Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[O:16]1[C:20]2[C:21]([CH:25]=O)=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1.C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][CH2:25][C:21]2[C:20]3[O:16][CH2:17][CH2:18][C:19]=3[CH:24]=[CH:23][CH:22]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1cccc2c1OCC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(NCc2cccc3c2OCC3)Cc2ccccc2C1
Reaction time: 0 h
Yield: 190.3 %

Procedure:
A 10 mL microwave reaction vessel is charged with 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) and dry tetrahydrofuran (THF, 5 mL). A stirring bar is added and stirring is initiated. After dissolution, 2,3-dihydro-1-benzofuran-7-carbaldehyde (361 mg, 2.43 mmol) is added. Stirring is continued. Phenylsilane ([694-18-1], 0.61 mL, 4.87 mmol) and dibutyltin dichloride (53 μL, 244 μM) are added. The reaction vial is crimped sealed and placed in a Smith Microwave Apparatus. The pre-stir time is set to 10 sec. Heating is set at 100° C. for 10 min. The contents of the reaction vial are transferred to a round bottom flask and evaporated by pumping to a constant weight yields 1.56 g of light yellow oil. This material is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g Cartridge (silica). The column is eluted with 5% EtOAc/heptanes for 3 column volumes followed by a linear gradient to 50% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions of UV active eluent are collected. Fractions 7 to 11 are combined and evaporated by pumping to constant weight yields 0.59 g of white solid material (0.52 g, 63%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[O:6]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:36][CH2:37]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: O=C(CCCCl)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-phenoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 483.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[C:17]1[S:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=1.[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([C:17]4[S:18][C:19]([C:22]([F:23])([F:24])[F:25])=[N:20][N:21]=4)[CH:12]=3)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(F)(F)F)s2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-[1,1′-biphenyl]-4-ol (195 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (157 mg) and tributylphosphine (213 mg) in THF (5.0 mL) was added ADDP (226 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (298 mg) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[C:11]([N+:23]([O-:25])=[O:24])[C:12]([OH:22])=[C:13]([O:18]C(=O)C)[CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1>CO.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3[C:15](=[CH:14][C:13]([OH:18])=[C:12]([OH:22])[C:11]=3[N+:23]([O-:25])=[O:24])[C:16]2=[O:17])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cc2c(c([N+](=O)[O-])c1O)CN(c1ccc(Cl)cc1)C2=O
Agent: Cl
Solvent: CO
Product: O=C1c2cc(O)c(O)c([N+](=O)[O-])c2CN1c1ccc(Cl)cc1

Procedure:
Acetic acid 2-(4-chloro-phenyl)-6-hydroxy-7-nitro-3-oxo-2,3-dihydro-1H-isoindol-5-yl ester (0.24 g raw material) was refluxed in methanol (15 ml) with three drops of concentrated hydrochloric acid for six hours. The reaction mixture was cooled and filtered.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]2[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ncccc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a glass microwave vial was added 3-bromo-2-fluoropyridine (4.6132 g, 26.2 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.88 g, 32.8 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (1.472 g, 2.097 mmol), and sodium carbonate (13.89 g, 131 mmol) in DME (41.9 mL) and water (10.49 mL) to stir at 80° C. overnight. Upon completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine. MS (ESI, pos. ion) m/z: 180.1.
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:12][CH2:13][C@@:14]12[CH2:26][CH2:25][CH2:24][N:15]1[C@@H](C(Cl)(Cl)Cl)[O:17][C:18]2=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC[C@@]1(C(OC)=O)CCCN1)C1C=CC=CC=1.[Li+].[BH4-]>CO.CCOCC>[CH2:5]([O:12][CH2:13][C@@:14]1([CH2:18][OH:17])[CH2:26][CH2:25][CH2:24][NH:15]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Agent: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: OC[C@]1(COCc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
SOCl2 (2.5 eq) was added at 0° C. to a 0.2M solution of (3R,7aR)-7a-[(benzyloxy)methyl]-3-(trichloromethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one in dry MeOH, and the mixture was stirred at RT for 20 min, then at reflux for 4 h. After removal of volatiles the residue was taken in EtOAc and washed with sat NaHCO3, water and brine, dried and concentrated. A 0.2M solution in dry Et2O of crude methyl 2-[(benzyloxy)methyl]-L-prolinate was added at 0° C. to a stirred mixture of LiBH4 (1.6 eq.) and MeOH (1.6 eq.) in dry Et2O (0.3M); the mixture was stirred for 2 h at RT, then quenched with water, diluted with EtOAc, washed with water and brine, dried and concentrated to afford {(2S)-2-[(benzyloxy)methyl]pyrrolidin-2-yl}methanol that was used as such. The material was dissolved in dry DCM (0.2M) and treated with carbonyl diimidazol (2.5 eq.) at RT overnight; after dilution with DCM the mixture was washed with 1N HCl, sat NaHCO3 and brine, dried over Na2SO4 and concentrated. Flash chromatography (PE:EtOAc 2:1) afforded the title compound in 43% overall yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2-c1cccc(OCCCn2ccnc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2-c1cccc(OCCCn2ccnc2)c1

Procedure:
0.9 g of 5-(4-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 20 h in 40 ml of THF in the presence of 0.15 g of 10% palladium/carbon. After filtration through Celite and chromatography of the residue on silica gel (methylene chloride/methanol 9:1) 5-(4-hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine (Rf=0.2 silica gel, methylene chloride/methanol 9:1) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:11]([O:13]C)=[O:12])[N:3]=1.[OH-].[K+].C1(C)C=CC=CC=1.C(O)(=O)C(O)=O>CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[N:3]=1
Reactant: COC(=O)C(Oc1nc(C)cc(C)n1)C(C)(C)C
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(OC(C(=O)O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
1.5 g of methyl 2-(4,6-dimethylpyrimidin-2-yl)oxy3,3-dimethylbutyrate was dissolved in 10 ml of methanol, and 10 ml of an aqueous solution containing 0.5 g of potassium hydroxide was added thereto. The mixture was stirred at room temperature for 12 hours and then shaked with 210 ml of toluene and 30 ml of water in a separatory funnel. The aqueous layer was acidified with an oxalic acid aqueous solution and extracted with 100 ml of ethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.2 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)COC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) in acetonitrile (10 ml) were successively added methoxyacetic acid (0.08 ml), triethylamine (0.17 ml), HOBt (0.18 g) and WSC (0.23 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate), and the obtained product was recrystallized from ethanol-water to give the title compound as colorless needle crystals (0.16 g, 44%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1>C(O)=O>[CH:5]([NH:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1)=[O:7]
Reactant: NCCN1CCn2nccc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCN1CCn2nccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (4.96 ml) and formic acid (2.51 ml) was stirred for 45 minutes at room temperature. The mixture was cooled to 5° C., and 1-(2-aminoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.0 g) was added to the mixture. The mixture was stirred for an hour under ice-cooling. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-formamidoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.6 g) as crystals.
Reaction SMILES: C([O:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[NH:24]C(=O)C)C1C=CC=CC=1.[OH-].[Na+].Cl>CCO>[NH2:24][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:9]([OH:28])=[O:8]
Reactant: CC(=O)Nc1cc(OCc2ccccc2)ccc1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(OCc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A suspension of 1.87 g (4.98 mmol) of 2-acetylamino-4-benzyloxy-benzoic acid benzyl ester in EtOH (20 ml) was treated with 1N NaOH (20–30 ml) and stirred at 95° C.–130° C. (oil bath temperature) until completion of the reaction according to TLC and NMR analysis (reaction time about 34 h). The reaction mixture was cooled to RT, brought to pH 6 on addition of 1N aqueous HCl, the precipitate that formed was filtered off by suction and dried in a high vacuum to give 1.19 g (91.7%) of the desired 2-amino-4-benzyloxy-benzoic acid as an off-white solid. ISP mass spectrum, m/e: 242.2 (M+1 calculated for C14H13NO3: 242).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH2:54][CH3:55])=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH2:54]([C:39]1[C:38]2[C:42](=[CH:43][CH:44]=[CH:45][C:37]=2[NH:36][C:34]([C:31]2[N:28]3[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]4)=[CH:26][C:27]3=[N:33][CH:32]=2)=[O:35])[N:41]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:40]=1)[CH3:55]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CC(C)N1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with solid potassium tert-butoxide (1.7 g, 14.8 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (2.88 g, 16.7 mmol), and tert-butanol (10 mL, 103 mmol). The mixture was stirred at ambient temperature for 1 hour before heating at 90° C. for 15 minutes to give a homogeneous mixture. 7-Fluoro-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.3 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature before pouring into a 250 mL round bottom flask containing 150 mL of water. Vigorous stirring at ambient temperature for 2 hours resulted in a beige precipitate. The precipitate was collected by filtration and dried under high vacuum to give the product. MS (APCI), positive scan, m/z=581.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:14][C:13](=O)[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:14][C:13](=[S:26])[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(c2ccc(F)c(Br)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(c2ccc(F)c(Br)c2)COCC(=S)N1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A solution of the (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-morpholin-3-one (intermediate X-4) (265 mg, 0.9 mmol) in tetrahydrofuran (5.3 ml) was treated with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (380 mg, 0.9 mmol). After 2.5 hours stirring at 70° C. the reaction mixture was evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-morpholin-3-thione was obtained as a light yellow gum (262 mg, 94% of theory). MS (ISP): m/z=302.2 [M−H]−, 304.1 [M+2−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16]([O:18]C)=[N:17][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[S:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[NH:17][C:16]1=[O:18]
Reactant: COc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2c(s1)CCNCC2

Procedure:
0.40 g (1.4 mmol) 2-methoxy-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester, 1.3 mL trifluoroacetic acid in 2.5 mL dichloromethane (DCM) were stirred at RT overnight. The reaction was concentrated to dryness. DCM and a small amount of methanol (MeOH) were added to the residue and filtrated. The precipitate were isolated and 90 mg 3,4,5,6,7,8-Hexahydro-thiazolo[4,5-d]azepin-2-one trifluoro-acetic acid was obtained. Yield: 90 mg (23% of theory). ESI-MS: m/z=171 (M+H)+; Rt(HPLC): 0.15 min (Method J).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77](=[O:80])[CH2:78][OH:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77](=[O:80])[CH2:78][OH:79])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CO)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 43.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)-2-hydroxyethanone (60 mg, 0.090 mmol) was hydrolyzed with lithium hydroxide (19 mg, 0.451 mmol) in THF/methanol/water (5/1/1 mL) to yield 20 mg (35.7% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.822-8.820 (d, 1H), 8.59 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.70-7.68 (d, 2H), 7.41-7.35 (q, 1H), 7.17-7.02 (m, 5H), 5.45 (s, 2H), 4.33 (s, 2H), 3.82-3.79 (t, 2H), 3.62 (s, 2H). MS: m/z=510.8 (M+1), HPLC: 90.93% in method A.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1
Reactant: CCOC(=O)c1cn(C2CCCCO2)nc1I
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a solution of ethyl 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (5 g, 14.2 mmol) in (1:1) THF/MeOH (32 mL) was added a solution of LiOH (1.8 g, 4.28 mmol) in water (16 mL). The reaction was stirred at rt for 4 h then evaporated under vacuum and the residue was treated with water (25 mL) and washed with ethyl acetate (30 mL×2). The aqueous layer was isolated acidified to ˜pH5 with 2N HCl and extracted with DCM (30 mL×3). The combined extracts were washed with brine (30 mL), dried and concentrated to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylic acid (3.5 g, yield: 76%). LCMS (method B): RT=2.18 min, m/z=321.0 [M−H]−.
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@H:27]([C@H:32]([C@@H:37]([C@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH:52]C(OCC1C=CC=CC=1)=O)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@H:27]([C@H:32]([C@@H:37]([C@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH2:52])[OH:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2,3,4,5,6-Penta-O-acetyl-L-gulonic acid (benzyl 3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide was hydrogenated as described under Ex. 13.B. and gave 2,3,4,5,6-penta-O-acetyl-L-gulonic acid (benzyl 3,4-di-O-acetyl-2-amino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide, [α]+75.50 (c 0.2; dioxan), MS: m/z 763.6 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CO>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:7]=1)[CH3:24]
Reactant: CCNCC
Reactant: COC(=O)Cc1ccc(OCC2CO2)cc1OCC(F)(F)F
Solvent: CO
Product: CCN(CC)CC(O)COc1ccc(CC(=O)OC)c(OCC(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of methyl 4-(glycidyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate (0.25 g, 0.81 mmol) from Step 1 of Example 34 in MeOH (3 mL) was added diethylamine (0.5 mL). The solution was kept at ambient temperature for 12 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 4-(3-diethylamino-2-hydroxypropyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate as a pale yellow oil (HPLC retention time=6.9 min (method A); TLC Rf =0.23 (95:5 CH2Cl2 :MeOH)).