Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](Cl)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([NH:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Reactant: NCCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a 0° C. solution of 2.3 g of product from Example 87 in 50 ml of methylene chloride is added, dropwise, 0.72 g of 2-(2-aminoethyl)pyridine followed by 1.77 g of pyridine. The reaction is stirred at room temperature for 16 hours, poured into chloroform and saturated sodium bicarbonate and extracted with chloroform. The combined chloroform layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 75% ethyl acetate/hexane) to give 2.2 g of the desired product as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][CH2:30][CH:31]=O.N1C=CC=CC=1C.B.C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH2:28][C:22]1[N:23]=[C:24]([NH:27][CH2:31][CH2:30][OH:29])[CH:25]=[CH:26][C:21]=1[C:19]1[O:18][N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: O=CCO
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccn1
Solvent: CC(=O)O
Product: Nc1nc(NCCO)ccc1-c1cc(Cc2ccc(OCc3ccccc3)nc2)no1
Reaction time: 1.67 h
Yield: 9.8 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N,N-dimethylformamide (0.5 mL) were 2-hydroxyacetaldehyde (7.7 mg, 0.13 mmol), α-picoline-borane (14 mg, 0.13 mmol), and acetic acid (40 μL) at room temperature, which was stirred for 100 minutes at the same temperature. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain a crude product, and then purified by NH silica gel column chromatography (ethyl acetate:methanol=50:1) to obtain the title compound (4.5 mg, 10%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of 2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid while removing water. The resulting reaction solution was then washed with water to remove sulfuric acid. The organic phase was then dried, concentrated, and purified by column chromatography to obtain 5.0 g of the objective ester (liquid, at room temperature, [α]D23 =+4.9° (CHCl3)). (Yield: 83%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2c1-c1ccc(C=O)cc1C2=O
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a stirred suspension of 1.53 g (6.83 mmol) of 4-hydroxy-7-formyl-fluoren-9-one, prepared in Step G of Example 43, in 25 mL THF at 0° C. was added 1.24 mL (8.88 mmol) of triethylamine and 0.58 mL (8.2 mmol) of acetyl chloride. The mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, 1N HCl, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by chromatography on silica gel using methylene chloride as eluant gave 1.46 g of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.C(Cl)(=O)C>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:3](=[O:5])[CH3:2])[CH2:29][CH2:28]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and acetyl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone. MS (M+H)+, 388.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]C)=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:14][CH2:15]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](C2CC2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 2.66 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate in 60 ml of methanol is added dropwise a solution of 255 mg of lithium hydroxide in 30 ml of water under ice-cooling. The reaction mixture is warmed to room temperature, stirred for one hour and evaporated under reduced pressure to remove methanol. Chloroform is added to the residue. The pH of the mixture is adjusted to about pH 2 with 10% hydrochloric acid under ice-cooling thereto. The chloroform layer is washed with brine, dried, and evaporated under reduced pressure to remove the solvent to give 2.65 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NNc1ccccc1Cl
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
Triethylamine (43 mL, 309 mmol) was added over 2-3 min to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 23.2 g, 103.8 mmol) in dry dichloromethane (260 mL), yielding a heavy precipitate. Dichloromethane (25 mL) was added, followed by N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 19.36 g, 79.8 mmol) in one portion. Dichloromethane (35 mL) was added and the mixture was stirred at 0° C. for 5 min and then heated in an oil bath at 50° C. for 4 h. The mixture was poured into cold water (500 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×300 mL) and the combined organic layers were washed with brine (200 mL), dried (magnesium sulfate), filtered, evaporated, and purified by silica gel chromatography, eluting with 20-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and dried under high vacuum to give N′-(2-chloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (23.4 g, 70%) as a pale foam.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([OH:34])[C:30](=[O:33])[O:31][CH3:32])=[CH:20][C:15]=2[O:14][CH2:13]1>CN(C)C=O.C(OCC)C>[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([O:34][CH3:3])[C:30](=[O:33])[O:31][CH3:32])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CON=C1COc2cc(OCc3ccccc3N(O)C(=O)OC)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: CON=C1COc2cc(OCc3ccccc3N(OC)C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
1.1 g of methyl iodide and 0.88 g of anhydrous potassium carbonate were added to a solution of 1.9 g of methyl N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxycarbamate in 20 ml of N,N-dimethylformamide, and they were stirred at room temperature for 24 hours. The reaction solution was diluted with 200 ml of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane: ethyl acetate) to obtain 1.5 g of the title compound (having a m.p. of 102-103° C. and 1H-NMR data shown in the following table].
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:47])[NH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([CH3:40])[CH3:39])[CH:31]=4)=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1.CN(C=O)C>C(O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:47])[NH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([CH3:40])[CH3:39])[CH:31]=4)=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1cccc(C(=O)NC(C)(C)c2ccccc2)c1)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
NaOH (500 μL, 0.500 mmol, 1M aq.) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate (50 mg, 0.080 mmol) in Ethanol (795 μL) at 60° C. The slurry was allowed to stir overnight. DMF (2 mL) was added along with additional portion of NaOH and the mixture was warmed to 70° C. and allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (49 mg, quant). LC-MS retention time: 2.36 min; m/z (MH+): 601. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[OH:11])[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (262.2 mg, 0.82 mmol) and 2-aminothiazole (165 mg, 1.65 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 2.60 mL, 1.81 mmol) was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and filtered through a pad of celite (ethyl acetate as eluent). The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (174 mg, 54.6%) as a white solid: mp 86–88° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+Na)+ 407.0358, found 407.0361.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][SiH:10]([CH3:12])[CH3:11]>[Pt]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: C[SiH](C)C
Agent: [Pt]
Product: C[Si](C)(C)CCCOCC1CO1
Temperature: 130 °C

Procedure:
Allyl glycidyl ether (30.3 g, 0.266 moles) and 3 mg of platinum catalyst are weighed into a 300 mL laboratory autoclave. The autoclave, together with its contents, is cooled in an acetone/dry ice bath in an atmosphere of argon and 19.7 g of trimethylsilane (0.266 moles with a boiling point of 6.7° C.) are siphoned over from the condensed phase. The autoclave is closed and heated to 130° C. At the same time, the internal pressure increases to 7.6 bar and then drops again to 3.2 bar, indicating a reaction.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:29]([F:32])([F:31])[F:30])[CH:4]=[C:5]([O:7][CH2:8][CH:9]([OH:28])/[CH:10]=[CH:11]/[CH:12]2[CH:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:15]([OH:26])[CH2:14][CH:13]2[OH:27])[CH:6]=1.[CH3:33]O>CC(O)=O>[OH:27][C@@H:13]1[CH2:14][C@H:15]([OH:26])[C@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:33])=[O:24])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([OH:28])[CH2:8][O:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]([C:29]([F:31])([F:30])[F:32])[CH:4]=1
Reactant: CO
Reactant: O=C(O)CCC/C=C\CC1C(O)CC(O)C1/C=C/C(O)COc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O

Procedure:
To fluprostenol in MeOH at 0° C. was added TMS-CH2N2 until the solution persisted a yellow color. AcOH (2 drops) were added to quench excess TMS-CH2N2 and the solvents were evaporated. Column chromatography 90%-100% EtOAc/Hexanes gave pure (Z)-methyl 7-((1R,2R,3R,5 S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hept-5-enoate (9).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=O)=[CH:15][CH:14]=3)([CH:7]2[CH2:10][O:11][CH3:12])[CH2:5]1)(=O)[CH3:2].B(F)(F)F.CCOCC.S(C)C.CO>C1COCC1>[CH2:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)([CH:7]2[CH2:10][O:11][CH3:12])[CH2:5]1)[CH3:2]
Reactant: COCC1C2CN(C(C)=O)CC12c1ccc(N2CCCC2=O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CC2C(COC)C2(c2ccc(N3CCCC3)cc2)C1
Yield: 45.5 %

Procedure:
To a solution of 1-(4-(3-acetyl-6-(methoxymethyl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)pyrrolidin-2-one (360 mg, 1.097 mmol) obtained in Step 1 of Example XXXIV, in dry THF (10 mL), was added BF3.OEt2 (0.027 mL, 0.21 mmol) at 40° C. The reaction mixture was heated at the same temperature for 20 min followed by the addition of BH3.Me2S (2.79 mL, 5.48 mmol, 2M solution). Reaction mixture was heated to reflux for 6 h. After the completion of the reaction as confirmed by TLC, methanol (15 mL) was added to the cold solution and refluxed further for 1 h. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to afford pure title compound (150 mg, 45%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26](C)([CH3:28])[CH3:27])=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:42]1[CH:47]=CC=C[CH:43]=1)=O>Cl.CO>[CH2:1]([C:3]1[N:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]3[CH:27]=[CH:47][CH:42]=[CH:43][CH:28]=3)=[CH:19][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate (1.1 g, 2.6 mmol) in 10% HCl-MeOH (20 mL) was heated at 50° C. for 2 h. After cooling, the volatile components were removed by evaporation and the resulting amorphous was dried under reduced pressure. Then, the amorphous was suspended in dichloromethane at 0° C. To the cooled mixture was added triethylamine (1.4 mL, 10 mmol) and phenyl chloroformate (380 μL, 3.0 mmol). After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 2:1) afforded 924 mg (85%) of the title compound as colorless amorphous. MS (ESI) m/z 430 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl chloride in 200 ml of dry tetrahydrofuran (THF) was added with vigorous shaking a solution of 13.76 g (80 mmol) of 4-bromoaniline in 300 ml of dry THF. The mixture stood at room temperature for 2 hours and was then treated with 80 g of ice followed by 200 ml of hexane. The organic layer was separated and the aqueous layer was extracted with 2×50 ml of hexanes. The organic layers were combined and washed successively with 30 ml of water and 2×30 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by recrystallization from an ethyl acetate and hexanes mixture to give the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:31])[CH:3]=1.Cl.[CH3:33][O:34][CH2:35][C@@H:36]([NH2:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:33][O:34][CH2:35][C@@H:36]([NH:38][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[F:31])[NH:8][N:7]=3)[N:12]=2)[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[CH:18]=1)=[O:22])[CH3:37]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Reactant: COC[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.39 g, 0.84 mmol), (S)-1-methoxypropan-2-amine hydrochloride (253 mg, 2.0 mmol), HBTU (457 mg, 1.27 mmol), and HOBT (125 mg, 0.93 mmol). Then added DMF (2 mL) followed by N,N-diisopropylethylamine (0.59 mL, 3.38 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 401 mg (89%) of 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a light yellow solid. MS: [M+H]+=533.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([OH:28])[C:26]#[CH:27].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:27]#[C:26][CH:25]([OH:28])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40 (800 mg), 3-butyn-2-ol (0.20 mL), PdCl2 (PPh3)2 (32.3 mg), and 1.16 mL Et3N in 4.64 mL anhydrous DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a red-brown residue. The residue is chromatographed eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 139.2 mg (20%) of the title compound as a brown solid.