Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3](=[O:23])[CH2:4][C:5]([CH3:22])([C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:8]=1)[CH3:6].[CH3:26][S+](C)(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=O>CS(C)=O.C1COCC1.CS(C)=O.O>[CH3:6][C:5]([C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)[CH:8]=1)([CH3:22])[CH2:4][C:3]1([C:2]([F:24])([F:1])[F:25])[CH2:26][O:23]1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 1,1,1-trifluoro-4-methyl-4-(5-pyrimidin-5-yl-2,3-dihydrobenzofuran-7-yl)pentan-2-one (620 mg, 1.8 mmol) in 5 mL of anhydrous DMSO-THF (1:1) was added 2.64 mL of a trimethylsulfoxonium ylide solution (stock solution prepared by reaction of NaH (242 mg, 60% dispersion in mineral oil) with trimethylsulfoxonium iodide (1.33 g, 6.0 mmol) in 7.50 mL of anhydrous DMSO for 30 minutes) dropwise over 5 minutes. After stirring for 2 hour at room temperature, the reaction mixture was poured into 40 mL of water and extracted with diethyl ether (200 mL total volume). The combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 651 mg (99% yield) of the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [C:1]1(NCC(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[C:18]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O>O>[C:24]1(=[O:33])[N:23]([C:18]2[CH:5]=[CH:6][CH:1]=[CH:2][C:3]=2[CH2:4][C:12]([OH:13])=[O:15])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C(O)CNc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 51.2 %

Procedure:
To a stirred mixture of phenylglycine (3.0 g, 20 mmol) and sodium carbonate (2.23 g, 21 mmol) in 450 mL of water is added N-carbethoxyphthalimide (4.38 g, 20 mmol). After 45 minutes, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. After 1 hour, the resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 2.88 g (51%) of 2-phthalimidophenylacetic acid as a white powder.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3](C(O)=O)[NH:2]1.ClCCl.ClC([O:20][CH2:21]C(C)C)=O.[NH2:25]C(C1C=CC(C(OC)=O)=CC=1)C>C(N(CC)CC)C>[C:1]1([C:21]([NH2:25])=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: COC(=O)c1ccc(C(C)N)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1nccc2ccccc12
Temperature: 0 °C

Procedure:
In Scheme 1, step A, a protected 3,4-dihydro-1H-isoquinoline-3-carboxylic acid, wherein Pg is a suitable nitrogen protecting group, such as a tert-butoxy carbonyl protecting group (BOC), is coupled with methyl 4-(1-aminoethyl)benzoate under standard conditions to provide the protected isoquinoline amide of structure (1). For example, the protected 3,4-dihydro-1H-isoquinoline-3-carboxylic acid is dissolved in a suitable organic solvent, such as dichloromethane, cooled to about 0° C., and treated with about 1.1 equivalents of a suitable organic base, such as triethylamine. Then about 1.1 equivalents of isobutyl chloroformate are added dropwise with stirring. The mixture is allowed to stir for about 20 minutes at 0° C., followed by addition of about 1.1 equivalents of the methyl 4-(1-aminoethyl)benzoate. The reaction mixture is then stirred for about 1 hour at room temperature. The protected isoquinoline amide (1) is then isolated using methods well known in the art, such as extraction techniques. For example, water is added to the mixture, the layers are separated, and the organic phase is washed with aqueous potassium bisulfate, followed by aqueous sodium bicarbonate. The organic phase is then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the protected isoquinoline amide (1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].Cl>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)ccc1F
Temperature: 120 °C
Yield: 96.9 %

Procedure:
A mixture of 4-Fluoro-3-methoxy-benzaldehyde (6.16 g, 40 mmol), and malonic acid (6.24 g, 60 mmol) in pyridine (30 ml) and piperidine (1 ml) was heated at 120° C. for 2 hrs. The mixture was cooled to room temperature and neutralized with concentrated HCl to PH<3, the white solid was collected and dried to give 7.6 g of product (97% yield). LC-MS: m/e 195 (M−1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].CO[CH:15](OC)[N:16](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:16]=[CH:15][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added Omesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:25])([F:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>CCCCCC.O1CCCC1.C(OCC)C>[CH2:26]([O:28][C:29]([C:21]1[S:20][C:19]([C:16]2[S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:24])[F:25])=[CH:13][CH:12]=3)=[N:18][CH:17]=2)=[CH:23][CH:22]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1ccc(-c2ncc(-c3cccs3)s2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
Under a dry nitrogen atmosphere, 1.6 ml of a 2.5 M solution of n-butyllithium in n-hexane was added dropwise to a stirred, cold (-78° C.) solution of 1.0 g (0.0032 mole) of 2-(4-trifluoromethylphenyl)-5-thien-2-ylthiazole in 15 ml of tetrahydrofuran. This mixture was stirred at -78° C. for two hours and then was added to a stirred, cold (-78° C.) solution of 0.70 g (0.0064 mole) of ethylchloroformate in 20 ml of tetrahydrofuran. After complete addition the mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was diluted with 100 ml of diethyl ether and was washed in succession with an aqueous, saturated ammonium chloride solution, water, and an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a solid. This solid was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (60:40) to yield 0.56 g of 5-(5-ethoxycarbonylthien-2-yl)-2-(4-trifluoromethylphenyl)thiazole as a solid, compound 1 of Table 1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:32])[N:22]3[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:18])=[O:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]([C@H:19]2[CH2:25][CH2:24][C@@H:23]3[CH2:26][N:20]2[C:21](=[O:32])[N:22]3[O:27][S:28](=[O:30])(=[O:29])[OH:31])=[O:18])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)[C@@H]1CCNC1

Procedure:
By using the procedure described in Step-4 of Example-1, and by using tetrabutylammonium salt of trans-3-[N′-(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-pyrrolidin-1-carboxylic acid tert-butyl ester (15 gm, 0.021 mmol), dichloromethane (37 ml) and trifluoroacetic acid (37 ml) to provide the title compound in 7.7 gm quantity as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([NH:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (S)-2-(tert-butoxycarbonyl)propanoic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (95 mg, 69%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)=[CH:8][CH:7]=1>C(OCC)(=O)C.CCCCCC>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:1]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C3OCCO3)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Yield: 95 %

Procedure:
Using N-(3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 82, the title compound was synthesized in the same manner as in Example 173. Yield: 95%. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18]O)[CH2:15][O:14]1>>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)[N:6]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC1(C)OCC(Cn2nc(I)c3cc(F)ccc32)O1
Yield: 52 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 1,2-isopropylideneglycerol in 52% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (300 MHz, CDCl3): δ 1.27 (3H, s), 1.31 (3H, s), 3.83-3.87 (1H, m), 4.07-4.11 (1H, m), 4.48-4.55 (3H, m), 7.10 (1H, dd, J=8.3, 2.3 Hz), 7.22 (1H, td, J=8.9, 2.3 Hz), 7.45 (1H, dd, J=9.1, 4.0 Hz). [M+H] calc'd for C13H14FN2O2, 377; found, 377.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: C1CCNCC1
Reactant: COc1cc(Br)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a stirred solution of 4-bromo-1-chloromethyl-2-methoxybenzene (1.50 g, 6.36 mmol) in acetonitrile (64 mL) was added potassium carbonate (1.05 g, 6.36 mmol) and piperidine (0.63 mL, 6.36 mmol) then the reaction mixture was heated under reflux for 15 h. The reaction mixture was cooled to ambient temperature and then filtered, the filtrate was then concentrated under reduced pressure to afford a residue that was then loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in methanol to afford the title compound (1.73 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 3.45 (s, 2H), 2.39 (t, J=5.0 Hz, 4H), 1.62-1.51 (m, 4H), 1.47-1.39 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH2:16]([C:18]1[C:22]([C:23](Cl)=[O:24])=[C:21]([CH3:26])[O:20][N:19]=1)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]([C:22]2[C:18]([CH2:16][CH3:17])=[N:19][O:20][C:21]=2[CH3:26])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1noc(C)c1C(=O)Cl
Reactant: Nc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1noc(C)c1C(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.3 grams (0.120 mole) of m-fluoroaniline and 20.9 ml. (0.150 mole of triethylamine in 120 ml. of toluene is treated by dropwise addition with 22.5 grams (0.129 mole) of 3-ethyl-5-methyl-4-isoxazole carbonyl chloride in 100 ml. of toluene while maintaining the temperature between 30°-35° during addition. The mixture is stirred at room temperature overnight, filtered and the filtrate washed with 2N hydrochloric acid. The toluene is dried and evaporated with the residue recrystallized from toluene to give N-(m-fluorophenyl)-3-ethyl-5-methyl-4-isoxazole carboxamide (m.p. 99.5°-101° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:47][CH2:48][CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN2CCCC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 mL) for 25 mins. N-(2-aminoethyl)pyrrolidine (Aldrich; 0.51 g, 4.48 mmol) in DMF (2 mL) was added and the solution stirred at ambient temp for 2 hours.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].I[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH2:28])[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=[C:19]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:2]3[S:1][CH2:5][CH2:4][N:3]=3)=[O:8])[C:27]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: O=C(NC1=NCCS1)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(C(=O)NC3=NCCS3)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
A solution of [3-((4,5-dihydrothiazol-2-yl)carbamoyl)phenyl]boronic acid (19 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA30 (17.8 mg, 67% yield).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[C:16]2[C:11](=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:7]>ClC(Cl)C>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][N:9]=[C:8]([CH2:6][CH3:7])[C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1n[nH]c2c1ccc[n+]2[O-]
Solvent: CC(Cl)Cl
Product: CCc1n[nH]c2nccc(Cl)c12
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Phosphorus oxychloride (11.1 mL) was added to a suspension solution of compound (3b) (19.5 g) in dichloroethane (240 mL) at room temperature, followed by stirring for 30 min. The solvent of the reaction solution was distilled away, and then acetonitrile (40 mL), methanol (40 mL), and water (80 mL) were added to the residue. After adjustment of pH to 9 with an aqueous sodium hydroxide solution, water (400 mL) was added thereto. The precipitate was collected by filtration, washed by sprinkling methanol (40 mL), water (300 mL), ether (60 mL), and hexane (30 mL), sequentially, and dried under reduced pressure to obtain compound (3c) (10.2 g, 47%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH2:5]2.[CH3:32][N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:26]1([CH2:25][C@H:12]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:37]4[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=4)[CH:3]=3)[C:7]2=[O:11])[CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Br)ccc2C1=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](CC1CCCCC1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 28.9 %

Procedure:
A mixture of 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (103.5 mg, 0.2151 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47 mg, 0.23 mmol), N,N-diisopropylethylamine (0.11 mL, 0.63 mmol), and bis(tri-t-butylphosphine)palladium (0.011 g, 0.021 mmol) in 1,4-dioxane (4 mL, 50 mmol) and water (0.2 mL, 10 mmol) was stirred at 110° C. for 40 min under microwave irradiation. Direct purification on prep.—HPLC afforded 30 mg (29% yield) of the desired intermediate. LC-MS found: 483.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:17][OH:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>S(OC)(OC)(=O)=O.ClCCl>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Solvent: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Product: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., first triethylamine (175.6 ml) and then a solution of pyridine/sulfur trioxide complex (221 g) in dimethyl sulfate (0.84 liters) are added dropwise over a period of 45 minutes, with stirring, to a solution of 2(S)-(tert-butoxycarbonyl)amino-4(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methyl-hexanol (184.8 g) in dichloromethane (1.34 liters). When the addition is complete, the batch is stirred for a further 30 minutes at 0° C. and then ice-water (1.6 liters) is added. The mixture is extracted with dichloromethane (3×1.6 liters), and the combined organic phases are washed with saturated sodium hydrogen carbonate solution (2×1.6 liters), water (1.6 liters) and saturated sodium chloride solution and filtered through cotton wool and the solvent is removed in vacuo. The residue is dried under a high vacuum, yielding the crude title compound in the form of an oil (190 g): Rf (ethyl acetate/hexane 1:1)=0.44. IR (CH2Cl2) 3430, 2960, 1710, 1589, 1515 cm-. 1H-NMR (CDCl3): δ 0.86 (m, 6H), 1.44 (s, 9H), 1.55-1.8 (m, 4H), 2.09 (m, 2H), 2.4-2.7 (m, 2H), 3.35 (s, 3H), 3.57 (t, J=6.4 Hz, 2H), 3.83 (s, 3H), 4.10 (t, J=6.4 Hz, 2H), 4.05-4.20 (m, 1H), 4.89 (d, br., 1), 6.7-6.8 (m, 3H), 9.50 (s, 1H).