Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:19]=[C:18]2[CH3:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:26]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:19]=[C:18]2[CH3:25])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:26])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Cc1cc(=O)n(-c2ccc(NCCN3CCOCC3)c(F)c2)c(C)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cc1cc(=O)n(-c2ccc(N(C)CCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 20.1 %

Procedure:
To a suspension of 3-(3-fluoro-4-((2-morpholinoethyl)amino)phenyl)-2,6-dimethyl pyrimidin-4(3H)-one (0.24 g, 0.69 mmol) and K2CO3 (0.48 g, 3.47 mmol) in acetonitrile (15 mL) was added CH3I (0.30 g, 2.11 mmol). The mixture was stirred at rt for 36 h, then filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH (V/V)=50:1) to give the title compound as a white solid (50 mg, 20%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:11]=1.[CH2:16]=[O:17].Cl>O1CCCC1.II>[CH3:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([CH2:16][OH:17])=[CH:11][N:10]2[CH:12]=1
Reactant: Cc1cn2cc(Br)ccc2n1
Reactant: C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1cn2cc(CO)ccc2n1
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
In a nitrogen atmosphere, 78.56 g of magnesium was added to 2 l of tetrahydrofuran and 0.3 g of iodine and 18 ml of bromoethane were added to the obtained mixture to prepare a Grignard reagent. A solution of 170.5 g of 6-bromo-2-methylimidazo[1,2-a]pyridine and 162 ml of bromoethane in 500 ml of tetrahydrofuran was slowly dropped into the above reaction mixture. After the completion of the dropping, the obtained mixture was heated under reflux for 30 minutes and then cooled with ice. Formaldehyde gas generated by heating a container containing 242 g of paraformaldehyde to 200° C. was introduced into the reaction mixture by the use of a nitrogen stream. After 30 minutes, dilute hydrochloric acid was added to the resulting mixture and the obtained mixture was filtered to remove insolubles. The filtrate was alkalinized with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 120 g of the title compound as a pale-yellow solid (yield: 91.9%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH2:15]O.O>C1(C)C=CC=CC=1>[Cl:4][CH2:15]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: F/C=C(/CCl)CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Cool to -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution in toluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-l-ol (24.7 g, 30% by weight in toluene, 0.124 mol). After 18 hours, add water (500 mL) and stir for 30 minutes. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Cc1cccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1N
Product: CC(=O)Nc1c(C(=O)c2ncccc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(3-methylpyridine-2-carbonyl)indole (Example 367) and acetyl chloride. m.p.: 173-175° C. (recrystallized from ethyl acetate)
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:38])[C:11](=[O:37])[NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14](=[O:33])[N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:32])[NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)C(=O)OC(C)(C)C.CO.C(Cl)[Cl:42]>CC#N.CC([O-])=O.CC([O-])=O.[Cu+2]>[ClH:42].[CH3:1][NH:2][C@@H:10]([CH3:38])[C:11]([NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:32])=[O:33])=[O:37]
Reactant: C#CC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: ClCCl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC#N
Product: C#CC[C@H](NC(=O)[C@H](C)NC)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Product: Cl

Procedure:
The title compound of Example 3 (600 mg, 1.14 mmol) and Cu(OAc)2 (1.05 g, 5.76 mmol) were dissolved in CH3CN (7.6 mL). This was refluxed for 20 mins. By TLC (10% MeOH/CH2Cl2), starting material was still present, so the mixture was refluxed for an additional 20 mins. By TLC, starting material had been consumed. Removed CH3CN via rotary evaporation and vacuum pump. Residue was then partitioned between ethyl acetate and water. Aqueous phase was discarded and organic phase was washed with brine and dried over Na2SO4. Oily residue was purified via flash column chromatography (a gradient of 100% ethyl acetate to 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to afford the title compound as a white solid. 1H NMR (CD3OH): consistent with proposed structure. MS (m/z): 1047.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH:17][S:36]([CH3:35])(=[O:38])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2.5 h

Procedure:
(S)-N6-Benzyloxycarbonyllysine (1.5 kg) was slurried in methylene chloride (7.5 l) and chlorotrimethylsilane (1.36 l) added over 10 minutes. The mixture was heated under reflux for 30 minutes to give a solution which was cooled to 3° C. before simultaneously adding diisopropylethylamine (1.87 l) and methanesulphonyl chloride (435 ml) at such a rate as to keep the temperature below 25° C. The reaction was stirred for a further 2.5 hours then poured into 2 M aqueous hydrochloric acid solution. The layers were separated and the methylene chloride phase was washed with 2 M aqueous hydrochloric acid solution followed by water. The solvent was removed under reduced pressure and replaced with n-butyl acetate. The solution was cooled and the resulting crystalline material was collected by filtration, washed with n-butyl acetate and dried under reduced pressure to provide the title compound (1.63 kg), m.p. 83.5-84° C. [α]D25−13.4° (c=1, methanol). Found: C,50.23; H,6.40; N,7.76.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:25][C@:26]1([CH3:51])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:29][C@H:27]1[OH:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.COCCOC>[C:1]([O:28][C@@H:27]1[O:29][C@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C@@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@:26]1([CH3:51])[O:25][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:25][C@:26]1([CH3:51])[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:29][C@H:27]1[OH:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: C[C@]1(OC(=O)c2ccccc2)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1

Procedure:
One preferred embodiment of the present invention is exemplified in FIG. 1 and comprises reacting D-fructose in the presence of CaO/water at 23-40° C. for 6-22 hours, and then adding CO2 and oxalic acid to the reaction mixture and allowing the reaction to proceed for 8-12 hours to form 2-C-methyl-D-ribonic-γ-lactone (1); reacting 2-C-methyl-D-ribonic-γ-lactone (1) with 4-dimethylaminopyridine (DMAP) and triethylamine (TEA) in 1,2-dimethoxyethane (DME) at temperature of from about 5° C. to 25° C. for about 30 minutes, and then cooling the mixture to about 5° C. and adding benzoyl chloride to provide 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribonic-γ-lactone (2); reacting 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribonic-γ-lactone (2) with Red-Al/ethanol in toluene at a temperature of from about −5 to 0° C. for about 40 minutes to provide 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose (3); and finally adding benzoyl chloride/TEA to a cold solution of 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose (3) in the presence of DMAP and DME and allowing the reaction to proceed for from about 4 hours to about 12 hours at a temperature of from about 5 to about 50° C., thereby providing the final product (4), 2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranose.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]1[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NC(=O)c1ccccc1O
Product: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21

Procedure:
Salicylamide (40.0 g.) and anhydrous chloral (400 ml.) were heated together on a steam-bath for 3 hours, the reaction mixture was cooled, and the excess of chloral was evaporated under reduced pressure. The syrupy product was mixed with concentrated sulphuric acid (500 ml.) and heated on a steam-bath for 1 hour. The mixture was cooled and poured into crushed ice (3 kg.), and the precipitated solid was filtered off, triturated with diethyl ether (300 ml.) and filtered again. The solid product was stirred with water (1 l.), filtered, washed well with water, dried and crystallised from ethanol (400 ml.) to yield 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].[Cl:15]C1C=C2C(=CC=1)NC(=O)C2=O.BrCCC>>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available 5-chloroisatin (purchased from Fisher Scientific) and 1-bromo-propane (purchased from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.88 (d, 1H), 3.69 (t, 2H), 1.74 (m, 2H), 1.00 (t, 3H)
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[F-:29].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:29][CH2:2]/[CH:3]=[CH:4]/[C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1
Reactant: [F-]
Reactant: BrC/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: FC/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A stirred solution of E-1-bromo-3(1-trityl-1,2,4-triazol-3-yl)prop-2-ene) (34.47 g, prepared as described in Example 12) in dry dichloromethane (150 ml) was treated, under nitrogen, with tetrabutylammonium fluoride (160 ml, 1M in tetrahydrofuran). The mixture was heated under reflux for thirty minutes, cooled, washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give E-1-fluoro-3(1-trityl-1,2,4-triazol-3-yl)prop-2-ene (19.37 g, m.p. 149° C.). NMR (CDCl3): δ4.95, 5.15(2H,dd), 6.7-6.9(2H,m), 7.1-7.3(15H,m), 7.9(1H,s). JCH=CH 16.1 Hz, JHF 46.8 Hz. 19F NMR (CDCl3): -216.4 ppm vs. CFCl3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([NH2:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH2:25]([NH:27][C:18]([C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:15]([CH3:23])[CH:16]=1)=[O:20])[CH3:26]
Reactant: CCN
Reactant: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid (0.866 g, 2.70 mmol), ethanamine hydrochloride (0.264 g, 3.24 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.777 g, 4.05 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.621 g, 4.05 mmol) were suspended in DMF (Volume: 3.68 ml) and 4-methylmorpholine (1.486 ml, 13.52 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. It was diluted with water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with 1N HCl(aq., 25 mL), NaHCO3 (sat. aq., 25 mL), water (25 mL), brine (25 mL), dried (MgSO4), concentrated in vacuo and dried under vacuum to afford tert-butyl 4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9327 g, 2.68 mmol, 99% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.24 (t, J=5.4 Hz, 1 H), 7.66 (d, J=1.8 Hz, 2 H), 7.03 (d, J=8.3 Hz, 1 H), 3.42-3.52 (m, 4 H), 3.20-3.27 (m, 2 H), 2.78-2.87 (m, 4 H), 2.28 (s, 3 H), 1.43 (s, 9 H), 1.10 ppm (t, J=7.2 Hz, 3 H). ESI-MS: m/z 348.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1.[CH3:21][NH2:22].[I-].[Na+]>C(#N)C.O>[CH3:21][NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1
Reactant: O=c1c2ccccc2sc2ccc(OCCCCl)cc12
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNCCCOc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
26 g (85 mmol) 2-(3-chloropropoxy)-9H-thioxanthen-9-one is suspended in 140 mL acetonitrile. 66 g (73.2 mL, 0.85 mol) of a 40% solution of methyl amine in water was added and the mixture was heated to 60° C. After four hours, 1.3 g (8.5 mmol) sodium iodide and 20 mL of a 40% solution of methyl amine in water were added and the reaction was allowed to continue for 16 hours at 60° C. The precipitated compounds were isolated by filtration and washed three times with 100 mL acetonitrile. The pooled acetonitrile fractions were evaporated under reduced pressure. The crude 2-(3-methylaminopropoxy)thioxanthen-9-one was crystallized from 200 mL hexane, isolated by filtration and dried. 19 g of 2-(3-methylaminopropoxy)thioxanthen-9-one was isolated. 2-(3-methylaminopropoxy)thioxanthen-9-one was further purified by preparative column chromatography on a Prochrom LC80 column, using Kromasil C18 100A 10 mm as silica and methanol/1M ammonium acetate 68/32 as eluent at a flow rate of 150 mL per minute.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[C:40](Cl)(=[O:42])[CH3:41]>N1C=CC=CC=1>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:41])=[O:42])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O

Procedure:
Here, 10-deacetylbaccatin III is reacted with a large excess of TES-Cl and pyridine to produce C-7 TES protected 10-deacetylbaccatin III. The product is next acylated utilizing an excess of acetyl chloride and pyridine to produce C-7 TES baccatin III.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]C(=O)C)[CH2:5][CH2:4]1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([S:10][CH2:9][CH:6]1[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SCC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A solution of 0.86 g (15.2 mmol) of potassium hydroxide in ethanol (78 mL, degassed and under nitrogen) was added to 0.81 g (4.66 mmol) of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester. The reaction was stirred at room temperature under nitrogen for 0.5 h. Then 2.1 mL (14.1 mmol) of ethyl α-bromoisobutyrate were added and the reaction stirred for 4 h. The resulting precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL) and dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure, followed by column chromatography of the residue (silica, eluent: heptanes, 0-20% ethyl acetate) afforded 0.76 g of 2-methyl-2-(tetrahydro-pyran-4-ylmethylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[C:13]([CH3:33])=[N:14][S:15][C:16]=1[NH:17][C:18](=[O:32])[CH2:19][C:20]1[CH:31]=[CH:30][C:23]2=[N:24][N:25]([CH2:27][CH2:28][CH3:29])[N:26]=[C:22]2[CH:21]=1.Cl[CH2:35][O:36][CH2:37][CH3:38].O>O1CCCC1>[Cl:11][C:12]1[C:13]([CH3:33])=[N:14][S:15][C:16]=1[N:17]([CH2:35][O:36][CH2:37][CH3:38])[C:18](=[O:32])[CH2:19][C:20]1[CH:31]=[CH:30][C:23]2=[N:24][N:25]([CH2:27][CH2:28][CH3:29])[N:26]=[C:22]2[CH:21]=1.[CH2:37]([O:36][CH2:35][N:14]1[CH:13]([CH3:33])[CH:12]([Cl:11])[C:16](=[N:17][C:18](=[O:32])[CH2:19][C:20]2[CH:31]=[CH:30][C:23]3=[N:24][N:25]([CH2:27][CH2:28][CH3:29])[N:26]=[C:22]3[CH:21]=2)[S:15]1)[CH3:38]
Reactant: CCOCCl
Reactant: CCCn1nc2ccc(CC(=O)Nc3snc(C)c3Cl)cc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1nc2ccc(CC(=O)N(COCC)c3snc(C)c3Cl)cc2n1
Product: CCCn1nc2ccc(CC(=O)N=C3SN(COCC)C(C)C3Cl)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 3.3 ml, 0.0033 mol) was added dropwise to a solution of N-(4-chloro-3-methylisothiazol-5-yl)-(2-propylbenzotriazol-5-yl)acetamide (Compound No. A3.1) (0.699 g, 0.002 mol) in tetrahydrofuran (10 ml) and once the addition was complete the mixture was stirred at room temperature for 30 minutes. Chloromethylethyl ether (0.620 g, 0.0066 mol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water, neutralised, and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was further purified by flash column chromatography, eluting initially with 2:1 hexane:ethyl acetate and then with ethyl acetate to give N-(4-chloro-3-methylisothiazol-5-yl)-N-(ethoxymethyl)-(2-propylbenzotriazol-5-yl)acetamide (0.135 g) as an orange gum and N-[2-ethoxymethyl-4-chloro-3-methylisothiazolin-5-ylidene]-(2-propylbenzotriazol-5-yl)-acetamide (0.128 g) as a colourless solid, m.p. 108–109° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:25](=[O:34])[C:24]3=[O:35])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1.[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[N+:39]([O-:62])[CH:40]=[C:41]([Cl:61])[C:42]=1[CH2:43][C@@H:44]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[C:48]([O:56][CH2:57][CH:58]2[CH2:60][CH2:59]2)[CH:47]=1)[O:32][C:31](=[O:33])[CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:29][CH:28]=2)[C:24](=[O:35])[C:25]1=[O:34]
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt (0.319 g, 0.607 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.170 g, 0.405 mmol), EDC (0.233 g, 1.214 mmol), and DMAP (0.099 g, 0.809 mmol) in DCM (25 ml) was stirred at room temperature for 3 days. The mixture was diluted with DCM and washed with aqueous 5% NaHCO3 and with sat. NH4Cl; the organic phase was dried over sodium sulfate, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1 to 95:5). An additional purification by chromatography on silica gel column (DCM:MeOH=98:2 to 97:3) was performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.113 g, 0.139 mmol, 34.3% yield, MS/ESI+ 813.19 [MH]+, [αD]=−26.83, c=0.24, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.69 (d, 1H), 7.68 (dd, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.04 (dd, 1H), 4.69 (d, 1H), 4.58 (d, 1H), 3.93 (d, 2H), 3.74 (t, 2H), 3.46-3.55 (m, 4H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (s, 3H), 2.37 (t, 2H), 2.28-2.34 (m, 4H), 1.08-1.36 (m, 1H), 0.47-0.66 (m, 2H), 0.27-0.49 (m, 2H).