Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5].[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:9]([O:8][C:7]([NH:6][C@@H:3]([CH2:4][CH3:5])[CH2:2][O:1][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4Cl solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc(Cl)c2ncc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 400 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one, 0.16 ml of phosphorus oxychloride, 221 mg of N,N-diisopropylethylamine and 6 ml of toluene was stirred at 100° C. for 30 minutes. The reaction mixture was cooled, and the precipitated solid was filtered. The resulting solid was sequentially washed with a saturated aqueous sodium bicarbonate solution, water and toluene, and then dried to obtain 320 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine (Compound of Present Invention 17).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:5]2[CH:16]=[CH:17][C:18]([S:20][CH2:21][CH3:22])=[CH:19][C:4]=2[N:3]=1.[C:23](OCC)(=[O:26])[C:24]#[CH:25]>C(O)C>[CH2:21]([S:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)=[N:7][CH2:8][C:2]3[N:3]([CH:25]=[CH:24][C:23](=[O:26])[N:1]=3)[C:4]=2[CH:19]=1)[CH3:22]
Reactant: C#CC(=O)OCC
Reactant: CCSc1ccc2c(c1)N=C(N)CN=C2c1cccc(F)c1
Solvent: CCO
Product: CCSc1ccc2c(c1)-n1ccc(=O)nc1CN=C2c1cccc(F)c1

Procedure:
In the manner given in Example 1, 2-amino-8-ethylthio-5-(m-fluorophenyl)-3H-1,4-benzodiazepine, ethyl propiolate and ethanol were refluxed. The mixture was chromatographed to give 10-ethylthio-7-(m-fluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O-2].[Mg+2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(Br)c1
Reactant: BrCc1ccccc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: Brc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 47 h
Yield: 63.4 %

Procedure:
A mixture of 16 g of 3-bromoaniline, 15 g magnesium oxide and 31.8 g benzylbromide in 100 mL dry dimethylformamide was stirred for 47 hours at room temperature, under nitrogen. The precipitated magnesium salts were filtered. The filtrate was diluted with water and extracted with ether. The ether extracts were combined, washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the ether evaporated in vacuo to give a brownish solid. The brownish solid was recrystallized from isopropanol to yield 20.75 g of N,N-dibenzyl-3-bromoaniline as a white solid. The structure was confirmed by NMR.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[OH:16]O.[OH-].[Na+].Cl>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:16])=[CH:10][CH:9]=1
Reactant: OO
Reactant: N#Cc1ccc(CCC2OCCO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(CCC2OCCO2)cc1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a stirred solution of 4-(2-(1,3-dioxolan-2-yl)ethyl)benzonitrile (1.50 g, 7.34 mmol) (prepared according to the method described in Kelly, S. M., Liquid Crystals 10: 273? 287 (1991)) in MeOH (50 mL) at room temperature were added 30% H2O2 (25.70 mmol) and 6 N NaOH (7.34 mmol) solution. The mixture was warmed to 50? 60? and stirred for 2 h, and to it, 1 N HCl solution was added to adjust to pH 7? 8 at 0?. The MeOH solvent was evaporated off under reduced pressure, and the residue was extracted with CH2Cl2 (3×30 mL). The CH2Cl2 solution was washed with brine (30 mL), dried (anhydrous Na2SO4), filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19, then 1:9 (v/v)) as eluent to give 1.58 g (97%) of 4-(2-(1,3-dioxolan-2-yl)ethyl)benzamide as a solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, 2H), 7.29 (d, 2H), 6.01 (br s, 1H), 5.71 (br s, 1H), 4.89 (t, 1H), 3.99 (m, 2H), 3.88 (m, 2H), 2.80 (m, 2H), 1.99 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[F:26][C:18]1([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:17]1[N:11]1[CH:10]=[CH:9][C:15]([NH:16][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])=[N:14][C:12]1=[O:13]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(C)COC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 97 %

Procedure:
Using Method A and isobutyl chloroformate, gemcitabine hydrochloride was converted to 22 (white solid, 97% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.25-8.26 (d, 1H), 7.12-7.14 (d, 1H), 6.35 (s, 1H), 6.19-6.22 (t, 1H), 5.33 (s, 1H), 4.22-4.24 (d, 1H), 3.91-3.96 (m, 3H), 3.83-3.85 (d, 1H), 3.68-3.70 (d, 1H), 1.91-1.97 (m, 1H), 0.94-0.95 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methylbenzoic acid (1.00 g, 4.65 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [N+:1]([C:4]1[C:12]2O[C:10]3[CH2:13]CC[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:16]([OH:18])[CH3:17]>[Ni]>[CH2:10]1[C:9]2[C:8]3[CH:12]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[O:18][C:16]=2[CH2:17][CH2:13]1
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc2c3c(oc12)CCC3
Agent: [Ni]
Product: Nc1ccc2oc3c(c2c1)CCC3
Reaction time: 2 h

Procedure:
The core molecule was synthesized following method A. Potassium t-butoxide (12 g, 110 mmol) was added in portions to a cooled (0° C.) solution of cyclopentanone oxime (9.9 g, 100 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-fluoro-4-nitrobenzene (14 g, 100 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water to provide cyclopentanone O-(4-nitro-phenyl)-oxime (17 g). Cyclopentanone O-(4-nitro-phenyl)-oxime (14 g, 62 mmol) was dissolved in glacial acetic acid (40 mL) and 1.9 N hydrochloric acid (40 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated. The solid was mixed with water (250 mL) and allowed to stand for 1 hour. The crude mixture was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4) and concentrated. The crude material was dissolved in toluene (350 mL) and p-toluenesulfonic acid (2.0 g, 10 mmol) was added. The reaction mixture was heated to reflux for 4 hours and water was removed with a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated to give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (10 g). A mixture of give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (5.4 g, 27 mmol) and Raney nickel (˜5 g wet weight) in ethanol (50 mL) was hydrogenated at 50 PSI on a Parr shaker for 2 hours. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by column chromatography to provide 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (4.0 g). Mp 86.5-88.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:32][C:33](=[O:34])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)NC4CCCCC4)cc3)cc2C1=O

Procedure:
The compound of example 33 was prepared analogous to compound of example 7 by reaction of compound of example 6 with cyclohexyl isocyanate. The compound of example 33 was used directly without isolation for the preparation of compound of example 34.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][S:16]2(=[O:21])=[O:20])[CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:24][C:23]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)([CH3:30])[CH3:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][S:16]2(=[O:21])=[O:20])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1,1-dioxido-isothiazolidin-2-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=437.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: NCc1cc(CCC(=O)O)no1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1cc(CCC(=O)O)no1

Procedure:
7 g (0.04313 mol) of the product from Example 12 are suspended in a solution of 70 ml of acetic anhydride in 140 ml of pyridine with intensive stirring, the starting material slowly going into solution. After completion of the reaction (TLC checking), the mixture is concentrated in vacuo and the product is crystallized from acetone. Yield: 5.5 g; melting point: 134° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccsc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1sccc1Br
Reaction time: 0.17 h

Procedure:
7.4 ml of fuming nitric acid was slowly added to 92.1 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 52.1 ml of acetic anhydride containing 25 g of 3-bromothiophene was slowly added in such a manner that the bulk temperature did not exceed 10° C., followed by stirring at 10 ° C. for 2 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 17.4 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl>[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 1 h
Yield: 831.6 %

Procedure:
In 100 ml of chloroform was dissolved 5.0 g of 1-methylpiperazine, and to the solution was added 6.9 g of anhydrous potassium carbonate. To the mixture was added dropwise 200 ml of a chloroform solution containing 1.4 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred for one hour under cooling with ice, and then the reaction solution was washed with 50 ml of a 5N aqueous sodium hydroxide solution and extracted twice with 50 ml of a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three times with 100 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 50 ml of a 5N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 14.9 g of 1-(5-isoquinolinesulfonyl)-4-methylpiperazine [i.e., Compound (36)] dihydrochloride in a yield of 82%.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[OH:42][C:34]1[CH:33]=[CH:32][C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)=[CH:36][C:35]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 10) according to the procedure of Example 1 as a pale yellowish solid; mp>120° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-3.00 (m, 5H), 2.92 (s, 3 H), 3.50-3.90 (m, 6 H), 4.49 (dd, J=8.0, 4.2 Hz, 1 H), 6.82 (d, J=8.5 Hz, 1 H), 6.95-7.07 (m, 3 H), 7.18 (d, J=2.0 Hz, 1 H), 7.45 (d, J=8.9 Hz, 2 H),7.50 (s, 1 H); MS (ES) m/z: 300.6 ((M+2 H)2+, 100%), 600.1 (MH+, 50%); HRMS Calcd. for C29H37N5O5S2 (MH+): 600.2314. Found: 600.2330.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:17][CH2:18][C:19](Br)=[O:20]>CCOCC>[Br:17][CH2:18][C:19]([NH:6][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[C:1](=[O:3])[CH3:2])=[O:20]
Reactant: O=C(Br)CBr
Reactant: CC(=O)c1cccc(C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cccc(C)c1NC(=O)CBr
Temperature: 0 °C

Procedure:
To a mixture of 4.8 g of 2-acetyl-6-methylaniline, 3 g of sodium acetate and 120 ml of ether was simultaneously added a solution of 13.2 g of bromoacetyl bromide in 30 ml of ether and 60 g of ice at -3° to 0° C. for 15 minutes. The resultant mixture was stirred at 0° to 5° C. for 2 hours. The ether layer was separated, washed with an aqueous solution of sodium carbonate, dried over anhydrous sodium sulfate and evaporated to give 2-bromo-2'-acetyl-6'-methylacetanilide as crystals. m.p. 97° - 100° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
Sodium hydroxide (1.80 g, 45 mmol) was added to a solution of methyl 4-(benzyloxy)benzoate (2.18 g, 9 mmol) in methanol (5 mL) and water (10 mL). The reaction mixture was stirred at 65° C. for 3 hours. After the reaction, the solvent was removed in vacuo. 3N hydrochloric acid was added to make pH 2, and the product was extracted with dichloromethane (100 mL×3). The combined organics phase was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4-(benzyloxy)benzoic acid (1.95 g, 95%). LRMS (M+H+) m/z: calcd 227.08. found 227.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[H-].[Na+].Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].[Cl-].[Na+]>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][N:15]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:12]3=[N:13][CH:14]=2)[O:5]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Yield: 92 %

Procedure:
3.00 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine are suspended in 40 ml of tetrahydrofuran in a flask. 0.73 g of sodium hydride (60% in paraffin oil) are added in portions with ice-cooling. 3.94 ml of chlorotriisopropylsilane is subsequently added dropwise at about 25° C., and the mixture is heated at 40° C. (bath temperature) under nitrogen until the boronic acid ester has reacted completely (HPLC check, about 5 hours). The excess sodium hydride is deactivated using 10 ml of saturated sodium chloride solution. The solvent is removed in vacuo. The residue is diluted with about 50 ml of water and extracted three times with diethyl ether. The combined organic phases are dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 15 min.), giving 4.55 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as white solid (yield 92%, content 92%); MS-FAB (M+H+)=401.2; Rf (nonpolar method): 3.61 min.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([O:34]CC4C=CC=CC=4)=[O:33])=[C:30]([O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:29]=3)[CH:24]=2)[O:19]1)C(OC(C)(C)C)=O)(C)C.Cl>C(O)C.O1CCOCC1.[Pd]>[OH:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([OH:34])=[O:33])=[C:30]([O:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:29]=3)[CH:24]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3ccc(C(=O)OCc4ccccc4)c(Oc4ccccc4)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1Oc1ccccc1

Procedure:
Phenylmethyl 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate (Example 191, 69 mg, 0.086 mmol) was stirred over a suspension of 10% Pd/C (7 mg) in ethanol (5 mL) under a hydrogen atmosphere for 15 hours. Solids were removed by filtration through Celite®, and the filtrate was concentrated in vacuo. The carboxylic acid intermediate was collected as a colorless oil (25 mg, 41%): 1H NMR (300 MHz, CD3OD) δ 8.66-8.58 (m, 2 H), 7.99 (d, 1 H), 7.92 (d, 1 H), 7.58-7.54 (m, 2 H), 7.51-7.41 (m, 2 H), 7.37-7.34 (m, 2 H), 7.21-7.16 (m, 2 H), 7.10 (d, 2 H), 6.86 (d, 1 H), 5.27-5.15 (m, 1 H), 4.38-4.31 (m, 1 H), 3.86-3.54 (m, 4 H), 2.96-2.90 (m, 2 H), 2.13-2.00 (m, 1 H), 1.87-1.75 (m, 1 H), 1.56 (d, 9 H), 1.00 (s, 9 H), 0.18 (d, 3 H), 0.00 (s, 3 H). The carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the di-hydrochloride salt (16 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 9.04 (broad s, 1 H), 8.89 (broad s, 1 H), 8.77 (d, 1 H), 8.15 (t, 1 H), 8.00 (d, 1 H), 7.46 (d, 1 H), 7.38-7.33 (m, 4 H), 7.14-7.08 (m, 2 H), 6.98 (d, 3 H), 5.45 (d, 1 H), 4.50 (t, 1 H), 3.76-3.55 (m, 5 H), 3.52-3.35 (m, 2 H), 2.99-2.85 (m, 2 H), 2.18-2.11 (m, 1 H), 1.85-1.75 (m, 1 H); MS m/z 497.2 (MH+ of the free base).