH major), 3.55-3.59 (1.2H, m, OCH2CHOH major and FmocNCH major), 3.64 (0.6H, d, J=3.69 Hz, CHOCH3 major), 3.65-3.70 (1H, m, FmocNCH2), 3.75-3.79 (0.8H, m, OCH2CHOH minor and CHOCH3 minor), 3.85 (0.4H, dd, J=9.85 and 4.46 Hz, OCH2CHOH minor), 4.22-4.26 (1.4H, m, FmocNCH minor and Fmoc CH), 4.37 (0.6H, d, J=4.64 Hz, OCHCHOCH3 major), 4.40-4.44 (1.2H, m, Fmoc CH2 minor and OCH2CHOH minor), 4.60 (0.4H, d, J=4.94 Hz, OCHCHOCH3 minor), 4.70 (0.6H, dd, J=10.80 and 3.96 Hz, Fmoc CH2 major), 4.82 (0.6H, dd, 4.25 Hz, Fmoc CH2 major), 7.29-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 47.248/47.378 (Fmoc CH), 49.754/50.177 (FmocNCH2), 56.868/56.996 (OCH3), 65.736/67.270 (Fmoc CH2), 68.262/69.085 (FmocNCH), 73.760/74.008 (OCH2CHOH), 75.812/76.145 (OCH2CHOH), 81.509/82.286 (OCHCHOCH3), 83.496/84.166 (OCHCHOCH3), 119.805, 119.982, 120.003, 124.494, 124.576, 124.958, 124.975, 127.019, 127.034, 127.404, 127.488, 127.637, 127.726, 127.754 and 127.865 (Fmoc aromatic CH), 143.633, 143.909, 143.943 and 144.037 (Fmoc quaternary), 154.255/155.025 (Fmoc C═O).