Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:31])[CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20](C(C)=C)[C:19]3=[O:30])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(O)C.Cl>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH3:31])[CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:30])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C=C(C)n1c(=O)n(CC(C)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CC(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Cn1c(=O)[nH]c2ccccc21

Procedure:
A stirred solution of 8 parts of 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}-2-methylpropyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 120 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. The whole is stirred and refluxed for 5 minutes. The reaction mixture is evaporated. The residue is taken up in water and the whole is alkalized with a concentrated ammonium hydroxide solution. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}-2-methylpropyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 176° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.C(O)(=O)C>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
4-Fluoroaniline (100 g) and 2,5-dimethoxytetrahydrofuran (124.9 g) were added to acetic acid (500 ml) and the mixture was stirred at a refluxing temperature for 1 h. After cooling to room temperature, the reaction mixture was added to water (2.5 Liters) and the mixture was stirred further for 30 min. The precipitated crystals were recrystallized from a mixed solvent of methanol-acetone (ratio=2:1) to give 1-(4-fluorophenyl)pyrrole (156 g), melting point: 57–58° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([S:29](Cl)(=[O:31])=[O:30])[C:25]([CH3:33])=[N:24]1>>[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([S:29]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:30])=[O:31])[C:25]([CH3:33])=[N:24]1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1nn(C)c(C)c1S(=O)(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 80 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=273-275° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88-7.85 (m, 1H), 7.64-7.58 (m, 1H), 7.56-7.52 (m, 1H), 7.32-7.29 (m, 1H), 3.72 (s, 3H), 3.50-3.44 (m, 2H), 3.09 (s, 2H), 2.71-2.65 (m, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 2.11-2.05 (m, 2H), 1.91-1.82 (m, 2H); LCMS: 474 [M+H].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:27]=[CH:26]C3N[C:23](=O)[NH:24][C:20]=3[CH:19]=2)=[N:15][N:14]=1.IC.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:40][N:41]([CH:43]=[O:44])[CH3:42]>C(OCC)(=O)C>[CH3:40][N:41]1[C:42]2[CH:26]=[CH:27][C:18]([C:16]3[O:17][C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][N:15]=3)=[CH:19][C:20]=2[N:24]([CH3:23])[C:43]1=[O:44]
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]c(=O)[nH]c3c2)o1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3c(c2)n(C)c(=O)n3C)o1
Reaction time: 18 h
Yield: 13 %

Procedure:
5-[5-(5-Methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1,3-dihydro-benzoimidazol-2-one (200 mg, 0.56 mmol) was heated in DMF (2 mL) until the suspension turned into solution. After the solution was cooled to ambient temperature iodomethane (38 μL, 0.61 mmol) was added and stirred for 18 h at this temperature. The resulting suspension was diluted with DMF (2 mL) and warmed until the reaction mixture became homogeneous. A solution of potassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol) was added and stirred for 1 h at ambient temperature. Additional iodomethane (38 μL, 0.61 mmol) was added and stirring was continued for another 18 h. Additional potassium bis(trimethylsilyl)amide (0.91 M in THF, 673 μL, 0.61 mmol) was added, stirred for 15 min at ambient temperature, treated with iodomethane (0.38 μL, 0.61 mmol) and stirred for 5 h at this temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL), water (20 mL) and brine (20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (29 mg, 13%) as a white solid. MS: m/e=388.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SSc1ccccc1)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 6.24 g (0.0287 m) of N-methyl-N-(phenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 100 ml of dioxane. 2-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 7.0 g of a white solid. m.p. 73°-74° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH2:22])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18].[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>CC(N(C)C)=O>[Br:23][CH:24]([CH3:28])[C:25]([NH:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH:22][C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH:16][C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18])=[O:26]
Reactant: CC(Br)C(=O)Br
Reactant: NCCN(CCN)C(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(Br)C(=O)NCCN(CCNC(=O)C(C)Br)C(=O)c1c(I)c(NC(=O)C(C)Br)c(I)c(C(=O)O)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (77.8 mmol) of N,N-bis-(2-aminoethyl)-5-amino-2,4,6-triiodoisophthalic acid amide is dissolved in 500 ml of dimethylacetamide, and 75.5 g (350 mmol) of 2-bromopropionic acid bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate, and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[CH2:26][CH2:25]N[CH2:23][CH2:22]1>O>[CH3:20][N:21]1[CH2:26][CH2:25][N:1]([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(c2cccc(C#N)c2C#N)CC1
Yield: 54 %

Procedure:
A mixture of 3-nitrophthalonitrile (2.121 g, 12.3 mmol), freshly dried potassium carbonate (5.45 g, 39 mmol) and N-methylpiperazine (12 mL) were heated at reflux for 2 h. The reaction mixture was poured into water (200 mL) to precipitate the product, which was filtered off and washed with water to give 5 as a beige powder (1.59 g, 54%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.COC1CNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH:26]([O:25][CH3:24])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC1CNC1
Agent: Cl
Product: COC1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxyazetidine hydrochloride and isolated as white solid (11.0 mg, 60%). MS (m/e): 387.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH2:29]([S:31]SCC)[CH3:30]>O1CCCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([S:31][CH2:29][CH3:30])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCSSCC
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCSc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a solution 5-bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 3.3 g, 10.5 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6M, 10 mL, 16 mmol) dropwise. After stirring for 20 min at −78° C., ethyl disulfide (1.96 g, 16 mmol) was added. The resulting mixture was stirred for 1 h, quenched with a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (2×100 mL), dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by flash column chromatography (Qingdao silica gel, 300 mesh, 10% dichloromethane/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.2 g, 71%): LC/MS m/e calcd for C15H26N2SSi [M+H]+ 295.54.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[OH2:28].O=O>CN(C=O)C.CCOC(C)=O.[Cu]Cl.[Pd](Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1)(=[O:28])[CH3:21]
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 52 %

Procedure:
A round-bottom flask was charged with copper(I) chloride (49 mg, 0.5 mmol), and a solution of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (80 mg, 0.2 mmol) in DMF (3 mL) was added, followed by H2O (0.5 mL) and palladium(II) chloride (18 mg, 0.1 mmol). The reaction mixture was vigorously stirred under a balloon of oxygen at rt overnight. The reaction was diluted with EtOAc (5 mL), and filtered. The filtrate was separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-1-(4-acetylphenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 52%). 1H NMR (CDCl3): 1.34 (m, 1H), 1.49 (m, 3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.11-2.27 (m, 3H), 2.46 (s, 3H), 2.84 (m, 2H), 3.51 (m, 2H), 5.64 (m, 1H), 6.86 (m, 2H), 7.26 (m, 6H), 7.51 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:6]1.Cl.C(#N)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CC(=O)C(C)(C)C)CC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CC2CNCC(C1)O2
Temperature: 0 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (i) above; 0.265 g, 0.812 mmol) in ethyl acetate (10 mL) was treated, at 0° C., with ethyl acetate saturated with gaseous hydrochloric acid. The mixture was stirred at 0° C. for 5 h, and then evaporated. Acetonitrile (15 mL) and K2CO3 (1 g, 7.2 mmol) were added, and the mixture was stirred overnight before being filtered and evaporated to yield 0.159 g (86%) of the sub-title compound.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N+:11]([O-:13])=[O:12])=[N+]=[N-].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.O>[F:10][C:6]1[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]=[P:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=Nc1cccc(F)c1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
To a solution of 1-azido-3-fluoro-2-nitrobenzene (500 mg, 2.75 mmol) in THF (4 mL) and water (1 mL) was added triphenylphosphine (720 mg, 2.75 mmol). The reaction mixture was stirred at room temperature for 45 min then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si—PCC, Et2O) to give the desired product as a yellow solid (844 mg, 73%). LCMS (Method A): RT 4.36 min; [M+H]+ 417
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([Cl:28])[N:30]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
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: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Yield: 54.1 %

Procedure:
A mixture of compound 1e (15.00 g), 2,4-dichloropyrimidine (7.56 g) and tetrakis(triphenylphosphine)palladium(0) (4.51 g) in a solution of ethylene glycol dimethyl ether (200 mL) and aqueous Na2CO3 (2M, 60 mL) was refluxed overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was concentrated and the residue was purified on silica gel column (eluted with 100% dichloromethane and 3% acetone in dichloromethane) to provide 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (1f) (7.83 g, 54%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=8.0 Hz, 1H), 8.62 (d, J=5.6 Hz, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.47 (s, 1H), 8.28 (d, J=7.6 Hz, 2H), 7.63 (t, J=7.6 HZ, 1H), 7.57 (d, J=5.2 Hz, 1H), 7.53 (t, J=8.0 Hz, 2H), 7.35 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 371 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].[CH2:22]1COCC1.C(N(C(C)C)CC)(C)C.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH2:1]([O:3][C:4]([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2c(c1O)CCN(C(=O)OCC)CC2
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step b) (2.3 g, 7.3 mmol) was dissolved in 60 mL of 1:1 MeOH:THF. Diisopropylethylamine (1.9 mL, 10.9 mmol) was added followed by TMSCHN2 (10.9 mL of 2M). The reaction was stirred overnight at room temperature then quenched carefully with 0.4 ML HOAc. After stirring ½ hour, the reaction was partitioned between DCM and 1M HCl (100 mL each). The organic layer was dried over MgSO4 and concentrated to give 2.75 g of the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C1CCCCC1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(C)CC2)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A suitable dry reaction vessel having a mechanical stirrer, low temperature thermometer and addition funnel was charged with 250 g (1.34 mol) of m-bromoanisole (Aldrich Chemical Company, Milwaukee, Wis.) in 675 ml of dry tetrahydrofuran and the solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath. A solution of 1357 ml. of sec.-butyllithium in cyclohexane (1.71 mol) was added dropwise to the reaction mixture at such a rate so that the temperature did not rise above -50° C. The resulting white suspension was stirred at -50° C. for 1 hour followed by the addition of 174.2 g (1.54 mol) of 1-methyl-4-piperidone (Aldrich Chemical Company) in 440 ml of dry tetrahydrofuran so as to maintain the reaction temperature below -40° C. When the addition was complete the temperature was allowed to rise to approximately -20° C. over approximately 11/2 hours and then to room temperature over a 1 hour period. Residual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution followed by the addition of 525 ml of water. The aqueous phase was separated and extracted twice with 350 ml portions of methylene chloride. The combined organic extracts were extracted in two portions, each with 1250 ml of 1N hydrochloric acid. The separated aqueous extracts were made basic (pH=10) with 28 percent ammonium hydroxide and extracted 3 times with 350 ml portions of methylene chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was slurried in 1000 ml of hot hexane and the slurry was cooled and filtered. The isolated crystalline product was dried in a vacuum oven to provide 225.6 g of 98% pure product.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[OH:10][CH2:9][C:3]1([CH3:2])[CH2:8][CH2:7][N:6]([C:12]2[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=2)[CH2:5][CH2:4]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CC1(CO)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(CO)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 25 °C

Procedure:
(4-Methylpiperidin-4-yl)methanol hydrochloride (2.09 g, 12.63 mmol), (2-chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and triethylamine (1.8 mL, 12.630 mmol) in ethanol (15 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to r.t. and concentrated in vacuo to give the title compound as an orange semi-solid. This material was used without any further purification. HPLC-MS: MH+ m/z 252.2, RT 0.34 minutes.