Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[C:10](CO)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)C1C=CC=CC=1.C(Cl)Cl.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[O:16]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:17][C:13]=2[CH2:14][CH2:15]1
Reactant: OCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2c(c1)CCO2
Temperature: 10 °C
Reaction time: 15 h

Procedure:
A flame dried 1-liter, 3-neck flask fitted with a dropping funnel, mechanical stirrer, N2 inlet, and an internal thermometer was charged with 5-benzyloxy-6-hydroxymethyl-2,3-dihydrobenzofuran (28.90 g, 0.11 moles), methylene chloride (250 ml) and triethylamine (16 ml, 0.11 moles). The reaction mixture was chilled to 10° C. and methanesulfonyl chloride (8.9 ml, 0.11 mole) was added dropwise, while maintaining an internal reaction temperature of 10° C. The resultant yellow-green mixture was warmed to room temperature and stirred for 15 hours. Water (100 ml) was added to the reaction, the layers partitioned and separated. The organic phase was washed sequentially with saturated sodium bicarbonate solution (2×100 ml) and brine (1×100 ml) to remove some greenish color. The yellow organic layear was dried over MgSO4, suction filtered and the filtrate concentrated in vacuo to afford 5-benzyloxy-6-methanesulfonyloxymethyl)-2,3-dihydrobenzofuran a yellow precipitate (33.0 g, 88%). The crude product was used in the next step without further purification which was not necessary for the subsequent reaction.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.[Cl-].[Na+]>CN(C)C(=O)C>[C:3]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
0.192 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.843 g of 4-acetyl-2-butylimidazole-5-carbonitrile [prepared as described in Preparation 24(i)] in 17 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 20 minutes. 1.68 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate was then added, and the resulting mixture was stirred at 55° C. for 2.5 hours. At the end of this time, an aqueous solution of sodium chloride was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting oily residue was purified by column chromatography through silica gel, using 4:1 and 2:1 by volume mixtures of hexane and ethyl acetate as the eluent, to afford 1.14 g of the title compound as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([CH2:17][CH2:16][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: OCCn1ccnc1
Product: CC1(C)CC(=O)c2ccc(OCCn3ccnc3)cc2O1

Procedure:
Following the procedure of Example 30 but using 7-hydroxy-2,2-dimethyl-4-chromanone and 1-(2-hydroxyethyl)imidazole, there was obtained the title compound as a solid, mp 84-86° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 287 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[N:18]([O-])=[O:19].[Na+]>C(O)C.O>[N:18]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8]1)=[O:19]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CC(c1ccncc1)CN2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=NN1CC(c2ccncc2)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 3-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline (0.4 g, 0.0019 mol) in ethanol (1.7 mL) was added 1N hydrochloric acid (1.7 mL). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (0.262 g, 0.0038 mol) in water (5.5 mL) was added at 0° C. The reaction mixture was warmed to RT and stirred for 1 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure to obtain product as a brown colored oil (0.41 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.O1CCCC1.[CH3:17][NH2:18]>C1(C)C=CC=CC=1.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][NH:18][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:2]=[CH:1][CH:11]=1
Reactant: CN
Reactant: O=C1CCCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1cccc2ccccc12
Temperature: -40 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Into a solution of 10 g (68 mmol) of α-tetralone in 140 mL of toluene is added 200 mL (400 mmol) of a 2.0 M tetrahydrofuran solution of methylamine at -5° C. to 0° C. After the addition is complete, the reaction mixture is cooled to -40° C. and 34.6 mL (34.6 mmol) of a 1 M solution of titanium tetrachloride in methylene chloride is added over a 15 minute period. After this addition is complete, the reaction mixture is allowed to warm to ambient temperature. After stirring at ambient temperature for 16 hours, the reaction mixture is filtered and the filtrate is concentrated to a crude oil. The crude oil is then dissolved in 150 mL of xylene and 200 mg of 5% palladium on charcoal catalyst is added. The reaction mixture is then heated to reflux for 16 hours. The palladium catalyst is then removed by filtration and the filtrate is concentrated to give 9 g of a crude oil which is purified by flash chromatography (silica gel, 2.5% ethyl acetate in hexane) to give 6 g of an oil in 60% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: CN1CCNCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C)CC4)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.200 g, 0.469 mmol), N-methyl piperazine (0.062 mL, 0.563 mmol), 1-hydroxy benzotriazole (0.070 g, 0.516 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.099 g, 0.516 mmol) were combined in amine-free N,N-dimethylformamide (1.9 mL), followed by the addition of N,N-diisopropylethyl amine (0.123 mL, 0.704 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform to afford 0.224 g of the title compound as an oil. The oil thus obtained was dissolved in diethyl ether and diluted with hexane to afford a pale yellow solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([Cl:29])=[C:10]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2=[O:28])[CH:11]=1.C(N(CC)CC)C>O1CCCC1>[Cl:29][C:9]1[CH:8]=[C:7]([F:30])[C:6]([N:5]=[C:1]=[S:2])=[CH:11][C:10]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]1=[O:28]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N=C=S)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thiophosgene (0.50 mL, 6.5 mmol) is added over 45 minutes to a solution of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (2.5 g, 6.5 mmol), and triethylamine (1.8 mL, 13.0 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 4 hours, diluted with tetrahydrofuran, and filtered. The filtrate is concentrated in vacuo to give the title product as an orange oil which is identified by NMR spectral analyses.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=[O:38])[CH2:9]1)=O)(C)(C)C.O.[ClH:41]>O1CCOCC1>[ClH:41].[ClH:41].[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@@H:12]2[CH2:13][NH:8][CH2:9][C@H:10]([C:37]([OH:39])=[O:38])[CH2:11]2)=[O:20])=[CH:26][N:25]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (102 mg) was dissolved in 1,4-dioxane (3 ml), water (100 μl) and 6 N hydrochloric acid (3 ml) were added and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was concentrated under reduced pressure to give the object compound (99 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16](O)[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.CCOCC>[C:19]([O:23][C:24]([N:26]([CH:16]([CH3:17])[CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C=Cc1cccc(Oc2ccccc2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
(-)-(E)-1-3(-Phenoxyphenyl)but-1-en-3-ol from step (d) (2.6 g), N,O-bis(t-butoxycarbonyl)hydroxylamine (2.65 g), and triphenylphosphine (4.25 g) were taken up in toluene (30 ml) and cooled to -78° C. under N2. A solution of DEAD (2.9 g) in toluene (10 ml) was then added and the mixture allowed to warm to room tempterature. 40/60 pet.ether (60 ml) was added to precipitate Ph3P=O as a dark gummy mass. The mother liquor was decanted off and stripped to give a tan/orange oil which was eluted through a silica gel column using methylene chloride. The eluate was stripped to give a pale yellow oil which was eluted through a second silica gel column using ether/methylene chloride/40-60 pet.ether (1:1:8) and the eluate stripped to give the desired product as a colourless oil which was dried under high vacuum. Yield 1 97 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:13]O>>[Cl:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
Hydrogen chloride gas is bubbled into a mixture of 4-chlorosalicylic acid (100 g, 0.579 mol) in methanol while maintaining the temperature at 45°-50° C. The reaction mixture is then stirred at room temperature for several hours, concentrated in vacuo and extracted with ether. The combined organic extracts are washed sequentially with brine, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. The oil is distilled under reduced pressure to give the title product as a colorless oil which is identified by NMR spectral analyses.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:16]=1
Reactant: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 92.9 %

Procedure:
3-(4-Benzyloxy-phenyl)-pyridine (1.15 g, 4.4 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.5 g) over period of 48 h at rt under H 2 balloon. Reaction mixture was filtered through Celite and concentrated to obtain the product (700 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:50][C:51]1[S:52][C:53]2[CH:59]=[C:58]([OH:60])[CH:57]=[CH:56][C:54]=2[N:55]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:50][C:51]2[S:52][C:53]3[CH:59]=[C:58]([OH:60])[CH:57]=[CH:56][C:54]=3[N:55]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc3ccc(O)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (276 mg, 1.203 mmol), of HATU (549 mg, 1.444 mmol) and of diisopropylethylamine (187 mg, 1.44 mmol) in 3 ml of DMF is stirred at room temperature for 15 minutes. The 2-aminobenzothiazol-6-ol (intermediate 1) (200 mg, 1.203 mmol) dissolved in 3 ml of DMF is added in a single portion. The reaction medium is stirred at room temperature for 2 hours, poured into a 10% solution of Na2CO3 in water (20 ml) and extracted with ethyl acetate. The crude reaction product is purified by column chromatography (eluent: EtOAc/heptane (1/1)) to give 401 mg of 4-(6-hydroxybenzothiazol-2-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (white solid).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[C:3]([C:20]2[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1ccc(C=O)s1)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(b), by reaction of 4.2 g (17 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 2.17 g (11.3 mmol) of 5-bromo-2-thiophenecarboxaldehyde, 2.1 g (60%) of the expected aldehyde are obtained, with a melting point of 130-5° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)(O)[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29]([C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: COc1cnc2c(c1)cc(C(O)(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(C(=CC3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 38 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethanol (184 mg, 0.33 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo and the residue was washed with methanol to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 64.1%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.3.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40]>C(Cl)Cl>[F:48][C:42]1[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reaction time: 0.83 h

Procedure:
Benzoyl isothiocyanate (2.1 ml) was added to a solution of [(2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl]methanol, obtained in Preparation Example 4-(23), (7.04 g) in DCM (26 ml) at 0° C. After stirring for 10 h and 50 mins at same temperature, the mixture was directly purified by silica gel column chromatography (gradient from 20% to 50% EtOAc in heptane) to afford the titled compound (9.47 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:30][CH2:31]Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC(N(C)C)=O>[C:17]([O:30][CH2:31][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 74.1 %

Procedure:
In 100 ml of dimethylacetamide were dissolved 19.51 g (0.15 mol) of 5-fluorouracil and 75.90 g (0.75 mol) of triethylamine. To this mixture was added dropwise at room temperature 41.05 g (0.165 mol) of chloromethyl laurate and the mixture was reacted together for 20 hours. After completion of the reaction, the triethylamine and dimethylacetamide were removed by distillation and the residue was poured into 400 ml of water. The mixture was stirred, filtered and washed with water whereby crystals were obtained which were then recrystallized from 200 ml of ethanol to obtain 38.06 g of 1-lauroyloxymethyl-5-fluorouracil having a melting point of 113.7~114.2° C. in a yield of 74.2%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:28][CH2:29][C:30]1([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])[O:34][CH:33]([CH2:35]OS(C)(=O)=O)[CH2:32][O:31]1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:28][CH2:29][C:30]1([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])[O:34][CH:33]([CH2:35][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)[CH:15]=4)[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH2:32][O:31]1
Reactant: Cc1ccc(-c2cc(N3CCN(c4ccc(O)cc4)CC3)nc(C)n2)cc1
Reactant: CS(=O)(=O)OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(N3CCN(c4ccc(OCC5COC(CBr)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)nc(C)n2)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A mixture of 3.605 g (10 mmol) of 1-(4-hydroxyphenyl)-4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazine, 80 ml of toluene, 4.20 g (10 mmol) of 2-bromomethyl-2-(2,4 -dichlorophenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane (cis/trans mixture), 0.65 g of tetrabutylammonium bromide and 13.5 ml of 50% strength sodium hydroxide solution was stirred vigorously for 4 hours at 55° C. The phases were subsequently separated at room temperature, the sodium hydroxide solution was extracted by shaking three times with ether, and the tolune and ther phases were combined. These were washed three times with water, dried, filtered and evaporated in vacuo. The residue remaining (7.4 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.6 cm, height 11 cm) with elution using CH2Cl2. After elution, the fractions which were unary according to TLC were combined and evaporated in vacuo. 6.27 g (=91.6% yield) of 2-bromomethyl-2 -(2,4-dichlorophenyl)-4-[4-(4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (cis/trans mixture) were obtained as a highly viscous oil;
Reaction SMILES: C([O:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@](C)(CO)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@](C)(O)CO
Yield: 92.8 %

Procedure:
22 g of ethyl (R)-2-benzyloxy-3-hydroxy-2-methyl-propionate (manufactured in accordance with Example 1) in 150 ml of ethyl acetate were hydrogenated with hydrogen gas in the presence of 11 g of 5% by weight palladium/carbon catalyst up to the cessation of the hydrogen uptake. The catalyst was filtered off, washed with ethyl acetate (2×50 ml), the filtrate was concentrated in the vacuum and the residual oil was distilled at 56°-57°/0.1 mmHg. There were obtained 12.7 g of ethyl (R)-2,3dihydroxy-2-methylpropionate in the form of a colorless viscous liquid. [α]D =+0.339° (undiluted);=11.6° (c=2.12 in chloroform).