Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 82.4 %

Procedure:
From 3.2 g (0.01 mol) of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 25), 90 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing for twenty-four hours, following the procedure of Example 27, there is obtained 2.5 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carbonitrile; mp 349°-351° C. after recrystallization from pyridine.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1.O.Cl[Pd]Cl>[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:3]2[CH:2]=[C:11]3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:9]=[CH:10]3)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Reactant: Ic1cccc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccccc3c2)c1
Reaction time: 24 h
Yield: 137.5 %

Procedure:
12 ml of THF/H2O was added to 0.6199 g (2.44 mmol) of iodonaphthalene, and 0.122 g (5 mol %) of PdCl2 (dppf) was added in a darkroom. 1 g (2.44 mmol) of 3,5-bis-tert-butyldimethylsilyloxymethyl Phenylboronic acid dissolved in 12 ml of THF/H2O was added, 3.66 ml (3 eq) of 2N NaOH aq was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 24 hours. Completion of the reaction could not be confirmed because the raw material iodonaphthalene overlaps the target product in TLC (Hex only). Fluorescence was confirmed with the naked eye. This was extracted with EtOAc, and the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure to obtain 1.6530 g of a mixture of the target product and iodonaphthalene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:27])[CH3:26])[CH:5]=[CH:6][CH:7]=1.[Cl:28][C:29]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:31]2[CH:37]=[CH:36][N:35]([Si](C(C)C)(C(C)C)C(C)C)[C:32]2=[N:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([C:2]2[CH:3]=[C:4]([N:8]3[CH:13]=[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:11](=[O:24])[CH:10]=[C:9]3[CH:25]([OH:27])[CH3:26])[CH:5]=[CH:6][CH:7]=2)=[C:31]2[CH:37]=[CH:36][NH:35][C:32]2=[N:33][CH:34]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)c(Cl)cnc21
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(C)O)cc2=O)cc1
Product: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C(C)O)cc2=O)cc1
Temperature: 85 °C

Procedure:
To a 250 mL round-bottom flask were added 2.25 g (5.23 mmol) of the first eluting enantiomer of 1-(3-bromophenyl)-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 4.55 g (10.46 mmol) 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, and 0.427 g (0.523 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The flask was equipped with a condenser, evacuated, and purged with nitrogen. Evacuation was repeated three times and 50 mL THE and 25 mL 1 M aq cesium carbonate were added. The reaction mixture was heated at 85° C. for 15 h. Upon cooling, the organic layer was separated, washed with 10 mL water, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-100% hexane-ethyl acetate gradient, followed by 10% methanol wash) afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one. LCMS (M+H)+ 502.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Yield: 95.6 %

Procedure:
By the method of Example 3, Step A, 23.15 g (0.147 mole) of 3-fluoro-4-nitrophenol and 29.92 g (0.175 mole) of 2-iodopropane were reacted in the presence of 20.73 g (0.150 mole) of anhydrous potassium carbonate in 450 mL of acetone, yielding 28.0 g of 4-isopropoxy-2-fluoronitrobenzene as an oil. The NMR was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([O:21][Si](C(C)(C)C)(C)C)[C@H:19]([O:29][Si](C(C)(C)C)(C)C)[C@@H:18]([CH2:37][O:38][CH3:39])[O:17]2)=[C:9]([NH:40][CH2:41][CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:8]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][S:2]([O:5][CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:29])[C@@H:18]([CH2:37][O:38][CH3:39])[O:17]2)=[C:9]([NH:40][CH2:41][CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:8]=1)(=[O:4])=[O:3]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (240 mg, 0.3 mmol) (preparation 16) was dissolved in stirred tetrahydrofuran (1 ml) and a 1 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.6 ml, 0.6 mmol) added. The reaction mixture was stirred at room temperature for 24 hr. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5) increasing in polarity to dichloromethane:methanol (90:10). This gave the title compound (140 mg) as a foam. MS: 570 (MH+).
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:4])=[O:3].C([Li])CCC.CCCCCC.[CH:42](=O)[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>C1C=CC=CC=1>[N:46]1[CH:47]=[CH:48][C:43]([CH:42]=[CH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N+:2]([O-:4])=[O:3])=[CH:44][CH:45]=1
Reactant: O=Cc1ccncc1
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccccc1C=Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
In 120 ml of benzene was suspended 12.00 g of 2-nitrobenzyltriphenylphosphonium bromide and, under argon gas, 20 ml of 1.6M n-butyllithium/n-hexane was added dropwise under ice-cooling with care exercised so that the internal temperature would not rise beyond 20° C. The mixture was then stirred at room temperature for 2 hours, after which 3.05 g of isonicotinaldehyde was added dropwise under ice-cooling and the mixture was stirred at room temperature for another 4 hours. This reaction mixture was poured upon ice-water and extracted with ether. This extract was evaporated under reduced pressure to remove the solvent and the residue was diluted with chloroform and extracted with 2N-hydrochloric acid. The aqueous layer was made basic by adding 30% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue was purified by silica gel column chromatography (chloroform alone) to provide 2.53 g of the title compound as tan-colored oil. This product was subjected to the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=O)[NH:14][C:15]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)([C:17](=[O:19])[NH2:18])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)([CH3:16])[C:17](=[O:19])[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NC(C)(C(N)=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1C1=NC(=O)C(C)(c2ccc(Br)cc2)N1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2-[1-(4-bromo-phenyl)-1-carbamoyl-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in ethanol (10 mL) was added 1 N NaOH (5 mL), and stirred at ambient condition for 3 hours. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (120 mg, 79%). m/z 421.8, 423.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:19].[CH2:20](OC(OCC)CN(C)C)[CH3:21].O.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[NH:19][CH2:20][CH3:21]
Reactant: CCOC(CN(C)C)OCC
Reactant: Nc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCNc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Temperature: 60 °C
Yield: 20.6 %

Procedure:
To a stirring solution of 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.121 g, 0.386 mmol), (dimethylamino)acetaldehyde diethyl acetal (0.720 mL, 3.94 mmol), glacial acetic acid (24.0 mL) and water (0.100 mL, 5.55 mmol) was added sodium cyanoborohydride (0.140 g, 2.22 mmol). The solution was heated at 60° C. for 5 days and then the solution was stirred at room temperature until a precipitate formed. The suspension was filtered, the filter cake was washed with EtOAc (10 mL) and then the filtrate was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), gave 0.027 g (20%) of the title compound as a white solid. 1H NMR (CDCl3): 7.60 (d, 1H, J=5.2 Hz), 7.44-7.35 (m, 3H), 7.13 (d, 1H, J=5.2 Hz), 4.33 (br s, 1H), 3.37-3.28 (m, 2H), 1.36 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1cnccn1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Product: CN1Cc2cc(-c3cnccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 47 %

Procedure:
A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline with 2-chloropyrazine. (+)-4-(3,4-Dichlorophenyl)-6-fluoro-2-methyl-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline was obtained in 47% yield as a brown oil: ESI MS m/z 388 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][OH:15])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(COS(C)(=O)=O)CC2CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice-cold solution of 3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.52 grams, 11.83 mmol) in dry dichloromethane (10 mL) was added triethylamine (2.5 mL, 17.75 mmol) followed by methanesulfonyl chloride (1.0 mL, 13.01 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane. Organic layer was washed with saturated sodium bicarbonate solution followed brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography using 230-400 mesh silica gel to obtain title compound, 3.09 grams as gummy liquid. Yield: 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][CH2:7][C@@:8]32[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([NH:16]C(=O)OC(C)(C)C)=[N:9]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:35])([F:34])[C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[NH2:16][C:10]1[N:11]([CH3:15])[C:12](=[O:14])[CH2:13][C@@:8]2([C:24]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31]([C:28]4([C:27]([F:35])([F:34])[F:26])[CH2:30][CH2:29]4)=[O:32])[CH:25]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: CN1C(=O)C[C@]2(CCc3ccc(N)cc32)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CN1C(=O)C[C@]2(CCc3ccc(NC(=O)C4(C(F)(F)F)CC4)cc32)N=C1N

Procedure:
The coupling of tert-butyl [(1S)-6-amino-1′-methyl-6′-oxo-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidin]-2′-yl]carbamate (intermediate F6) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=381.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH3:33])[C:22]3[CH:26]([CH2:27][C:28]([OH:30])=[O:29])[O:25][B:24]([OH:31])[C:23]=3[CH:32]=2)[CH:15]=[CH:14][N:13]=1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH3:33])[C:22]3[CH:26]([CH2:27][C:28]([OH:30])=[O:29])[O:25][B:24]([OH:31])[C:23]=3[CH:32]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1cc(Oc2ccnc(NCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccnc(NCCN)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of {6-[2-(2-tert-butoxycarbonylamino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.21 g, 0.46 mmol) in dioxane (7 mL) was treated with 4N HCl in dioxane (2 mL) at room temperature. The mixture was stirred for 3 hours at room temperature. The precipitated solid was collected by vacuum filtration, dissolved in water and lyophilized to give {6-[2-(2-amino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid hydrochloride salt as a yellow solid (0.142 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ 8.57 (br s, 1H), 8.35-8.20 (br m, 1H), 8.02 (br s, 3H), 7.40-7.30 (br m, 1H), 7.15 (br s, 1H), 6.48 (br s, 1H), 5.53 (d, J=9.38 Hz, 1H), 3.36 (br m, 2H), 3.07 (d, J=14.07 Hz, 1H), 2.95-2.70 (m, 2H), 2.30 (s, 3H), 2.14 (m, 1H). MS (ESI) m/z: 357 [M−1]. 1H NMR (400 MHz, CD3OD) δ8.27 (d, J=6.64 Hz, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 6.70 (d, J=6.64 Hz, 1H), 5.68 (dd, J=8.21, 3.13 Hz, 1H), 3.48 (br m, 2H), 3.19 (dd, J=15.63, 2.74 Hz, 1H), 2.98 (br m, 2H), 2.50 (br m, 1H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH3:48])=[C:17]([C:21]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[NH2:35])=[C:30]4[C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([NH:37]C(=O)OCC5C=CC=CC=5)=[CH:27][C:28]=3[NH:29]4)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Br>C(Cl)Cl>[NH2:37][C:26]1[CH:27]=[C:28]2[C:23]([C:22]3[C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([N:9]5[CH2:8][C:7]6[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=6)[C:10]5=[O:14])[C:16]=4[CH3:48])=[CH:33][CH:32]=[C:31]([C:34]([NH2:35])=[O:36])[C:30]=3[NH:29]2)=[CH:24][CH:25]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NC(=O)OCc5ccccc5)ccc4c23)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: Br
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O

Procedure:
A solution of benzyl 5-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-8-carbamoyl-9H-carbazol-2-ylcarbamate (Example 51-4, 65 mg, 0.102 mmol) in hydrogen bromide (30-35% in acetic acid, 5 mL, 27.6 mmol) was stirred at rt for 1.5 h. The mixture was diluted with DCM and concentrated. The residue was dissolved in DCM containing a small amount of methanol and the solution was mixed with 1 M aqueous sodium hydroxide. The organic phase was separated, washed with water, dried and concentrated, and the residue was triturated with hexane. The residue was purified by column chromatography (eluting with a gradient from 97:2.7:0.3 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 7-amino-4-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide as a white solid (Example 54-3, 45 mg, 88%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 10.32 (1 H, s), 7.89 (1 H, d, J=8.35 Hz), 7.57 (1 H, d, J=7.91 Hz), 7.49-7.55 (2 H, m), 7.35-7.47 (3 H, m), 7.04 (1 H, d, J=7.47 Hz), 6.93 (1 H, d, J=8.35 Hz), 6.74 (1 H, d, J=1.76 Hz), 6.46 (1 H, dd, J=8.57, 1.98 Hz), 4.79 (2 H, d, J=2.20 Hz), 3.84 (2 H, br. s.), 1.96 (3 H, s), 1.40 (9 H, s). Mass spectrum m/z 503.3 (M+H)+. Also obtained was 7-amino-6-bromo-4-(3-(5-tert-butyl-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide as a white solid (Example 54-4, 5 mg, 8%). 1H NMR (400 MHz, chloroform-d) δ 10.34 (1 H, s), 7.89 (1 H, d, J=7.91 Hz), 7.53-7.59 (3 H, m), 7.44-7.48 (2 H, m), 7.35 (1 H, dd, J=5.71, 3.08 Hz), 7.05-7.08 (2 H, m), 6.84 (1 H, s), 4.83 (2 H, s), 4.22 (2 H, br. s.), 1.95 (3 H, s), 1.40 (9 H, s). Mass spectrum m/z 581, 583 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(F)cc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Fc1cc(Br)cc(OC(F)F)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 3-bromo-5-fluorophenol. (6.1 g, 31.0 mmol; see step (ii) above) and chlorodifluoromethane (13.0 g, 150.0 mmol) in i-PrOH (100 mL) and 30% KOH (80 mL) was heated in a sealed flask for 18 h at 80–85° C. The reaction mixture was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo to afford a colourless oil. The aqueous layer was extracted with Et2O (3×30 mL). The crude oil and the combined organic extracts were washed with 2N NaOH (3×30 mL) and H2O (3×30 mL). The organics were then dried (Na2SO4), filtered through a small silica gel plug, and concentrated in vacuo to afford the sub-title compound (6.1 g, 79%) as a colourless oil that was used without further purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([C:49](OC)=[O:50])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B(OC)(OC)OC.[BH4-].[Li+].O>C(OCC)C>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][OH:50])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
A stirred solution of methyl 9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (7.2 g, 9.64 mmol) (preparation 14) in dry diethyl ether (150 ml) was treated with trimethyl borate (0.11 ml, 0.97 mmol) and lithium borohydride (212 mg, 9.64 mmol) and the mixture heated at reflux for 1 hr under a nitrogen atmosphere. The mixture was then cooled to room temperature, water (100 ml) carefully added and stirring continued for 10 minutes. The organic phase was separated, washed with brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of diethyl ether:pentane (1:1) changing to diethyl ether:pentane (3:1) to afford the title compound as an oil (5.17 g). MS: 721 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[CH:33]=O)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:33][C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[S:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:6]1[CH3:15]
Reactant: O=Cc1ccncc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccncc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-(4-fluorobenzenesulfonyl)pyridine-4-carbaldehyde.