Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[C:6]([O:8][C:9](=[O:11])[CH:10]=1)=[O:7])([OH:4])(=[O:3])=[O:2].[CH2:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-:25].[Na+:26]>O>[CH2:12]([O:24][CH:10]([CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[C:6]([O-:25])=[O:7])[C:9]([O-:8])=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Na+:26].[Na+:26].[Na+:26]
Reactant: O=C1C=C(S(=O)(=O)O)C(=O)O1
Reactant: [OH-]
Reactant: CCCCCCCCCCCCO
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCOC(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Temperature: 100 °C
Yield: 64.2 %

Procedure:
Sulfomaleic anhydride (10 gm) is mixed with 80 gm (0.45 mole) of n-dodecanol and heated at 100°C for 14 hours. A solution of 7.04 gm of sodium hydroxide in 50 ml water is then added and the mixture heated at 60°C for 2 hours. The heated mixture is then extracted three times with 300 cc portions of acetone (at reflux) and the acetone insoluble fraction is then filtered, washed with additional acetone and dried to give 16.2 gm of the title compound (structure confirmed by NMR and ion exchange of a sample followed by titration with standard sodium hydroxide: neutralization equivalent: found 147.0, theory 149.3).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7](F)[N:6]=1.O1CCC[CH2:18]1>>[Cl:11][C:9]1[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7]([N:2]([CH3:3])[CH3:1])[N:6]=[C:5]([NH:4][CH3:18])[N:10]=1
Reactant: C1CCOC1
Reactant: Nc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: CNC
Product: CNc1nc(Cl)c(OC(F)F)c(N(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.9 g (0.0417 mol) of gaseous dimethylamine were passed over the course of 10 minutes into a stirred mixture of 8.9 g (0.0417 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoropyrimidine and 100 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 1 hour and at 25° C. for 2 hours and worked up as usual, resulting in 9.7 g (97.5% of theory) of the title compound of melting point 127-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: c1ccc(OC2CCNCC2)nc1
Agent: Cl
Product: Brc1ccc2nccc(N3CCC(Oc4ccccn4)CC3)c2c1
Yield: 79.4 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 540 mg 2-(4-piperidyloxy) pyridine dihydrochloride were reacted by the same method as in Production Example 82, to give 629 mg of the title compound as an orange oil.
Reaction SMILES: C1COC([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)(C2C=CC=CC=2)O1.Cl.[OH2:29].CO>CC(C)=O>[C:18]([C:16]1[CH:17]=[CH:12][C:13]([C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:15]=1)(=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: Oc1ncnc2c(-c3ccccc3C3(c4ccccc4)OCCO3)cnn12
Reactant: O
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 2 h

Procedure:
A mixture of 8-(4-α,α-ethylenedioxybenzylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (0.20 g), conc. hydrochloric acid (0.5 ml), water (1 ml), methanol (4 ml) and acetone (1 ml) is stirred at 45°-60° C. for 2 hours. After cooling, the resulting precipitate is separated by filtration, washed with water and dried to give the title compound (0.15 g).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][CH2:49][OH:50]>CN(C)C=O>[OH:50][CH2:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:36])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: OCCCCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (360 mg, 0.70 mmol) (Example 22(a)) was dissolved in dimethylformamide (2.1 ml) . Sodium iodide (15 mg, 1 mmol), triethylamine (142 mg, 1.4 mmol) and 3-chloro-1-propanol (132 mg, 1.4 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 3 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (3 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the dichloromethane solution and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (6 ml). The aqueous solution was washed with ether (6×3 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 192 mg (68%), FAB MS: 405(M+1). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck flask [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.78 mmol, prepared in example 1), 4-carboxybenzene boronic acid (188 mg, 1.13 mmol), potassium carbonate (156 mg, 1.13 mmol) and tetrakis(triphenyl phosphine)palladium(0) (52 mg, 0.05 mmol) were combined in dioxane/water (30 mL, 3:1). The mixture was then heated at 100° C. with stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated, washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (350 mg) as a tan solid. The crude material was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (91 mg, 31%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].[Cl:12][C:13]([CH2:15]Cl)=[CH2:14].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11][CH2:15][C:13]([Cl:12])=[CH2:14]
Reactant: C=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)CSc1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of 2-chloro-5-nitro-benzenethiol (1.0 g, 5.27 mmol, prepared in accordance with the procedure described by Still et al. Synth. Comm. 13, 1181 (1983)) in 15 mL DMF was treated with 2,3-dichloropropene (693 μL, 7.52 mmol) and K2CO3 (433 mg, 3.13 mmol). The mixture was heated at 80° C. for 2 h and then allowed to cool to rt. EtOAc (200 mL) and H2O (100 mL) were added. The organic phase was washed with H2O (2×250 mL), saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with 20% EtOAc in hexanes to give compound 260A (1.09 g, 89%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 6-chloropurine (0.051 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (3 mL). N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=68 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (1 H, s), 8.11 (1 H, s), 8.08 (1 H, s), 8.00 (1 H, dd, J=8.2, 1.2 Hz), 7.93 (1 H, dd, J=7.4, 1.2 Hz), 7.42-7.67 (5 H, m) Mass Spectrum (ESI) m/e=421.0 and 423.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-chlorophenol (1 g, 4.82 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.332 g, 9.64 mmol) and benzyl bromide (0.630 ml, 5.30 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 297 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=O)[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.CN=C=[S:32].CN=C=O.[CH:37]1([N:42]=[C:43]=[S:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:28])[C@H:18]([OH:27])[C@@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[S:32])[O:20]2)[CH2:2]1.[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:28])[C@H:18]([OH:27])[C@@H:19]([CH2:21][NH:22][C:43]([NH:42][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[S:44])[O:20]2)[CH2:2]1
Reactant: CN=C=S
Reactant: S=C=NC1CCCC1
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: CN=C=O
Product: CNC(=S)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Product: O[C@@H]1[C@H](O)[C@@H](CNC(=S)NC2CCCC2)O[C@H]1n1cnc2c(N[C@@H]3CCOC3)ncnc21

Procedure:
Compound 77 was prepared in the manner of compound 24 substituting methyl isothiocyanate for methyl isocyanate and refluxing for 16 h [MS 410.3 (M+1)]. 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(cyclopentylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol (78) Compound 78 was prepared in the manner of compound 24 substituting cyclopentyl isothiocyanate for methyl isocyanate and refluxing for 16 h [MS 464.3 (M+1)].
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2([CH3:22])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([OH:19])[C:14]=3[CH3:18])[O:9]2)=[O:7])[CH2:3][CH2:2]1.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[C:8]([OH:23])([CH3:22])[CH2:17][CH2:16][C:15]2[C:10](=[O:9])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13](=[O:19])[C:14]=2[CH3:18])[CH2:3][CH2:2]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC1CC1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC2CC2)=C(C)C1=O
Yield: 88.4 %

Procedure:
Oxidation as described in protocol B, using 76.7 mg (0.253 mmol) of N-(cyclopropylmethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 435 mg CAN (0.794 mmol) yielded 71.4 mg of N-(cyclopropylmethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.C(N(CC)CC)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:45]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:46])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Reactant: O=C(Cl)N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a suspension of 0.15 g (0.42 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 5 ml dioxane 44 mg (1.0 mMol) NaH (dispersion in mineral oil 60%) were added and stirred for 1 h at room temperature. Then 0.174 ml (1.24 mMol) triethyl amine and 0.114 ml (1.0 mMol) morpholine-4-carbonyl chloride were added and stirred for 16 h at room temperature. After addition of 10 ml water the mixture was extracted three times with 15 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate) to yield 0.135 g (69%) 4-{4-methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colorless foam. ES-MS m/e (%): 475 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][NH:9][C:8](=[O:11])[NH:7][C:6]=2[N:12]=1.[Br:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C(O)C>[Br-:13].[CH3:1][C:2]1[N+:3]([CH2:14][C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[CH2:10][NH:9][C:8](=[O:11])[NH:7][C:6]=2[N:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ncc2c(n1)NC(=O)NC2
Solvent: CCO
Product: Cc1nc2c(c[n+]1CC(=O)c1ccccc1)CNC(=O)N2
Product: [Br-]
Yield: 21.8 %

Procedure:
2-Methyl-7-oxo-5,6,7,8-tetrahydropyrimidino[4,5-d]pyrimidine (0.1 g, 0.6 mmole) and 2-bromo-1-phenyl-1-ethanone (0.12 g, 0.6 mmole) in ethanol (20 mL) were heated at reflux for 32 hr. After cooling, the precipitated hydrobromide (mp>310 C.) of the starting heterocycle was filtered out, and the filtrate was diluted with ether to form a precipitate which was recrystalized from methanol-ether to yield 47.5 mg of the title compound, mp 249-250 C.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]C)=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.[Cl:28]C1C=CC=C(C(OO)=O)C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[ClH:28].[ClH:28].[ClH:28].[SH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([SH:26])=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(CNCCCNCCCNCc2ccc(SC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cl
Product: Sc1ccc(CNCCCNCCCNCc2ccc(S)cc2)cc1

Procedure:
Dissolve 1,9-bis[(4-methylmercaptophenyl)methyl]-1,5,9-triazanonane (2.02 g, 5 mmol) in chloroform (20 mL) and treat with metachloroperbenzoic acid (863 mg, 5 mmol). Add calcium hydroxide (556 mg, 7.5 mmol) and stir for 15 minutes. Filter and evaporate the solvent in vacuo. Dissolve the residue in trifluoroacetic anhydride (10 mL) and heat at reflux for 30 minutes. Evaporate the volatiles in vacuo and dissolve the residue in a mixture of methanol-triethylamine (1:1, 100 mL) and evaporate the solvent in vacuo. Dissolve the resdiue in chloroform, wash with saturated ammonium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the crude 1,9-bis[(4-mercaptophenyl)methyl]-1,5,9-triazanonane.
Reaction SMILES: [CH3:1][C@H:2]([CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:3][CH2:4][O:5][C@@H:6]([CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:7][OH:8].ClC(Cl)(Cl)C(=N)O[C@H:51]1[O:76][C@H:75]([CH2:77][O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C@@H:66]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C@H:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:52]1[O:53][C:54](=[O:56])[CH3:55].C([Si](OS(C(F)(F)F)(=O)=O)(CC)CC)C>C(Cl)Cl>[C:54]([O:53][C@H:52]1[C@@H:57]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@H:66]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C@@H:75]([CH2:77][O:78][CH2:79][C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[O:76][C@@H:51]1[O:8][CH2:7][CH:6]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:31][CH2:32][CH2:33][C@H:34]([CH3:46])[CH2:35][CH2:36][CH2:37][C@H:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:9][O:10][CH2:11][CH2:12][C@H:13]([CH3:30])[CH2:14][CH2:15][CH2:16][C@H:17]([CH3:29])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:56])[CH3:55]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@H](C)CCOC[C@@H](CO)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CC(=O)O[C@@H]1[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OCC(COCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)OCC[C@H](C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a mixture of (2R)-2,3-Bis[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyloxy]propan-1-ol (archaeol) (720 mg; 1.1 mmol), 2-O-acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl trichloroacetimidate (1.4 g; 2.2 mmol) and molecular sieves 4A° (3 g) was added CH2Cl2 (15 ml). After stirring at R.T. under an argon atmosphere for 1 h, triethylsilyltrifluoromethanesulfonate (25 μL; 0.11 mmol) was added and the stirring continued for 40 min. The reaction was quenched with diisopropylethylamine (100 μL). The whole reaction was adsorbed on silica gel and then purified by silica gel chromatography eluting with hexanes:ethyl acetate 9:1 to yield pure product as a viscous oil (0.58 g; 47%) plus some mixed fractions.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18][F:19])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH2:18][F:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CF)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(CF)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 91.6 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropanamido)methyl)benzoate (100 mg, 0.30 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (24 mg, 0.60 mmol) to afford 84 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.30 (t, 1H), 7.39-7.29 (m, 2H), 4.47-4.28 (m, 4H), 1.14 (s, 6H).
Reaction SMILES: C(CN1C2C(=CC=C3C(=O)C([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)=C(C4C=CC=CC=4)OC3=2)C=N1)#N.I[C:43]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][C:52]3[NH:57][C:56](=[O:58])[CH2:55][O:54][C:53]=3[C:46]=2[O:45][C:44]=1[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.CC1(C)C(C)(C)OB(C2C=CC(C3(NC(=O)OC(C)(C)C)CCC3)=CC=2)O1>>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:43]3[C:48](=[O:49])[C:47]4[C:46](=[C:53]5[C:52](=[CH:51][CH:50]=4)[NH:57][C:56](=[O:58])[CH2:55][O:54]5)[O:45][C:44]=3[C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C1COc2c(ccc3c(=O)c(I)c(-c4ccccc4)oc23)N1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cnn(CC#N)c54)c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Yield: 52 %

Procedure:
Following the procedure used to prepare tert-butyl (1-(4-(1-(cyanomethyl)-6-oxo-8-phenyl-1,6-dihydropyrano[3,2-g]indazol-7-yl)phenyl)cyclobutyl)carbamate reacted 8-iodo-9-phenylchromeno[8,7-b][1,4]oxazine-3,7(2H,4H)-dione (150 mg, 0.358 mmol), tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (170 mg, 0.455 mmol) was reacted to give the title compound (100 mg, 52%). LCMS (Method I): RT=6.87 min, [M+H]+=539.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:11]2=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]3[CH:14]=[C:15]([Cl:19])[CH:16]=[CH:17][C:18]=3[N:10]2[CH2:9]CN1)=[O:4].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].[I-].[Na+].[CH2:33](O)C>>[Cl:19][C:15]1[CH:16]=[CH:17][C:18]2[N:10]3[CH2:9][CH2:33][N:5]([C:3](=[O:4])[CH2:2][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH2:6][C:11]3=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:14]=1
Reactant: O=C(CCl)NC1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Reactant: CCNCC
Reactant: CCO
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)CC(=O)N1CCn2c(c(-c3ccccc3)c3cc(Cl)ccc32)C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 2-chloroacetamido-8-chloro-10-phenyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (6.80 g, 0.0189 mole), diethylamine (3.46 g, 0.0473 mole) and sodium iodide (2.85 g, 0.019 mole) in ethanol (250 ml) is refluxed for 10 hours, then cooled to room temperature. The solid is removed by filtration and the filtrate is concentrated. The residue is taken up in dichloromethane (350 ml) and extracted with 10% hydrochloric acid (300 ml) in 4 portions. The dichloromethane solution is concentrated to a brown gummy residue. This is extracted with boiling water (500 ml), filtering off the insoluble material. The aqueous solution is basified to pH 10 with excess solid potassium carbonate. A solid is formed which is collected by filtration and is recrystallized from heptane to give the above titled product, 5.30 g (70.9% yield) melting at 117°-119° C.