Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cn(-c2ccccc2)nc1OCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 55 %

Procedure:
Using [3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.79 g) synthesized in Example 66(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.68 g, 55%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[C:9]=1[C:16](=[O:18])[NH2:17])=[O:6])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:15])=[O:25])[C:9]=1[C:16]([NH2:17])=[O:18])=[O:6])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)Nc1cccc(SC)c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cccc(S(C)=O)c1C(N)=O

Procedure:
A mixture of 2.0 g. of [2-carbamyl-3-(methylthio)phenyl] oxamic acid ethyl ester and 1.44 g. of m-chloroperoxybenzoic acid in 200 ml. of methylene chloride is stirred for 2 hours. 0.6 g. of sodium bicarbonate in 20 ml. of water is added, the methylene chloride layer is separated, dried and evaporated. The residue is recrystallized from ethanol-diethyl ether, m.p. 164°-166° C.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(isopropylsulfonyl)aniline (B-3) (32 g, 0.16 mol) in DMF (300 mL) at 0° C., was added NaH (13 g, 0.32 mol). After stirred at 0° C. for 0.5 h, 2,4,5-trichloropyrimidine (35 g, 0.13 mol) was dropwised to the mixture at 0° C. The solution was stirred for 12 h at RT, then poured into water, extracted with EtOAc, washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1 to 5:1) to give the title compound (B) as a yellow solid. MS-ESI (m/z): 346 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11]C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cnccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2cnccc2n1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A 50% TFA/DCM mixture (10 mL) was added to tert-butyl 1,6-naphthyridin-2-ylcarbamate (2.7 g, 11.0 mmol) from the above step. After 30 minutes, the reaction mixture was concentrated and diluted with 30 mL of water. A saturated NaHCO3 solution (15 mL) was added, and the reaction mixture was extracted twice with 50 mL of EtOAc. The organic layers were combined, concentrated, and purified by chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient 0-15% MeOH/DCM to give 1,6-naphthyridin-2-amine (1.6 g, 99% yield). MS m/z: 145 (M+1). 1H NMR (400 MHz, (CD3OD)): δ ppm 6.93 (d, J=9.00 Hz, 1H), 7.41 (d, J=6.06 Hz, 1H), 8.05 (d, J=9.00 Hz, 1H), 8.37 (d, J=5.87 Hz, 1H), 8.83 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:25](C=O)C>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([C:17]([NH2:25])=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc2c1CN(Cc1ccccc1)C2
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc2c1CN(Cc1ccccc1)C2

Procedure:
A mixture of 35.0 g of 2-benzylisoindoline-4-carboxylic acid, 150 ml of thionyl chloride, and 1 ml of DMF was heated under reflux for 10 hours. After cooling, the reaction mixture was concentrated to the extent that the acid chloride crystals does not deposit. To the concentrate was added dropwise 28% aqueous ammonia under ice cooling and stirring After stirring for 3 hours crystals produced was collected by filtration and washed with water. The crystals were dissolved in chloroform, washed with 5% sodium hydroxide and water, and concentrated. The residue was recrystallized from ether to obtain 24.1 g of 2-benzylisoindoline-4-carboxamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[S:17][C:16]([Cl:18])=[N:15][C:14]=1[Cl:19])[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[S:17][C:16]([Cl:18])=[N:15][C:14]=1[Cl:19])[O:12][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)c1sc(Cl)nc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC(OC1CCCCO1)c1sc(Cl)nc1Cl

Procedure:
A soln. of 3-((tert-butyldimethylsilyl)oxy)-1-(2,4-dichlorothiazol-5-yl)propan-1-ol (6.62 g, 19.3 mmol), 3,4-dihydro-2H-pyran (8.9 mL, 96.7 mmol) and PPTS (0.49 g, 1.93 mmol) in DCM (75 mL) was stirred under reflux for 2 h. Subsequently, the volatiles were removed in vacuo and the residue was purified by means of CC (1-10% EtOAc/Hept) to provide the product as colorless oil as an isomeric mixture.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:24]1[C:12]2[N:11]=[C:10]([C@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc2c1nc([C@@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1nc([C@@H](C)N)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of [(R)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (404 mg, 1.15 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at RT for 3 h. Additional TFA (0.5 mL) was added and stirring was continued for 30 min. Volatiles were then removed under reduced pressure and the residue was dissolved in a small amount of DCM and loaded onto an SCX-2 cartridge. The cartridge was initially washed with 10% MeOH in DCM and the product was eluted with 2M NH3/MeOH affording (R)-1-(4-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (273 mg, 94%). LCMS: RT 2.14 [M-NH2]+ 235.1
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:6][CH2:5]1.[N:7]1([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:6]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH:8]1[CH2:9][NH:10][CH2:11][CH2:12][N:7]1[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1
Reactant: BrCCC1CO1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(N3CCNCC3CCC3CO3)nsc2c1
Yield: 73.8 %

Procedure:
A mixture of 4-bromo-1,2-epoxybutane (1.06 g; 7.02 mmol), 3-(1-piperazinyl)-1,2-benzisothiazole (1.65 g; 7.52 mmol), potassium carbonate (1.6 g; 11.3 mmol) and acetone (20 ml) was stirred under reflux for 19 hours. Confirming complete consumption of the starting materials, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the objective compound (1.5 g). Yield, 73.8%. IR νmaxfilm (cm-1): 1590, 1560, 1490, 1460.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1>C(#N)C.C([O-])(O)=O.[Na+]>[C:15]([O:14][C:12]([NH:11][C@@H:4]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[C:3]([OH:19])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(Cc1nccs1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
To 2-tert-butoxycarbonylamino-3-thiazol-2-ylpropionic acid methyl ester (500 mg, 1.75 mmol) in a mixture of acetonitrile (6 mL) and 0.2 M aqueous NaHCO3 (12 mL) was added Alcalase (2.4 L, 0.08 mL), and the solution was stirred vigorously at room temperature for about 2.5 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The aqueous phase was acidified with 6N HCl to pH 3 and the solution was extracted with ethyl acetate. The combined organic layers were then dried and evaporated to yield 2(S)-tert-butoxycarbonylamino-3-thiazol-2-ylpropionic acid (204 mg).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCCO)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (36 mg, 0.260 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (62.2 mg, 0.260 mmol) and heated at 90° C. for 4 h. The mixture was filtered, the filtrate was treated with hydrogen chloride (4 M in dioxane, 1 mL) and the solution was stirred at rt overnight. The solution was concentrated under vacuum and the residue was purified by preparative HPLC to provide 7-(2-hydroxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an off-white solid (16.5 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1 H, s), 8.17 (1 H, br. s.), 7.94 (1H, d, J=7.9 Hz), 7.53-7.65 (3 H, m), 7.49 (3 H, t, J=7.8 Hz), 7.27-7.39 (2 H, m), 6.99 (1 H, d, J=7.7 Hz), 6.92 (1 H, d, J=8.8 Hz), 6.59 (1 H, dd, J=8.8, 2.4 Hz), 4.75-4.98 (3 H, m), 3.95-4.07 (2 H, m), 3.69-3.80 (2 H, m), 2.44 (3 H, s). Mass spectrum m/z 506.0 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15](I)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C[Si]([C:28]#[CH:29])(C)C.C(N(CC)CC)C>CN(C)C=O.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([C:28]#[CH:29])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(I)cc3c12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc2[nH]c3cnc(C(=O)OC(C)C)c(COC)c3c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g of 6-iodo-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 30 ml of dimethylformamide in succession with 1.53 ml of trimethylsilylacetylene, 15 ml of triethylamine, 50 mg of copper (I) iodide and 100 mg of tetrakis (triphenylphosphine)-palladium (O) and heated for 3 hours under argon to 60° C. solution temperature. After removal of the solvent the residue is taken up in ethyl acetate and in succession is washed with saturated sodium bicarbonate and common salt solution. The organic phase was dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=12:1. The correspondingly combined fractions are stirred for 1 hour in 50 ml of methylene chloride with 4 ml of tetrabutylammonium fluoride at room temperature. The solution is washed with water, dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 830 mg of 6-ethinyl-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, melting point 191°- 193° C. (ethyl acetate/hexane) is obtained by the corresponding combination of the fractions.
Reaction SMILES: C[Al]1[CH2:7][CH2:6][CH2:5][CH2:4]O1.[C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccccc1
Reactant: C[Al]1CCCCO1
Product: c1ccc2c(c1)CCCC2

Procedure:
Methylalumoxane (MAO) was received from Albemarle as a 30% wt/V toluene solution and used as such and the silica was received from INEOS (ES70Y, 100 microns).
Reaction SMILES: Cl.CO[C:4]([C:6]1[N:7]([NH2:12])[CH:8]=[CH:9][C:10]=1[Cl:11])=[O:5].FC(F)(F)C(O)=O.[CH2:20]([N:22](CC)CC)[CH3:21]>C(#N)C>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]2[C:6]=1[C:4](=[O:5])[NH:22][C:20]([CH3:21])=[N:12]2
Reactant: COC(=O)c1c(Cl)ccn1N
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nn2ccc(Cl)c2c(=O)[nH]1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
A mixture of 1-amino-3-chloro-1H-pyrrole-2-carboxylic acid methyl ester, hydrochloride salt (11.0 g, 52.1 mmol) and trifluoroacetic acid (6.0 mL, 77.9 mmol) in acetonitrile (230 mL) was heated at 85° C. overnight. The reaction mixture was concentrated and treated with fresh acetonitrile (200 mL) and triethylamine (22.0 mL, 157.8 mmol). The reaction mixture was heated at 85° C. overnight and concentrated to small volume and diluted with water (100 mL). The mixture was then stirred at rt for 20 min. The precipitate was collected, washed with water and dried to give the title compound as a brown solid (7.67 g, 80%): 1H NMR (CD3OD): δ 7.28 (s, 1H), 6.42 (s, 1H), 2.20 (s, 3H); MS (ESI+) 184.02, 186.10 (M++H).
Reaction SMILES: I[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:11]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26](N(OC)C)=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[Si:11]([O:18][CH2:19][CH:20]1[CH2:21][CH2:22][CH:23]([C:26]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[O:27])[CH2:24][CH2:25]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Ic1ncnc2[nH]ccc12
Reactant: CON(C)C(=O)C1CCC(CO[Si](C)(C)C(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CCC(C(=O)c2ncnc3[nH]ccc23)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuran solution (1.3 M, 39.2 mL, 51.0 mmol) was added dropwise to 4-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.00 g, 20.4 mmol) obtained in Reference Synthetic Examplea 1 in tetrahydrofuran (50 mL) at −50° C., and stirred at −50° C. for 1 hour. The reaction mixture was mixed with 4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamide (6.44 g, 20.4 mmol) in tetrahydrofuran (30 mL) at −50° C. and then stirred at room temperature for 23 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v)) to give the title compound as a colorless oil (5.14 g, yield 67%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[S:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:27]4[S:23][C:24]5[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=5[CH:26]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4cc5ccccc5s4)cc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and benzo[b]thiophene-2-carbonyl chloride (0.59 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give benzo[b]thiophene-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.75 g, 56% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.03 min (96.23%); mp: 318-320° C.; 1H NMR (DMSO-d6) δ 1.96-2.17 (m, 1H, CHH), 2.54-2.68 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.68 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.39-7.55 (m, 2H, Ar), 7.79-8.10 (m, 5H, Ar), 8.16 (s, 1H, Ar), 9.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.64, 49.01, 122.07, 122.83, 123.63, 124.97, 125.25, 126.32, 129.93, 131.66, 133.54, 139.10, 139.27, 140.25, 147.13, 161.80, 166.96, 167.10, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C23H17N3O5S: C, 61.74; H, 3.83; N, 9.39. Found: C, 61.59; H, 3.53; N, 9.29.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].[C:13]([C@@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:13]([C@@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)=[CH:19][CH:18]=1)#[N:14]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)c(F)c2)cc1
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
A solution of 4-cyano-3-fluorophenylboronic acid (0.736 g) dissolved in dioxane (10 mL) was added to a stirred solution of (S)-tert-butyl 1-cyano-2-(4-iodophenyl)ethylcarbamate (1.51 g) and bis[bis(1,2-diphenylphosphino)ethane]palladium (0) (0.037 g) in dioxane (20 mL) under nitrogen. The resulting mixture was stirred for 10 min. A solution of potassium carbonate (1.121 g) in water (5 mL) was added and the resulting solution was stirred at 75° C. for 3 h. The cooled mixture was evaporated to dryness. The residue was taken up in ethyl acetate (150 mL) and washed with saturated brine (3×50 mL), dried over sodium sulfate and adsorbed onto silica. The crude product was purified by flash silica chromatography, eluting with 20% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitle compound as a colourless solid (0.568 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)nc1
Temperature: 85 °C
Reaction time: 5 h
Yield: 37.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CCl4 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yield 5 g (37%) of 6-(bromomethyl)pyridine-3-carbonitrile as a beige solid.
Reaction SMILES: C1(C[N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH:12]3[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9]2)C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH:10]12[O:15][CH:13]([CH:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)NC1CC2CN(Cc3ccccc3)CC1O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CC2CNCC1O2
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of 1,1-dimethylethyl [3-(phenylmethyl)-8-oxa-3-azabicyclo[3.2.1]oct-6-yl]carbamate (560 mg, 1.76 mmol) in EtOH (18 mL) at 25° C. was added Pd(OH)2 (336 mg, 60 wt %). The suspension was hydrogenated at 50 psi using a Parr Shaker. After 12 h, the solution was filtered through Celite®, concentrated and purified through a pad of silica (5% MeOH in DCM (1% NH4OH)) affording the title compound (400 mg, quant.) as a white solid: LC/MS (ES) m/e 229 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15]>C(O)C>[OH:6][C:4]1[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:14]=[N:15][C:3]=1[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1O

Procedure:
Sodium metal (3.8 g, 164 mmol) was added to absolute ethanol (200 mL). The mixture was stirred under reflux until a clear solution was obtained. Diethyl malonate (26.3 g, 164 mmol) was added to this solution which was again heated to reflux, and a solution of 1-(azidomethyl)-4-methoxybenzene (i.e. the product of Step A, 25.5 g, 156 mmol) in ethanol (50 mL) was added at once. The reaction mixture was stirred at reflux for 24 h then the reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) and acidified to pH 2 with 1 M aqueous hydrochloric acid, stirred for 30 min, and the solid was filtered off and washed with water. The solid was dried over phosphorus pentoxide. The solid was stirred in chloroform (500 mL) and the insoluble solids were filtered off. Hexanes (400 mL) were added to precipitate the product, which was removed by filtration and dried to afford the title compound (12.0 g) as a beige solid.