Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N.CO.CCOC(C)=O>CC(O)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Br:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.1 mmol) in 10 ml of AcOH was added Br2 (0.057 ml, 1.1 mmol) in a portion. The resulting reaction mixture was stirred for 1 h at 25° C. Concentration of reaction mixture in vacuo yields a brown oil which was subjected to column chromatography (30% NH3 sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of the desired product. The product obtained was recrystallized from MeOH to afford 0.22 g (56%) of the product as a light brown solid: mp 320-321° C.; Anal. Calc. for C10H9N5Br2 requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Crude 5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.5 g) is dissolved in 5 mL of methylene chloride containing TFA (2 mL) and TFMSA (1.6 mL). The reaction mixture is stirred at room temperature overnight. After routine workup, the obtained crude product is purified by column chromatography to give 730 mg of product as gray solids. MS (ESI) m/z 256.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>CN(C=O)C>[C:32]1([C:29]2[O:28][C:27]([C:25]([N:23]3[CH2:24][CH:21]([O:1][C:2]4[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=4)[CH2:22]3)=[O:26])=[N:31][N:30]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
4-Hydroxybenzaldehyde (1.10 g, 9.17 mmol), cesium carbonate (3.49 g, 10.70 mmol) and 53B (2.70 g, 7.64 mmol) were mixed with DMF (80 mL). The mixture was stirred at 110° C. for 18 h and then cooled to RT. The solids were filtered off and the filtrate was evaporated. The residue was treated with methanol and the formed solid was collected by filtration. Drying under vacuum afforded 1.8 g (62%) of 68A as a beige solid. 1H NMR (500 MHz, DMSO-d6): δ 3.85 (s, 3H), 4.13 (dd, 1H), 4.57 (dd, 1H), 4.65 (dd, 1H), 5.12 (dd, 1H), 5.29 (m, 1H), 7.10 (d, 2H), 7.16 (d, 2H), 7.90 (d, 2H), 8.00 (d, 2H), 9.90 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:18])[CH:7]([NH:13][C:14](=[O:17])[CH2:15][Cl:16])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)C>O.C(O)C>[Cl:16][CH2:15][C:14]([NH:13][CH:7]([C:8]1[N:9]=[CH:10][S:11][CH:12]=1)[C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)C(NC(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CCl)NC(C(=O)O)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2.5 g of potassium hydroxide in a mixture of 10 ml of water and 100 ml of ethanol is added 3.0 g of 2-chloroacetamido-4-thiazolyl acetic acid ethyl ester, and the mixture is stirred for one hour at room temperature. The solvent is evaporated under reduced pressure. To the residue is added 10 ml of water. The resulting aqueous solution is washed with ethyl acetate, and then adjusted to pH 2 with 10% hydrochloric acid, whereupon crystals separate out. The crystals are collected by filtration, washed with water, and dried to yield 2.2 g (84%) of 2-chloroacetamido-4-thiazolyl acetic acid, m.p. 193°-195° C.
Reaction SMILES: C([O-])(=O)C.[Cu+2:5].C([O-])(=O)C.[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[NH2:10][CH2:11][C:12]([O-:14])=[O:13].[Cu+2:5].[NH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: NCC(=O)[O-]
Reaction time: 2 h

Procedure:
1.8 g (9.8 mmol) copper (II) acetate is dissolved in 100 ml hot methanol, and a solution of 1.5 g (20 mmol) glycine in 50 ml methanol is added with stirring. The solution becomes turbid due to precipitation of the product. Stirring is continued for two hours at a temperature causing precipitation. The precipitated product is filtered off and dried.
Reaction SMILES: [O-2].[Mg+2:2].[NH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(O)C>[NH2:3][CH2:4][C:5]([O-:7])=[O:6].[Mg+2:2].[NH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: NCC(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: NCC(=O)[O-]
Reaction time: 5 h
Yield: 99.8 %

Procedure:
The ethanol solvent recovered from Example 1, approximately 80 ml, was distilled to remove any impurities and then combined with fresh ethanol to total 100 ml for this experiment. 4.0 grams (0.1 Mole) of magnesium oxide and 15 grams (0.2 Mole) of glycine were placed into a beaker provided with a reflux condenser. The 100 ml ethanol was added and the mixture was stirred and boiled at atmospheric pressure for 5 hours. The reaction mixture was then cooled, and thereafter filtered yielding 17.2 grams of magnesium glycinate having the physical characteristic of a fine white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:10]([CH3:9])=[CH:11][C:12]([CH3:13])=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2ccc(N)nc2n1
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (43.6 g., 0.4 mole), 40.0 g (0.4 mole) of 2,4-pentanedione, 200 ml. of glacial acetic acid and 5 ml. of 96% sulfuric acid were mixed, then refluxed with stirring for 24 hours. The cold solution was added slowly with good stirring and ice bath cooling to 160 g of sodium hydroxide in enough water to make 600 ml. The brown solid, which crystallized, was filtered after the solution had been cooled overnight at 5°, washed twice with cold water and dried, 25.3 g., m.p. 125°-200°. This crude material was dissolved in 130 ml. of boiling 95% ethanol and the solution chilled overnight at -15°, 19.5 g. (28%), m.p. 215°-220°. This material was suitable for the following experiment.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:24][CH2:14][C:15]2[CH:23]=[CH:22][C:21]3[O:20][CH2:19][O:18][C:17]=3[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 96.9 %

Procedure:
A mixture comprising 3.6 g of 2,4,6-trichloroquinazoline, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was heated under reflux for 1.5 hours and hot-filtered to give 5.2 g of the title compound as a filter cake.
Reaction SMILES: CCCCCCCCCCC.[CH2:12]([C:15]1([CH3:25])[CH:21]2[CH2:22][C:18]([CH3:23])([CH2:19][CH2:20]2)[CH2:17][C:16]1=[O:24])[CH:13]=[CH2:14].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:12]([C:15]1([CH3:25])[CH:21]2[CH2:22][C:18]([CH3:23])([CH2:19][CH2:20]2)[CH2:17][CH:16]1[OH:24])[CH:13]=[CH2:14]
Reactant: C=CCC1(C)C(=O)CC2(C)CCC1C2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCC
Product: C=CCC1(C)C(O)CC2(C)CCC1C2
Temperature: 75 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Preparation of 2,4,8-Trimethyl-5-oxa-tricyclo[6.2.1.0*2,6]undecane (Structure 4): 4-Allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-one (288 g, 1.5 mol, obtained as above in EXAMPLE IV) was added to a solution of Red-Al (65%, 506 g, 1.5 mol) in toluene at 75° C. The reaction mixture was aged for 3 hours while the temperature was maintained at 75° C., then cooled to room temperature, and subsequently quenched with a solution of sodium bicarbonate (NaHCO3). Distillation of the organic layer provided 4-allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-ol (288 g, 1.5 mol), which was then added to a MSA solution (30 g) in toluene (500 mL) and heated to reflux for 3 hours. The reaction mixture was subsequently washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 2,4,8-trimethyl-5-oxa-tricyclo[6.2.1.0*2,6*]undecane (170 g) having a boiling point of 62° C. at a pressure of 0.3 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, 5% Pd/C catalyst (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 5-10 psi of hydrogen pressure for a period of 10-15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100-105 g, 80-83%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C1COCC1.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: C1CCOC1
Reactant: CC(=O)OCC(F)Br
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionealdehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionealdehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.[H-].C([Al+]CC(C)C)C(C)C.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:14][C:13]([F:15])([F:16])[C:10]1[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of the ester obtained in step 1 (37.1 g) in toluene (310 ml) at 0° C. was added dropwise diisobutylaluminum hydride (1.2M in toluene, 317 ml) and the solution was stirred at 0° C. for 1 h. Water (47.6 ml) was carefully added at 0° C. followed by sodium hydroxide 2M (47.6 ml) and finally water (95.1 ml). The mixture was allowed to stir at room temperature for 1 h. After filtration, the solution was washed with hydrochloric acid 2N, water and brine, dried over sodium sulfate and concentrated in vacuo to give 29.5 g of the desired alcohol as a solid (96%) which was characterized by its mass and NMR spectra.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol (1.0 g, 4.5 mmol), phthalimide (1.0 g, 6.8 mmol) and triphenylphosphine (1.8 g, 6.8 mmol) in THF (20 mL), di-tert-butyl azodicarboxylate (1.6 g, 6.8 mmol) was added slowly at 0° C. The resulting mixture was stirred at 0° C. for 3 h. After concentrated concentrating under reduced pressure, the crude product was purified by silica gel column chromatography (eluting with 0-70% EtOAc in hexanes) to give a solid, which was further treated with DCM and hexanes to yield sub-title compound (1.55 g, 98%). LCMS calc. for C19H16N3O4 (M+H)+: m/z=350.1. Found: 350.3.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1(O)[CH2:13][CH2:12]C[CH2:10][CH2:9]1.C1(NC2C=CC(C3C=CC(NC4C=CC=CC=4)=CC=3)=CC=2)C=CC=CC=1.[C-]#N.[K+].C(OC)(=O)C(C)=C.CO>>[C:1]([O:6][CH:7]1[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: OC1CCCCC1
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Solvent: CO
Product: C=C(C)C(=O)OC1CCCCC1
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
400 g of methyl methacrylate (4 mole), 200 g of cyclohexanol (2 mole) and 0.30 g of N,N'-diphenylbenzidine (500 ppm) are added to a 1 liter round-bottomed flask. Azeotropic dehydration is accomplished by conducting air through the resulting mixture, by way of a 1 m vigreux column. After cooling of the contents of the flask to about 75° C., 3 g of potassium cyanide (0.5%) are added, and the methyl methacrylate/methanol-azeotrope is distilled-off at a temperature of 65° C. at the head of the column. The trans-esterification is completed after 3.5 hours. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A residue of cyclohexyl methacrylate of 310 g = 85% will result.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][S:7]([CH2:10][CH2:11][OH:12])(=[O:9])=[O:8].CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl>[CH3:6][S:7]([CH2:10][CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
In a 50 mL round-bottomed flask, 2-(methylsulfonyl)ethanol (1.24 g, 9.99 mmol, Eq: 1.00) was combined with DCM (5 mL). To the resulting solution was added diisopropylethylamine (2.1 mL, 12.0 mmol, Eq: 1.2) and methanesulfonyl chloride (1.37 g, 931 μL, 12.0 mmol, Eq: 1.2). The ice bath was removed and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes) to give 2-(methylsulfonyl)ethyl methanesulfonate (1.01 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].I[CH3:14].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
980 mg (5.0 mmol) of 5-bromoindole were added to a solution of 420 mg (7.5 mmol) of pulverized KOH in dimethyl sulfoxide (15 ml) following stirring 15 min at RT. After stirring at RT a further 5 min, 342 μl (5.5 mmol) of iodomethane were added and the mixture was then stirred at RT over a period of 1 h. Following neutralization with 5% strength aq. hydrochloric acid, the reaction mixture was extracted with EA. The organic phase was successively washed with water and a satd aq. NaCl soln and dried over MgSO4. Following filtration and removal of the solvent in vacuo there were obtained 980 mg (4.7 mmol, 93%) of 5-bromo-1-methylindole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH:23]C(OCC[Si](C)(C)C)=O)[N:18]=[CH:17]1)=[O:12].CCOC(C)=O.CO.[NH4+].[OH-].[ClH:43]>C(#N)C>[ClH:43].[ClH:43].[ClH:43].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:21][CH2:22][NH2:23])[N:18]=[CH:17]1)=[O:12]
Reactant: C[Si](C)(C)CCOC(=O)NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCc1cn(CCNC(=O)CCSSc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
13 mg (0.026 mmol) of IV is dissolved in 1 ml of acetonitrile containing 0.15 ml of conc. HCl. The reaction mixture is stirred at room temperature for 2.5 hours. TLC on silica gel with EtOAc--MeOH--NH4OH (80:20:1) as the mobile phase shows that the trimethylsilylethyloxycarbonyl protective group has been completely removed after 2.5 hours. The reaction solution is evaporated, whereupon an NMR analysis is run in D2O+ deuterated acetonitrile. ##STR4## 1-CH2 -imidazole 4.18 t, --CH2NHCO 3.52 t, H3N+CH2 -- 3.18 t, 4-CH2 -imidazole about 3.0 t, --CH2S-- 3.0 t, --COCH2 -- 2.57 t.
Reaction SMILES: [CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:19]([O:22][C:23](=O)C)(=O)[CH3:20].C([O-])([O-])OCC>>[CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([C:6](=[CH:23][O:22][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1c(F)cc(F)c(F)c1C
Agent: CCOC([O-])[O-]
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Yield: 90 %

Procedure:
To 3.2 g of ethyl 2-methyl-3,4,6-trifluorobenzoylacetate were added 3.0 g of acetic anhydride and 2.7 g of ethyl orthoformate, followed by heating and refluxing for 1 hour. The resulting mixture was concentrated to give 3.5 g of ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([CH3:16])[C:13](Br)=[C:12]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[OH:27])[CH:11]=1>CN(C=O)C>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]2[O:27][C:21]3[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][S:18][C:12]=2[CH:11]=1)=[O:28]
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)SCc1cccc(Cl)c1O2
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Anhydrous potassium carbonate (6.71 g, 48 mmol) was added to a solution of Example 154a (3.9 g, 9.7 mmol) in DMF (200 ml) and the reaction mixture was stirred at 80° C. for 4.5 h. It was concentrated and treated with ethyl acetate, then washed with 10% aqueous HCl, water, brine, dried, concentrated and purified using flash chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound as a white solid. Yield: 1.2 g (40%); 1H NMR (CDCl3): δ 2.64 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 4.2 (s, 2H, CH2), 7.08 (m, 2H, Ar), 7.32 (q, 1H, Ar), 7.6 (s, 1H, Ar), 7.65 (s, 1H, Ar); MS: m/e (EI+) 320 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[C:17]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([O:31]CC6C=CC=CC=6)=[CH:27][CH:26]=5)[N:22](COCC[Si](C)(C)C)[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].[Na].C(OCC)(=O)C.O1CCCC1>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[C:17]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=5)[NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)n1ccc2cc(Oc3ncnc4[nH]c(-c5ccc(O)cc5)cc34)ccc21
Temperature: 52.5 °C
Yield: 25.6 %

Procedure:
After dissolving 30 mg of 5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]indole-1-carboxylic ethylamide in 1 ml of trifluoroacetic acid and 0.1 ml of thioanisole, the mixture was stirred at 50-55° C. The mixture was then returned to room temperature, saturated sodium bicarnobate water was added to alkalinity, and liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated, 1 ml of tetrahydrofuran and 1 ml of 2N aqueous sodium hydroxide were added to the residue, and the mixture was stirred at room temperature for 5 minutes. After neutralization with 1N hydrochloric acid, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 5 mg of the title compound.