Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([O:40][CH2:41][CH3:42])([C:6]([F:39])([F:38])[C:7]1(Cl)[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].C([SnH](CCCC)CCCC)CCC>>[CH2:41]([O:40][P:4]([O:3][CH2:1][CH3:2])([C:6]([F:38])([F:39])[C@@H:7]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:8]1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:5])[CH3:42]
Reactant: CCOP(=O)(OCC)C(F)(F)C1(Cl)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Product: CCOP(=O)(OCC)C(F)(F)[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
Following the procedure of Example 63, reduction of 1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-3,4,6-tris-O-(phenylmethyl)-D-fructofuranosyl chloride with tributyltin hydride, followed by column chromatography of the crude product gave the desired compound, the more polar component, as an oil, CMR δ 77.9 (doublet of triplets, O-C-CF2P).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[K+].C(S([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)=O)CCCCC.CCOCC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][N:2]([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:3](=[O:5])[CH3:4]
Reactant: CCCCCCS(=O)c1nc(C)co1
Reactant: CNC(C)=O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(=O)N(C)c1nc(C)co1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
N-Methyl-acetamide (1.02 g, 0.0140 m) in HMPA (10 ml) was stirred at 50° C. under nitrogen during the portionwise addition of 50% potassium hydride/oil dispersion (1.12 g, 0.0140 m). After the addition, the mixture was warmed to 100° C. and 2-n-hexylsulphinyl-4-methyloxazole (3.0 g, 0.0139 m) in HMPA (10 ml) was added and the mixture stirred at 100° C. for 5 hours. The mixture was then hydrolysed with water, solvent removed in vacuo and the product isolated by column chromatography on silica using ether. Recrystallisation from diethyl ether/hexane at -20° C. gave the title product as colourless needles, m.p. 27°-29° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][N+:16]([O-:9])=[CH:15][C:14]=1[F:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnccc1Cl
Solvent: ClCCl
Product: [O-][n+]1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
MCPBA (28.1 g) was added to a solution of 4-chloro-3-fluoro-pyridine (10.0 g) in DCM (150 ml) and the reaction mixture stirred for 60 h at RT. The reaction mixture was quenched with 10% aq. Na2S2O3 and the basicity of the aq. phase adjusted with aq. sat. Na2CO3 to pH 9. The aq. phase was extracted with EA (6×), and the combined org. phase was dried over MgSO4 and evaporated to dryness. The desired compound (8.4 g) was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[NH2:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (20.0 g, 84.2 mMol) in conc. HCl (90 mL) was added SnCl2.2H2O (60.0 g, 266 mMol) portionwise over 2 h. (The reaction got very warm to the touch.) The reaction was stirred at RT for 18 h, poured onto ice, and basified with aq. 6 N NaOH (300 mL). The resultant slurry was filtered, washed with H2O, and dried under vacuum to give the title compound (15.53 g, 89%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (d, J=2.3 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 5.90 (br. s., 2H); MS(ES) m/e 206.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:21]3[CH:22]=[C:17]([Cl:16])[N:18]=[C:19]([CH3:24])[N:20]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc2cc(Oc3cc(Cl)nc(C)n3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 6.0 g (29.7 mMol) 6-hydroxy-naphthalene-1-carboxylic acid methyl ester (see Step 3.1), 7.6 g (46.6 mMol) 4,6-dichloro-2-methylpyrimidine and 13.9 g (65 mMol) K3PO4 in 50 ml NMP is stirred for 4 days at rt. The mixture is poured into ½ l water and the title compound filtered off, washed with water and dried (HV, 80° C.): HPLC: tRet=17.2.
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[CH2:13]([S:15][C:16]1[N:20]=[CH:19][N:18]([C:21](Cl)=[O:22])[N:17]=1)[CH3:14].[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1.N1C=CC=CC=1>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[C:21]([N:18]1[CH:19]=[N:20][C:16]([S:15][CH2:13][CH3:14])=[N:17]1)=[O:22])[CH2:25][CH3:26]
Reactant: CCSc1ncn(C(=O)Cl)n1
Reactant: CCCNCCC
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 25.8 g. 3-ethylthio-1,2,4-triazole and 15.8 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 1 molecular proportion), with stirring and cooling to maintain the reaction temperature at 25° - 30° C. The mixture was stirred at 25° - 30° C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution of 3-ethylthio-1,2,4-triazole-1-carbonyl chloride was added dropwise a solution of 20.2 g. dipropylamine and 15.8 g. dry pyridine in 50 ml. dry tetrahydrofuran, with stirring and cooling to maintain the reaction temperature at 25° - 30° C. The mixture was stirred at 25° - 30° C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. The filtrate was evaporated under reduced pressure to remove solvent and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130° C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[CH2:29][S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29](=[CH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=Cc1ccccc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)SC(=Cc2ccccc2)C1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione (100 mg, 0.22 mmol, 1.00 equiv) in ethanol (20 mL) and benzaldehyde (47 mg, 0.44 mmol, 1.98 equiv) and piperidine (479.5 mg, 5.63 mmol, 25.14 equiv) were added. The resulting solution was stirred for 12 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 31 mg (24%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-5-(phenylmethylidene)-1,3-thiazolidine-2,4-dione as a light yellow solid. LC-MS: (ES, m/z): 535 (M+H)
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.C(N(CC)CC)C.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:41]=1O.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(OC(C)C)C.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:41]3[CH:42]=[C:43]([C:46]([F:48])([F:49])[F:47])[CH:44]=[CH:45][C:40]=3[F:39])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)OC(C)C
Product: Fc1ccc(C(F)(F)F)cc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 22 h
Yield: 114.2 %

Procedure:
A stirred mixture of 48 g (0.2 mole) of 1-(diphenylmethyl)azetidin-3-ol and 22 g (0.22 mole) of triethylamine in 800 mL of toluene was cooled to 5° C. in an ice bath under nitrogen while 28 g (0.22 mole) of methanesulfonyl chloride in 30 mL of toluene was added dropwise. After stirring for 22 h, the reaction mixture was diluted with 200 mL of 2-propyl ether and 300 mL of ice water was added to dissolve the triethylamine hydrochloride formed in the reaction. The aqueous portion was separated and the organic phase washed with ice water (3×200 mL) then returned to the reaction flask. The toluene solution was treated with 39.6 g (0.22 mole) of 2-fluoro-5-(trifluoromethyl)phenol, 28.3 g (0.07 mole) of Aliquat® 336 (tricaprylymethylammonium chloride) and 26.4 g (0.66 mole) of sodium hydroxide dissolved in 50 mL of water. The mixture was stirred vigorously while heating at reflux for 24 h an stirred an additional 48 h at ambient temperature. The basic aqueous layer was then removed. The organic layer was diluted with 200 ml of isopropyl ether, washed with warm water (4×200 mL), dried over magnesium sulfate, and concentrated in vacuo to give 91.7 g of amber oil. The oil was triturated with boiling hexanes and upon cooling, 40.2 g of white crystals were obtained, mp 88°-90° C. A sample was recrystallized for analysis from hexanes yielding fine white crystals, mp 88.5°-90° C. The filtrate was concentrated to an amber oil again and when triturated with ligroin yielded an additional 9.5 g of product. The total yield was 49.7 g (62%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:10]2([OH:24])[C@H:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@:4]2([O:25][C:26]([CH3:28])=[O:27])[CH2:3]1)[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3.[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][C@H:2]1[C@:10]2([OH:24])[C@H:11]3[C@:16]([OH:22])([CH2:17][C:18]([CH2:20][OH:21])=[CH:19][C@H:9]2[C@@H:5]2[C:6]([CH3:7])([CH3:8])[C@:4]2([O:25][C:26]([CH3:28])=[O:27])[CH2:3]1)[C:14](=[O:15])[C:13]([CH3:23])=[CH:12]3.[C:29]([O-:34])(=[O:35])[CH2:30][CH2:31][C:32]([O-:15])=[O:33]
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)O[C@@]12C[C@@H](C)[C@@]3(O)[C@@H](C=C(CO)C[C@]4(O)C(=O)C(C)=C[C@@H]34)[C@@H]1C2(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C([O-])CCC(=O)[O-]

Procedure:
Prostratin (1390 mg, 1 mmol) and succinic anhydride (120 mg, 1.2 mmol) were dissolved in dichloromethane (20 ml). DMAP (dimethylaminopyridine) at 50 mg was added under stirring and then stirred at room temperature for overnight. The solvent was evaporated and the residue subjected to chromatography on silica gel column (50 mg) with gradient of petroleum ether (60-90° C.) and acetone as eluent to give a fraction of pure prostratin succinate (Scheme (1), product 1) and another fraction containing a mixture of prostratin and prostratin succinate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[CH:28]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:34]3[CH2:35][CH2:36][N:31]([CH:28]4[CH2:30][CH2:29]4)[CH2:32][CH2:33]3)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C4CC4)CC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 120 mg (0.33 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 63 mg (0.50 mmoL) N-cyclopropyl piperazine, 139 mg (0.37 mmol) HATU and 96 μL DIPEA in 1.2 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 30 mg (20%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34]/[CH:35]=[CH:36]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1[N:7]=[C:6]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:21]2)[C:5]2[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[CH2:34][O:33][CH3:32])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC/C=C/c1ccc2c(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 110 °C
Yield: 74.5 %

Procedure:
(S)-tert-Butyl 3-(7-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.099 g, 0.20 mmol), trans-3-methoxy-1-propenylboronic acid pinacol ester (0.051 g, 0.23 mmol), Na2CO3 (0.066 g, 0.62 mmol), palladium tetrakistriphenyl phosphine (0.012 g, 0.011 mmol) was dissolved in a toluene (1 mL) and water (0.3 mL) and the mixture was degassed in a sealed tube. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was cooled and diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Further purification by silica column chromatography eluting with a gradient from 1% to 10% methanol in dichloromethane, gave the title compound as a yellow solid (0.071 g, 27%).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21](Cl)[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21]([NH:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1
Reactant: CCOP(=O)(COCCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(COCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of diethyl 3-aminooxypropoxymethylphosphonate (4 g,16.6 mmol), 4,6-dichloro-2,5-diformamidopyrimidine (3.9 g, 16.6 mmol) and diisopropylethylamine (8.67 ml, 49.8 mmol) in diglyme (80 ml) was heated at 100° C. for 2 h. After removal of the solvent under reduced pressure, the residue was chromatographed in chloroform/methanol (100:1, 50:1, 10:1) affording 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-2,5-diformamidopyrimidine as a yellow oil (4.61 g, 63%); νmax (film) 3200, 2990, 1690, 1590, 1220, 1040 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.85(2H, m, CH2CH2CH2), 3.65(2H, t, J6.3 Hz, CH2OCH2P), 3.40(2H, d, J8.2 Hz, CH2P), 3.92(2H, t, J6 Hz, CH2ON), 4.04(4H, m, (CH3CH2O)2), 8.15(1H, s, CHO), 9.25(1H, br.s, CHO), 9.43(1H, br.s, D2O exchangeable, NH), 10.76(1H, br s, D2O exchangeable, NH), 10.86(1H, br.s,D2O exchangeable, NH); Found: M+ 439.1015; C14H23ClN5O7P requires: M+ 439.1024.
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.Br[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:5][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 150 °C

Procedure:
1.15 ml (2.29 mmol) of a 2 M solution of trimethylaluminium in a hexane fraction were added to a solution of 250 mg (0.764 mmol) of the compound of Example 15A and 27 mg (0.023 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.5 ml of anhydrous THF, and the mixture was then, under an argon atmosphere, heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 120 min. After cooling to RT, about 10 ml of water were added, and the reaction mixture was extracted three times with in each case about 10 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness on a rotary evaporator. The product was isolated by preparative HPLC (Method 9). Concentration of the product fractions and drying of the residue under high vacuum gave 98 mg (47% of theory, 95% pure) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[S:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[S:55]([NH2:58])(=[O:57])=[O:56]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:25][CH2:26]3)[CH2:22][NH:58][S:55]([C:51]3[S:50][CH:54]=[CH:53][CH:52]=3)(=[O:57])=[O:56])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccs1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)c2cccs2)C2CC2)C1=O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (100 mg, 0.184 mmol; Example 263, Step C) and cyanomethylenetributylphosphorane (177 μL, 0.734 mmol) in toluene (0.92 mL) was added thiophene-2-sulfonamide (90 mg, 0.55 mmol) and the resulting solution was stirred at 35° C. overnight. The reaction was quenched (sat. NH4Cl), extracted (2×EtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 35% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: [CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[N:18](C)[CH:17]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([O:40][CH3:41])[C:15]=5[O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:10]=4[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:18]=4)[C:15]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:14]([O:40][CH3:41])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c1OCc1ccccc1)C(CCCO[Si](C)(C)C(C)(C)C)N(C)c1c-2ccc2cc3c(cc12)OCO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c(CCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
After 2,3-(methylenedioxy)-5-methyl-6-[3-(t-butyldimethylsiloxy)propyl]-7-benzyloxy-8-methoxy-5, 6-dihydrobenzo[c]phenanthridine (871 mg, 1.46 mmol) was dissolved in toluene (30 mL), activated manganese dioxide (4.36 g) was added to the solution. The mixture was stirred at 100° C. for 2 hours. Manganese dioxide was removed by filtration. Thereafter, the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with 33-66% methylene chloride-hexane) to provide 2,3-(methylenedioxy)-6-[3-(t-butyldimethylsiloxy)propyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (457 mg, yield 54%) as colorless powders.
Reaction SMILES: [OH-].[K+].FC(F)(F)C([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:22][O:23]C(=O)C)=[C:13]([CH2:17][O:18]C(=O)C)[CH:14]=2)[CH2:9]1)=O>O.CO>[NH2:7][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][OH:18])=[C:12]([CH2:22][OH:23])[CH:11]=2)[CH2:16]1
Reactant: CC(=O)OCc1cc2c(cc1COC(C)=O)CC(NC(=O)C(F)(F)F)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1Cc2cc(CO)c(CO)cc2C1

Procedure:
A solution of potassium hydroxide (10.10 g, 0.180 mol) in water (35 ml) was added to a solution of 2-(trifluoroacetylamino)-5,6-bis(acetoxymethyl)indane 47 (20.1 g, 53.8 mmol) in methanol (200 ml) at room temperature, and the mixture was heated to reflux for 2.5 hours. The solvent was removed under vacuum to leave 2-amino-5,6-bis(hydroxymethyl)indane (48) as a semisolid. The crude product was mixed with 1-bromopropane (27.1 g, 0.220 mol) and potassium carbonate (22.32 g, 0.162 mol) in acetonitrile (100 ml), and the mixture was stirred mechanically at reflux on the steam bath for 17 hours. 1-Bromopropane (6.8 g, 0.055 mol) was added, and the reflux was continued for 4 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a brown oil (15.75 g). Purification by flash chromatography (230-400 mesh silica gel, ethyl acetate to 30% tetrahydrofuran in ethyl acetate) gave the title compound (49) as a solid (12.1 g, 81%). A sample (0.50 g) was crystallized from ethyl acetate/hexane to give white crystals (0.48 g).