Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-].[C]>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C@H:10]1[C@@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: O[C@H]1CCN(Cc2ccccc2)C[C@H]1COc1ccccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O[C@H]1CCNC[C@H]1COc1ccccc1F
Temperature: 25 °C
Yield: 96.1 %

Procedure:
After dissolving 402 mg of cis-1-benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine in 20 ml of ethanol, 0.2 g of 20% palladium hydroxide-carbon (hydrous) was added and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm). The mixture was further stirred for 5.5 hours, and then ethyl acetate was added thereto and the insoluble portion was filtered off. The filtrate was distilled off under reduced pressure to obtain the title compound (276 mg, 94% yield).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Li+].Br[CH:16]([CH:20](Br)[C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18]>>[N:1]1([CH:16]([CH:20]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]([OH:23])=[O:22])[C:17]([OH:19])=[O:18])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(O)C(Br)C(Br)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(C(C(=O)O)N1CCNCCNCCNCC1)N1CCNCCNCCNCC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 16.2 %

Procedure:
To an aqueous solution of 1,4,7,10-tetraazacyclododecane (100 g, 580 mmol) and lithium hydroxide (5.2 g, 216 mmol) was added 2,3-dibromosuccinic acid (15.0 g, 54 mmol). After stirring at 60° C. for 3 days, the solution was cooled to ambient temperature and applied on an AG1-X8 anion exchange column [500 mL (OH-form)], the column was washed with water (1 L) and the product was eluted with 1M CH3COOH. Further purification by cation exhange chromatography on a AG5OW-X8 column [100 mL (H+form)] yielded 4.0 g (16%) of the title product as a white powder. 1H NMR (D2O) δ 2.4-3.0 (m, 32H), 3.2 (2H). 13C NMR (D2O) 40.4, 40.7, 42.9, 44.7, 61.5, 174.0. MS (FAB): m/e 459.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[Br:17][C:18]1[C:19]([F:28])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[S:21][C:22]=1Br>>[Br:17][C:18]1[C:19]([F:28])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[S:21][C:22]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: CC(C)COc1ccc(B(O)O)cc1C#N
Reactant: COC(=O)c1sc(Br)c(Br)c1F
Product: COC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)c(Br)c1F

Procedure:
Using (3-cyano-4-isobutoxyphenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate, methyl 4-bromo-5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate was obtained in accordance with the method of Preparation Example 1(1). To an ethanol (60 ml) suspension of 1.75 g of the compound was added 1.00 g of 10% palladium-carbon, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere at normal pressure. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain 0.39 g of methyl 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate. (2) The compound was dissolved in 15 ml of THF, and 2.5 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 5 hours. After cooling to room temperature, 2.5 ml of 1M hydrochloric acid and water were added thereto, followed by extraction with ethyl acetate. The resulting organic layer was dried and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate and hexane to obtain 252 mg of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid. (3) Then, 215 mg of sodium hydroxide was added to an ethanol (60 ml) solution of 1.81 g of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid, followed by stirring at 80° C. overnight. After the reaction solution was cooled to room temperature, the precipitate was collected by filtration to obtain 1.60 g of sodium 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])[C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccc(C)cc2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)OC(C)(C)C)c2ccc(C)cc2n1
Reaction time: 16 h

Procedure:
To a solution of 3.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 3.0 g of potassium carbonate and 3.8 g of Bromo-acetic acid tert-butyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 4.9 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ncccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
A solution of 7-azaoxindole (284 mg, 2.1 mmol), (prepared as described for the starting material in Example 2), in THF (10 mn) was added to a suspension of sodium hydride (112 mg, 2.8 mmol, prewashed with petroleum ether) in THF (6 ml). After stirring for 20 minutes at ambient temperature, a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (238 mg, 0.7 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was added. After stirring for 1 hour at 65° C., the volatiles were removed by evaporation. The residue was partitioned between water and ether. The aqueous layer was separated and adjusted to pH7 with 2M hydrochloric acid. After evaporation of water, the precipitate was triturated with ether, collected by filtration, washed with ether, and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (9515 followed by 90110). After evaporation of the solvent, the residue was suspended in methylene chloride/methanol (1/1) and 3M hydrogen chloride in ether was added. After removal of the solvent by evaporation, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(7-azaoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 51%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]([OH:37])[CH3:36])[N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(Cl)Cl.CCOC(C)=O>[C:35]([C:33]1[N:34]=[C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:38])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:4]=3)[O:17][C:16]2=[O:18])[S:31][CH:32]=1)(=[O:37])[CH3:36]
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 134) (31.0 mg, 0.052 mmol) in CH2Cl2 (6 mL) was added DMP (55 mg, 0.130 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. Next, the reaction was diluted with EtOAc (40 mL) and washed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (40% EtOAc/hexanes) afforded (4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.26 (40% EtOAc/hexanes). LCMS=597.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 8.27 (s, 1H), 7.89 (s, 1H), 7.77-7.82 (m, 4H), 7.71 (d, J=7.9 Hz, 1H), 5.68 (d, J=7.9 Hz, 1H), 5.22 (d, J=16.3 Hz, 1H), 4.85 (d, J=16.4 Hz, 1H), 4.08 (m, 1H), 2.70 (s, 3H), 0.71 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:13][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1cnc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
To a mixture of 6-chloro-5-fluoropyridin-3-ol (2.43 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (3.46 g), triphenylphosphine (6.48 g) and THF (25 mL) was added dropwise a toluene solution (1.9 M, 13.0 mL) of diisopropyl azodicarboxylate at room temperature, and the obtained mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.88 g).
Reaction SMILES: [NH:1]([C:3]([O:5][CH3:6])=[O:4])[NH2:2].N1C=CC=CC=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:17][C:18]([NH:2][NH:1][C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COC(=O)NN
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NNC(=O)CC(C)(C)C
Yield: 95 %

Procedure:
A solution of 65.5 g of hydrazinecarboxylic acid, methyl ester, 150 ml of dry pyridine and 500 ml of dry dichloromethane was stirred at 0° C. and 100 g of distilled t-butylacetyl chloride was added dropwise. After 2 hours at 0°-5° C. the solvent was removed in vacuo. The residue was taken up in 1.2 liters of ethyl acetate, washed with saturated sodium chloride and filtered through a bed of hydrous magnesium silicate with additional ethyl acetate. The filtrate was concentrated and the solid recrystallized from diisopropyl ether, giving 130 g of 2-(3,3-dimethyl-1-oxobutyl)hydrazinecarboxylic acid, methyl ester as white platelets, mp 83°-84.5° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 102.4 %

Procedure:
30 g of methyl 4-chlorobenzoate was dissolved in anhydrous THF, and 16.9 g of 60% sodium hydride was added under cooling with ice. 21.1 g of pinacolone was added dropwise, and the mixture was stirred under heating at 50° C. for 6 hours. Then, 100 ml of water was added dropwise under cooling with ice, and the solvent was distilled off under reduced pressure. 200 ml of water and 100 ml of 6N hydrochloric acid were added thereto, and then extraction with ethyl acetate was carried out. The extract layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform/hexane=2/8) to obtain 43 g of the desired product as a viscous liquid. nD20.0 1.5012
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:53])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]#[C:45][C:46]2[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:49]2[CH:50]=[CH:51][C:46]([C:45]#[C:44][C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:53])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:47][CH:48]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(C#Cc3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 0.154 mmol), (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh3)4 (10 mg, 0.00908 mmol), CuI (2 mg, 0.00908 mmol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 4 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (11 mg, 17%). 1H NMR (MeOH-d4, 400 MHz) 7.46 (d, J=3.9 Hz, 4H), 7.25 (s, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s, 6H), 2.32-2.00 (m, 10H), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH2:43])=[O:42].O>CN(C)C=O>[NH2:43][C:41](=[O:42])[CH2:40][O:22][C:18]1[CH:17]=[C:16]([S:13]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:11]2)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(N)=O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (215 mg, 0.66 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol), and then the reaction solution was stirred for 16 h. 50 mL of water was added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title product tert-butyl ((1-((3-(2-amino-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 2a (100 mg, a yellow oil) in 90% yield.
Reaction SMILES: [H][H].[O:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[N:27]([CH3:28])[CH:26]=[CH:25][C:12]3=[N:13][C:14]=2[C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[CH2:5][CH2:4]1>CO.[OH-].[OH-].[Pd+2]>[CH3:28][N:27]1[C:11]2[C:12](=[N:13][C:14]([C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])=[C:9]([CH:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[CH:10]=2)[CH:25]=[CH:26]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1=CCOCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottom flask fitted with a 3-way valve and a hydrogen-filled balloon, were added (S)-tert-butyl (1-(6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (1.23 g, 3.44 mmol) in MeOH (20 mL) along with palladium hydroxide on carbon (0.097 g, 0.688 mmol). The flask was evacuated and hydrogen introduced via the three-way valve. The reaction mixture was stirred overnight at RT. The next day an additional equivalence of Pd(OH)2 was added and the reaction mixture was stirred overnight. The reaction mixture was subsequently diluted with EtOAc, filtered through a pad of Celite, and concentrated to give the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:26]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3sc(N)nc3cc2C(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cc(C(C)(C)C)c(SS(=O)(=O)c3ccc(C)cc3)cc2s1

Procedure:
The title compound was prepared as described in Example BB-15 using toluene-4-thiosulfonic acid S-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in Example BB-1; 1.75 g, 4.47 mmol), acetyl chloride (4 mL), pyridine (5 mL), DMAP (0.3 g) and CH2Cl2 (20 mL). The crude product was purified by flash silica gel chromatography (20%-70% EtOAc in hexanes as eluents). MS(APCI): 435 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:3][CH:4]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 362.2 %

Procedure:
A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (100 mg) prepared in a similar manner according to Step 6 of Production Example 1, ((tert-butoxycarbonyl)amino)acetic acid (74 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 1-hydroxybenzotriazole (57 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate, and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica-gel with 3% methanol/chloroform as an eluent. The crystalline residue was collected and washed with ethyl acetate to give tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]-2-oxoethylcarbamate (580 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>ClC(Cl)C.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1cccs1
Reactant: Fc1ccc2c(-c3cccc(OC[C@@H]4CO4)c3)noc2c1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@@H](CNCc1cccs1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-thiophenemethylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=96%, [M+H]+=399.